COMPOUNDS AND METHODS FOR TREATING CORONAVIRUSES

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of United States Provisional Patent Application Nos. 63/255,186, filed October 13, 2021; 63/277,531, filed November 9, 2021; 63/314,357, filed February 25, 2022; and 63/352,580, filed June 15, 2022, the contents of each of which are incorporated by reference in their entirety herein.

FIELD OF THE INVENTION

The invention provides compounds and their methods of use and manufacture for the treatment of hosts infected with coronaviruses, for example, SARS CoV-2. The compounds inhibit papain-like cysteine protease (PLpro) and thus can be used to treat any virus that expresses a papain-like cysteine protease (PLpro).

BACKGROUND

Coronaviruses (Co Vs) (order Nidovirales, family Coronaviridae, subfamily Coronavirinae) are enveloped viruses with a positive sense, single-stranded RNA genome. CoVs have a large genome for an RNA virus, ranging in size from 26 to 32 kilobases (kb) in length. The CoV genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein, all of which are required to produce a structurally complete viral particle. See, e.g., PS Masters, The molecular biology of coronavirus. Adv. Virus Res. 2014: 101 : 105-12.

The novel coronavirus, SARS-CoV2, is the cause of the current respiratory disease COVID19 which started in Wuhan, China in late 2019. To date, over 400 million people globally have been infected and over 8 million people have died. The pandemic of SARS-CoV- 2 has caused pressure on the healthcare systems and governments globally.

Given the severe impact of coronaviruses, and notably SARS-CoV2, on persons and the healthcare system globally, it is important to provide new treatments for infected people.

It is therefore an object of the present invention to provide new drugs for the treatment of coronaviruses, including SARS-CoV2, to treat infected humans or those at risk of infection. SUMMARY

This invention provides new compounds and their pharmaceutically acceptable salts, along with their uses and manufacture, for the allosteric inhibition of the papain-like protease (PLpro), a key enzyme used by coronaviruses such as SARS-CoV2 that is involved in the generation of a functional replicase complex which enables the virus to replicate. The PLpro also cleaves ubiquitin and ISG15, which are known regulators of host innate immune pathways, and therefore, these allosteric inhibitors can be used to modulate certain immune pathways. Therefore, in certain embodiments, the invention includes new compounds, and the administration of such compounds or their pharmaceutically acceptable salts, in an effective amount to a host, for example a human, to treat a coronavirus including SARS-CoV2, either alone or in combination with another active antiviral or adjunctive agent.

Because of PLpro’ s unique mechanisms of action a compound of the present invention can both decrease viral replication directly and concurrently decrease the symptoms caused by the virus by inhibiting PLpro’ s protease activity in the host cell. For example, in certain embodiments a compound of the present invention or its pharmaceutically acceptable salt can inhibit the dysregulation of signaling cascades that are triggered by PLpro to lead to cell death of neighboring uninfected cells. By inhibiting the protease activity of PLpro, a compound of the present invention or its pharmaceutically acceptable salt can save the neighboring uninfected cells and thus decrease the viruses’ symptoms in the host.

In one aspect, provided herein are compounds of formula (I’), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (I”),

herein.

In some embodiments, the compound of formula (I’) or (I”) is a compound of formula (la’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (I’) or (I”) is a compound of formula (lb’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (F) or (I”) is a compound of formula (Ic’)i or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (I’) or (I”) is a compound of formula (Id’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (I”) is a compound of formula (le’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (1-1 ”),

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (II’), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (II”), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (IF) or (II”) is a compound of formula

(Ila’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (IF) or (II”) is a compound of formula (Ilb’)i or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In some embodiments, the compound of formula (IF) or (II”) is a compound of formula (lie’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (III”), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. In another aspect, provided herein are compounds of formula (IV”), or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided here are compounds of formula (VI”): stereoisomer or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (VII”): or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (VIII”)

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (IX”): or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein the variables are as defined herein.

In another aspect, provided herein are compounds of formula (X”) or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein the variables are as defined herein.

In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically salt thereof, and one or more pharmaceutically acceptable excipients. In another aspect, provided herein is a method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition disclosed herein.

In another aspect, provided herein is a method of preventing a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition disclosed herein

In some embodiments, the viral infection is a coronaviral infection. In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the coronavirus is SARS-CoV-2.

In another aspect, provided herein is a method of inhibiting PLPro in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition disclosed herein.

In another aspect, provided herein is a method of preventing replication of a virus in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition disclosed herein.

In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is SARS-Cov-2.

DETAILED DESCRIPTION

This invention provides compounds for the inhibition of papain-like proteases (PLpros) which are essential for viral replication. In certain embodiments inhibition of PLpro directly inhibits viral replication. In certain embodiments inhibition of PLpro inhibits the dysregulation of signaling cascades in infected cells that absent inhibition leads to cell death in surrounding uninfected cells.

DEFINITIONS

As used herein, the term "alkyl" refers to a saturated monovalent chain of carbon atoms, which may be optionally branched, the term "alkenyl" refers to an unsaturated monovalent chain of carbon atoms including at least one double bond, which may be optionally branched, the term "alkylene" refers to a saturated bivalent chain of carbon atoms, which may be optionally branched, and the term "cycloalkylene" refers to a saturated bivalent chain of carbon atoms, which may be optionally branched, a portion of which forms a ring.

As used herein, the term “alkynyl” refers to a monovalent chain of carbon atoms with one or more (e.g., one, two, three, or four) carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carboncarbon triple bonds). As used herein, the term "alkylene" is generally refers to a bivalent saturated hydrocarbon group wherein the hydrocarbon group may be a straight-chained or a branched- chain hydrocarbon group. Non-limiting illustrative examples include methylene, 1,2-ethylene, 1 -methyl- 1,2- ethylene, 1,4-butylene, 2, 3-dimethyl-l, 4-butylene, 2-methyl-2-ethyl-l,5- pentylene, and the like.

The term "cycloalkyl" as used herein generally refers to a monovalent, saturated hydrocarbon ring. The term "cycloalkenyl" as used herein refers to a monovalent hydrocarbon ring containing one or more (e.g., one, two, three, or four) unsaturated bonds.

As used herein, the term “carbocyclyl” or “carbocyclic” refers to a radical of a nonaromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“3-12 membered carbocyclyl”) and zero heteroatoms in the non-aromatic ring system.

As used herein the term “isotopic derivative” refers to compounds wherein one or more (e.g., one, two, three, or four) atoms is isotopically enriched for example with more than about 50%, 60%, 70%, 80%, 90%, 95%, or 99% of an isotope. Isotopes are atoms with the same number of protons but a different number of neutrons (for example hydrogen has one proton and the isotope of hydrogen named deuterium has one proton and one neutron). Non-limiting examples of isotopes include isotopes of hydrogen (for example deuterium), carbon, nitrogen, oxygen, fluorine, and chlorine.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). Aryl groups include, but are not limited to, phenyl and naphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more (e.g., one, two, three, or four) substituents.

The terms “bicycle” and “bicyclic” as used herein include molecular fragments or radicals that include two fused cycles wherein the cycles are independently selected from aryl, heteroaryl, cycloalkyl, heterocycle, and cycloalkenyl.

The terms “tricycle” and “tricyclic” as used herein include molecular fragments or radicals that include three fused cycles wherein the cycles are independently selected from aryl, heteroaryl, cycloalkyl, heterocycle, and cycloalkenyl.

The terms "heteroalkyl" and "heteroalkylene" as used herein includes molecular fragments or radicals comprising monovalent and divalent, respectively, groups that are formed from a linear or branched chain of carbon atoms and one or more (e.g., one, two, three, or four) heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, such as alkoxyalkyl, alkyleneoxyalkyl, aminoalkyl, alkylaminoalkyl, alkyleneaminoalkyl, alkylthioalkyl, alkylenethioalkyl, alkoxyalkylaminoalkyl, alkylaminoalkoxyalkyl, alkyleneoxyalkylaminoalkyl, and the like. It is to be understood that neither heteroalkyl nor heteroalkylene includes oxygen-oxygen fragments. It is also to be understood that neither heteroalkyl nor heteroalkylene includes oxygen-sulfur fragments, unless the sulfur is oxidized as S(O) or S(O) ₂ .

As used herein, the terms "heterocycle" and “heterocyclyl” refer to a non-aromatic ring comprising one or more (e.g., one, two, three, or four) heteroatoms (e.g., N, O, and/or S), or monovalent radical thereof, respectively, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur, such as, but not limited to, tetrahydrofuran, aziridine, pyrrolidine, oxazolidine, 3 -methoxypyrrolidine, 3 -methylpiperazine, and the like. A heterocycle or heterocyclyl may be optionally fused to an aromatic or non-aromatic ring. As used herein, the term “heterocyclylene” refers to a bivalent radical of a heterocycle.

As used herein, the term "cycloheteroalkyl" generally refers to an optionally branched chain of atoms that includes both carbon and at least one heteroatom, where the chain optionally includes one or more unsaturated bonds, and where at least a portion of the chain forms one or more rings. As used herein, it is understood that the term "cycloheteroalkyl" also includes "heterocycloalkyl," "heterocycle," and "heterocyclyl." The term "heterocycloalkenyl" as used herein refers to a monovalent chain of carbon atoms and heteroatoms containing one or more unsaturated bonds, a portion of which forms a ring, wherein the heteroatoms are selected from nitrogen, oxygen or sulfur. Illustrative cycloheteroalkyls include, but are not limited to, tetrahydrofuryl, bis(tetrahydrofuranyl), pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, dihydrofuryl, pyrrollinyl, dihydropyranyl, and the like. It is also to be understood that cycloheteroalkyl includes polycyclic radicals, including fused bicycles, spiro bicycles, and the like.

As used herein, the term "acyl" refers to hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl attached as a substituent through a carbonyl group, such as, but not limited to, formyl, acetyl, pivalolyl, benzoyl, phenacetyl, and the like.

“Heteroaryl” refers to a radical of a 5-14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms (e.g., O, N, and/or S) provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-12 membered heteroaryl”). In heteroaryl groups that contain one or more (e.g., one, two, three, or four) nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more (e.g., one, two, three, or four) heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more (e.g., one, two, three, or four) aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). As used herein, the term “heteroarylene” refers to a divalent radical of a heteroaryl.

As used herein, "haloalkyl" is generally taken to mean an alkyl group wherein one or more (e.g., one, two, three, or four) hydrogen atoms is replaced with a halogen atom, independently selected in each instance from the group consisting of fluorine, chlorine, bromine and iodine. Non-limiting, illustrative examples include, difluoromethyl, 2,2,2- trifluoroethyl, 2-chlorobutyl, 2-chloro-2- propyl, trifluoromethyl, bromodifluoromethyl, and the like.

“Alkoxyl” or “alkoxy” refers to an alkyl group singularly bonded to an oxygen atom, having the formula R-O. Alkoxyls include, for example, methoxy (CH3O-) and ethoxy, (CH3CH2O-). A “cycloalkoxyl” refers to a cycloalkyl group singularly bonded to an oxygen atom, which includes “aryloxy” groups, in which an aryl group is singular bonded to oxygen, for example a phenoxy group (CeHsO). Similarly, the term “heteroalkoxyl” refers to a heteroalkyl group singularly bonded to an oxygen atom and the term "cycloheteroalkoxyl" refers to a cycloheteroalkyl singularly bonded to an oxygen atom.

As used herein, the term “haloalkoxy” refers to a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHCF2 or -OCF3.

“Halo” or “halogen,” independently or as part of another substituent, generally refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term “halide” by itself or as part of another substituent, refers to a fluoride, chloride, bromide, or iodide atom.

As used herein, the term "optionally substituted" includes a wide variety of groups that replace one or more (e.g., one, two, three, or four) hydrogens on a carbon, nitrogen, oxygen, or sulfur atom, including monovalent and divalent groups. For example, optional substitution of carbon includes, but is not limited to, halo, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, arylalkyl, acyl, acyloxy, and the like. In one aspect, optional substitution of aryl carbon includes, but is not limited to, halo, amino, hydroxy, alkyl, alkenyl, alkoxy, arylalkyl, arylalkyloxy, hydroxyalkyl, hydroxyalkenyl, alkylene dioxy, aminoalkyl, where the amino group may also be substituted with one or two alkyl groups, arylalkylgroups, and/or acylgroups, nitro, acyl and derivatives thereof such as oximes, hydrazones, and the like, cyano, alkylsulfonyl, alkylsulfonylamino, and the like. Illustratively, optional substitution of nitrogen, oxygen, and sulfur includes, but is not limited to, alkyl, haloalkyl, aryl, arylalkyl, acyl, and the like, as well as protecting groups, such as alkyl, ether, ester, and acyl protecting groups, and pro-drug groups. It is further understood that each of the foregoing optional substituents may themselves be additionally optionally substituted, such as with halo, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, and the like.

It is understood that substitutions and any functional group may be independently ortho- , para-, or meta-. It is understood that cyclic groups may be aromatic or non-aromatic.

“Stereoisomers”: It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

COMPOUNDS

In one aspect, provided herein are compounds of formula (I’), or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from the group consisting of naphthyl, anthracenyl, 8-12 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-12 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R ¹ ; each X is independently selected from the group consisting of CH2, CH, NR ^h , and O (any hydrogen atom of the NH2, CH, NRh (when Rh=H) may be substituted with R _x ); each R ^x is independently Ci-6 alkyl or halo when R ^x is substituted on a carbon atom or each R ^x is independently Ci-6 alkyl when R ^x is substituted on a nitrogen atom; m is 0, 1, or 2;

= is a single bond or double bond; n is 1 or 2; each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy optionally substituted with phenyl, -O- Ci-6 alkylene-Ci-6 alkoxy, -C(O)OR ⁱ , -S(O) _t Ci. ₆ alkyl, -S-Ci- ₆ haloalkyl, -NR ^e R ^f , -C(O)NR ^s R ^h , -O-phenyl, and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, and Ci-6 alkoxy; wherein t is 0, 1, or 2;

R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and C3-6 cycloalkyl; R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, Co-6 alkylene-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-ealkyl, (Ci-ealkylene- OH), and -NR ^e R ^f ), -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , -(Co-ealkylene)-O- (3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of C1-6 alkyl, benzyl and -C(O)O-Ci-6 alkyl), C1-6 alkyl optionally substituted with -NR ^c R ^d , -O-(5-6 membered heteroaryl), Co-6 alkylene-CN, Co-6 alkylene-C(O)O(Ci-6alkyl), Co-6 alkylene-C(O)NR ^e R ^f , and - NR ^A R ^B , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ;

R ⁴ is selected from the group consisting of H, C1-6 alkyl, halo, hydroxy, and -NR ^e R ^f ; or R ³ and R ⁴ , together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl optionally substituted with -NR ^c R ^d , C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)- C(O)NR ^e R ^f , -C(O)-Ci. ₆ heteroalkyl, -C(O)-NCH ₃ OCH ₃ , -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-Ci-6 alkoxy, -(Co-6 alkylene)-OH, oxo, -C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci-ealkyl;

R ⁵ is selected from the group consisting of H, halo, and C1-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and C1-6 alkyl; each R ^3a is independently selected from the group consisting of Ci-6 alkyl, -NR ^A R ^B , Ci- 6 alkoxy, hydroxy, -C(O)NR ^c R ^d , 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and -(Co-6 alkylene)-(C3-6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-8 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C1-6 alkyl, Ci-e haloalkyl, -C(O)OC 1-6 alkyl, Ci-6 alkyelene- C3-7 cycloalkyl, phenyl, benzyl, C1-6 alkylene-OH, and Co-6 alkylene-Ci-6 alkoxy; each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, C1-6 alkylene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or C1-6 alkoxy, -(Co-6 alkyl ene)-phenyl, and - (Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy or C1-6 alkoxy; each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, benzyl, and -C(O)OCi-6 alkyl, or

R ^c and R ^d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; each R ^e and R ^f are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, -C(O)Ci-6alkyl, and -C(O)OCi-6alkyl; and each R ^s , R ^h , and R ¹ are independently, for each occurrence, H or Ci-6 alkyl.

In another aspect, provided herein are compounds of formula (I”), or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from the group consisting of naphthyl, anthracenyl, phenanthrenyl, 8-14 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-14 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R ¹ , wherein when ring A is 8-12 membered bicyclic heterocyclyl or 8-12 membered partially unsaturated bicyclic carbocyclyl, R ³ is C1-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ; each X is independently selected from the group consisting of CH2, CH, NR ^h , and O (any hydrogen atom of the NH2, CH, NRh (when Rh=H) may be substituted with R _x ); each R ^x is independently D, Ci-6 alkyl or halo when R ^x is substituted on a carbon atom or each R ^x is independently Ci-6 alkyl when R ^x is substituted on a nitrogen atom; m is 0, 1, 2, 3, or 4;

= is a single bond or double bond; n is 1 or 2; each R ¹ is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R ^la , Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, Ci-6 alkyl optionally substituted with hydroxy, C2-6 alkenyl optionally substituted with C3-6 cycloalkyl or phenyl substituted with Co-ealkyl, C2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, Ci-6 alkoxy optionally substituted with phenyl, -O-Ci-6 alkylene- Ci-6 alkoxy, -C(O)-Ci- ₆ alkyl, -C(O)OR ⁱ , -S(O) _t Ci. ₆ alkyl, -S-Ci-6 haloalkyl, -OS(O) _t Ci- ehaloalkyl, -NRiR ^k , -C(0)NR ^s R ^h , -O-phenyl, -B(OR ^m )2, and hydroxy, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, Ci-6 alkyl, Ci-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), Ci-ealkylene substituted with hydroxy, Ci-6 alkylene-NR ^A R ^B , -C(O)-3-6 membered heterocyclyl, hydroxy, Ci-6 haloalkyl, Ci-6 alkoxy, and -C(O)-Ci-6 alkyl; wherein t is 0, 1, or 2;

R ^la is selected from the group consisting of oxo, halo, Ci-ehaloalkyl, and Ci-ealkoxy;

R ⁵ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁷ is selected from H and Ci-6 alkyl;

R ² is selected from the group consisting of halo, Ci-6 alkyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 alkoxy, and C3-6 cycloalkyl;

R ³ is selected from the group consisting of C1-20 alkoxy, hydroxy, Co-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-ealkyl, (Ci-ealkylene- OH), -C(O)O-Ci-6 alkyl, and -NR ^e R ^f , -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , - (Co-ealkylene)-0-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(O)O-Ci-6 alkyl), Ci-e alkyl optionally substituted with -NR ^c R ^d , -O-(5- 6 membered heteroaryl), Co-6 alkylene-CN, Co-6 alkylene-C(O)O(Ci-6alkyl), Co-6 alkylene- C(0)NR ^e R ^f , and -NR ^AA R ^BB , wherein the Ci -20 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ;

R ⁴ is selected from the group consisting of H, Ci-6 alkyl, C2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, halo, hydroxy, and -NR ^e R ^f ; or

R ³ and R ⁴ , together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl optionally substituted with -NR ^c R ^d , C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)- C(O)NR ^e R ^f , -C(O)-Ci. ₆ heteroalkyl, -C(O)-NCH ₃ OCH ₃ , -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-Ci-6 alkoxy, -(Co-6 alkylene)-OH, oxo, -C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci-ealkyl, wherein the aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl is not an imidazole;

R ^AA and R ^BB are independently selected from the group consisting of H, C1-6 alkyl, Ci- ehaloalkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, C1-20 alkyl ene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or C1-6 alkoxy, -(Co-6 alkylene)-phenyl, -(Co-20 alkylene)-(3-10 membered heterocyclyl), and -(Co-6 alkylene)-C ₃ -6 cycloalkyl, wherein the C1-6 alkyl, C1-6 alkylene, 3-10 membered heterocyclyl, and C ₃ -6 cycloalkyl are each optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, hydroxy and C1-6 alkoxy; each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, C1-6 alkylene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or C1-6 alkoxy, -(Co-6 alkyl ene)-phenyl, and - (Co-6 alkylene)-C ₃ -6 cycloalkyl, wherein the C1-6 alkyl, C1-6 alkylene and C ₃ -6 cycloalkyl are each optionally substituted with hydroxy or C1-6 alkoxy; each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, benzyl, and -C(O)OCi-6 alkyl, or

R ^c and R ^d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; each R ^e and R ^f are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, -C(O)Ci-6alkyl, -C(O)OCi-6alkyl, and -S(O)2Ci-6alkyl; each R ^s , R ^h , and R ¹ are independently, for each occurrence, H or Ci-6 alkyl; and each R ¹ and R ^k are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl optionally substituted with phenyl, Ci-6 haloalkyl, -C(O)Ci-6alkyl, - S(O) ₂ Ci-6alkyl, and -C(O)OCi- ₆ alkyl; each R ^3a is independently selected from the group consisting of D, C1-6 alkyl, -NR ^A R ^B , C1-6 alkoxy, hydroxy, -C(O)NR ^c R ^d , 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and -(Co-6 alkylene)-(C3-6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-10 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, Ci-6 haloalkyl, -C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, phenyl, benzyl, Ci-6 alkylene-OH, and Co-6 alkylene-Ci-6 alkoxy; and each R ^m is independently selected from hydrogen and Ci-ealkyl or two (OR ^m ) groups can be taken together with the boron atom to which they are attached to form pinacol ester, with the proviso that, when ring A is naphthyl, R ⁴ is selected from the group consisting of hydrogen, -F, -Cl, Ci-6 alkyl, and -NR ^e R ^f ; R ⁵ is hydrogen; R ⁶ is hydrogen or halo; X is CH2; and n is 1;

R ² is selected from the group consisting of halo, Ci-6 alkyl, C2-6 alkynyl, Ci-6 alkoxy, and C3-6 cycloalkyl;

R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, Ci-6 alkylene- (3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R ^xx ), 3 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R ^xx , 4 membered heterocyclyl substituted with one or more (e.g., one, two, three, or four) R ^xx , 5 membered partially unsaturated heterocyclyl,

5 membered saturated heterocyclyl that has the point of attachment (to the phenyl) on the carbon atom of the heterocyclyl, 5 membered saturated heterocyclyl substituted with at least 2 (e.g., 2, 3, or 4) of R ^xx , 6-membered heterocyclyl with at least 2 (e.g., 2, 3, or 4) of R ^xx substituted on the carbon atoms of the heterocyclyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , -(Co-ealkylene)-0-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(O)O-Ci-

6 alkyl), Ci-6 alkyl optionally substituted with -NR ^c R ^d , -0-5-6 membered heteroaryl, Co- 6 alkylene-CN, Co-6 alkylene-C(O)O(Ci-6alkyl), Co-6 alkyl ene-C(O)NR ^e R ^f , and - NRAARBB, wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ; each R ^xx is independently selected from the group consisting of Ci-ealkyl, (Ci- ealkylene)-OH, -C(O)O-Ci-6 alkyl, and -NR ^e R ^f ; and R ^AA and R ^BB are independently selected from the group consisting of H, Ci-6 alkyl, Ci- 6 haloalkyl, Ci-6 alkoxy, -C(O)-Ci-6 alkyl, -(Co-6 alkylene)-phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy or Ci-6 alkoxy, and at least one of R ^AA and R ^BB is not hydrogen; or R ^AA is hydrogen and R ^BB is Ci-6 alkylene-NR ^c R ^d .

In another aspect, provided herein are compounds of formula (I’ ’-A), or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from the group consisting of naphthyl, anthracenyl, phenanthrenyl, 8-14 membered bicyclic or tricyclic heteroaryl, 8-12 membered bicyclic or tricyclic heterocyclyl, and 8-12 membered partially unsaturated bicyclic carbocyclyl, wherein the naphthyl, 8-14 membered bicyclic or tricyclic heteroaryl, and 8-12 membered partially unsaturated bicyclic carbocyclyl are optionally substituted by one or more (e.g., one, two, three, or four) R ¹ , wherein when ring A is 8-12 membered bicyclic heterocyclyl or 8-12 membered partially unsaturated bicyclic carbocyclyl, R ³ is Ci-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ; each X is independently selected from the group consisting of CH2, CH, NR ^h , and O (any hydrogen atom of the NH2, CH, NRh (when Rh=H) may be substituted with R _x ); each R ^x is independently D, Ci-6 alkyl or halo when R ^x is substituted on a carbon atom or each R ^x is independently Ci-6 alkyl when R ^x is substituted on a nitrogen atom; m is 0, 1, 2, 3, or 4;

= is a single bond or double bond; n is 1 or 2; each R ¹ is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R ^la , Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, Ci-6 alkyl optionally substituted with hydroxy, C2-6 alkenyl optionally substituted with C3-6 cycloalkyl or phenyl substituted with Co-ealkyl, C2-6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, Ci-6 alkoxy optionally substituted with phenyl, -O-Ci-6 alkylene- Ci-6 alkoxy, -C(O)-Ci- ₆ alkyl, -C(O)OR ⁱ , -S(O) _t Ci- ₆ alkyl, -S-Ci-6 haloalkyl, -OS(O) _t Ci- ehaloalkyl, -NRiR ^k , -C(O)NR ^s R ^h , -O-phenyl, -B(OR ^m )2, and hydroxy, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, Ci-6 alkyl, Ci-6alkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), Ci-ealkylene substituted with hydroxy, Ci-6 alkylene-NR ^A R ^B , -C(O)-3-6 membered heterocyclyl, hydroxy, Ci-6 haloalkyl, Ci-6 alkoxy, and -C(O)-Ci-6 alkyl; wherein t is 0, 1, or 2;

R ^la is selected from the group consisting of oxo, halo, Ci-ehaloalkyl, and Ci-ealkoxy;

R ⁵ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁷ is selected from H and Ci-6 alkyl;

R ² is selected from the group consisting of halo, Ci-6 alkyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 alkoxy, and C3-6 cycloalkyl;

R ³ is selected from the group consisting of C1-20 alkoxy, hydroxy, Co-6 alkylene-(3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-ealkyl, (Ci-ealkylene- OH), -C(O)O-Ci-6 alkyl, and -NR ^e R ^f , -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , - (Co-ealkylene)-0-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(O)O-Ci-6 alkyl), Ci-e alkyl optionally substituted with -NR ^c R ^d , -O-(5- 6 membered heteroaryl), Co-6 alkylene-CN, Co-6 alkylene-C(O)O(Ci-6alkyl), Co-6 alkylene- C(0)NR ^e R ^f , and -NR ^AA R ^BB , wherein the Ci -20 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ;

R ⁴ is selected from the group consisting of H, Ci-6 alkyl, C2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, halo, hydroxy, and -NR ^e R ^f ; or

R ³ and R ⁴ , together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl optionally substituted with -NR ^c R ^d , C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)- C(O)NR ^e R ^f , -C(O)-Ci. ₆ heteroalkyl, -C(O)-NCH ₃ OCH ₃ , -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-Ci-6 alkoxy, -(Co-6 alkylene)-OH, oxo, -C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci-ealkyl, wherein the aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl is not an imidazole;

R ^AA and R ^BB are independently selected from the group consisting of H, Ci-6 alkyl, Ci- ehaloalkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, C1-20 alkyl ene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or C1-6 alkoxy, -(Co-6 alkylene)-phenyl, -(Co-20 alkylene)-(3-10 membered heterocyclyl), and -(Co-6 alkylene)-C ₃ -6 cycloalkyl, wherein the C1-6 alkyl, C1-6 alkylene, 3-10 membered heterocyclyl, and C ₃ -6 cycloalkyl are each optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, hydroxy and C1-6 alkoxy; each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, C1-6 alkylene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or C1-6 alkoxy, -(Co-6 alkyl ene)-phenyl, and - (Co-6 alkylene)-C ₃ -6 cycloalkyl, wherein the C1-6 alkyl, C1-6 alkylene and C ₃ -6 cycloalkyl are each optionally substituted with hydroxy or C1-6 alkoxy; each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, benzyl, and -C(O)OCi-6 alkyl, or

R ^c and R ^d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; each R ^e and R ^f are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, -C(O)Ci-6alkyl, -C(O)OCi-6alkyl, and -S(O)2Ci-6alkyl; each R ^s , R ^h , and R ¹ are independently, for each occurrence, H or Ci-6 alkyl; and each R ¹ and R ^k are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl optionally substituted with phenyl, Ci-6 haloalkyl, -C(O)Ci-6alkyl, - S(O) ₂ Ci-6alkyl, and -C(O)OCi- ₆ alkyl; each R ^3a is independently selected from the group consisting of D, C1-6 alkyl, -NR ^A R ^B , C1-6 alkoxy, hydroxy, -C(O)NR ^c R ^d , 3-10 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and -(Co-6 alkylene)-(C ₃ -6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-10 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C1-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, Ci-6 haloalkyl, -C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, phenyl, benzyl, Ci-6 alkylene-OH, and Co-6 alkylene-Ci-6 alkoxy; and each R ^m is independently selected from hydrogen and Ci-ealkyl or two (OR ^m ) groups can be taken together with the boron atom to which they are attached to form pinacol ester,

R ^AA and R ^BB are independently selected from the group consisting of H, Ci-6 alkyl, Ci- 6 haloalkyl, Ci-6 alkoxy, -C(O)-Ci-6 alkyl, -(Co-6 alkylene)-phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy or Ci-6 alkoxy, and at least one of R ^AA and R ^BB is not hydrogen; or R ^AA is hydrogen and R ^BB is Ci-6 alkylene-NR ^c R ^d .

In some embodiments, the compound of formula (I’), (I”), or (I”-A)is a compound of formula (la’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

In some embodiments, the compound of formula (I’), (I”), or (I”-A) is a compound of formula (lb’): or a pharmaceutically acceptable salt thereof, wherein: each of G ¹ , G ² , G ³ , G ⁴ , G ⁵ , G ⁶ , and G ⁷ is independently selected from CH and N; s is 0, 1, 2, or 3; wherein X, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are as defined above. In some embodiments, the compound of formula (F), (I”), or (I”-A) is a compound of formula (Ic’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

In some embodiments, the compound of formula (I’), (I”), or (I”-A) is a compound of formula (Id’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I” -A), wherein G ¹ , G ² , G ³ , G ⁴ , G ⁵ , G ⁶ , and G ⁷ are CH. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein G ¹ is N, and G ² , G ³ , G ⁴ , G ⁵ , G ⁶ , and G ⁷ are CH; or G ² is N, and G ¹ , G ³ , G ⁴ , G ⁵ , G ⁶ , and G ⁷ are CH. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”- A), wherein G ³ is N, and G ¹ , G ² , G ⁴ , G ⁵ , G ⁶ , and G ⁷ are CH; or G ⁴ is N, and G ¹ , G ² , G ³ , G ⁵ , G ⁶ , and G ⁷ are CH. In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I”-A), wherein G ⁵ is N, and G ¹ , G ² , G ³ , G ⁴ , G ⁶ , and G ⁷ are CH; or G ⁶ is N, and G ¹ , G ² , G ³ , G ⁴ , G ⁵ , and G ⁷ are CH. In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I”-A), wherein G ⁷ is N, and G ¹ , G ² , G ³ , G ⁴ , G ⁵ , and G ⁶ are CH.

In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I” -A), wherein s is 0. In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I”-A), wherein s is 1. In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I”-A), wherein s is 2. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein Ring A is naphthyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’),

(I”), or (I”-A), wherein Ring A is selected from

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein Ring A is anthracenyl. In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein Ring A is phenanthrenyl.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein Ring A is 8-14 membered bicyclic or tricyclic heteroaryl. In some embodiments, Ring A is 10-membered bicyclic heteroaryl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I’ ’), or (I”-A), wherein Ring A is quinolinyl.

In some embodiments, compounds of the disclosure have a structure of formula (F),

In some embodiments, compounds of the disclosure have a structure of formula (F),

(I”), or (I”-A), wherein Ring

In some embodiments, compounds of the disclosure have a structure of formula (F),

(F ’), or (I”-A), wherein Ring A is isoquinolinyl, In some embodiments, compounds of the disclosure have a structure of formula (I’),

(I”), or (I”-A), wherein Ring A is selected from the group consisting

In some embodiments, the compound of formula (I”) or (I’ ’-A) is a compound of formula (le’): or a pharmaceutically acceptable salt thereof, wherein:

' represents cyclopropylene or oxetan-3-ylene (i.e., or selected from the group consisting of halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 haloalkyl, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, 5- or 6-membered monocyclic heteroaryl, 4- or 5-membered heterocyclyl;

R ^lbb is selected from the group consisting of H, halo, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl;

R ² is selected from the group consisting of halo, Ci-6 alkyl, and Ci-6 haloalkyl;

R ⁴ is selected from the group consisting of H, hydroxy, -NH2, -NH(CI-6 alkyl), -N(Ci- 6 alkyl)2, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl;

E is selected from the group consisting of -O-, -N(H)-, and -N(CI-6 alkyl)-;

R ^cc is H or Ci-2 alkyl;

R ^DD is H or Ci-2 alkyl; R ^c is H or Ci-6 alkyl; or

R ^cc is H, and R ^DD and R ^c can be taken together with the carbon and nitrogen atoms to which they are attached to form a 4- to 5-membered heterocycle; and

R ^d is H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le’),

In some embodiments, compounds of the disclosure have a structure of formula (le’),

In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^laa is Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^laa is C2-6 alkenyl.

In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^lbb is H. In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^lbb is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ² is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein E is -O-. In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein E is -N(H)-. In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein E is -N(CI-6 alkyl)-.

In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^cc is H, and R ^DD and R ^c are taken together with the carbon and nitrogen atoms to which they are attached to form a 4- to 5-membered heterocycle.

In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^d is H. In some embodiments, compounds of the disclosure have a structure of formula (le’), wherein R ^d is Ci-6 alkyl.

In some embodiments, the compound of formula (I’), (I”), or (I”-A) is a compound of formula (le”): or a pharmaceutically acceptable salt thereof, wherein: represents cyclopropylene or oxetan-3-ylene (i.e., or selected from the group consisting of halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 haloalkyl, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, 5- or 6-membered monocyclic heteroaryl, 4- or 5-membered heterocyclyl;

R ^lbb is selected from the group consisting of H, halo, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl;

R ² is selected from the group consisting of halo, Ci-6 alkyl, and Ci-6 haloalkyl;

R ⁴ is selected from the group consisting of H, hydroxy, -NH2, -NH(CI-6 alkyl), -N(Ci- 6 alkyl)2, and Ci-6 alkyl;

R ³ is selected from Ci-6 alkoxy or -NR ^A R ^B , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with Ci-6 alkyl; and

R ^A and R ^B are independently selected from the group consisting of H, Ci-6 alkyl, and - Ci-6 alkylene-NR ^c R ^d , wherein R ^c and R ^d are independently selected from H and Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^laa is Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^laa is C2-6 alkenyl.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^lbb is H. In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^lbb is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ² is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ³ is Ci-6 alkoxy. In some embodiments, the Ci-6 alkoxy is substituted with 3-8 membered heterocyclyl. In some embodiments, the Ci-6 alkoxy is substituted with 3-8 membered heterocyclyl substituted with methyl.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ³ is NR ^A R ^B .

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^A is -Ci-6 alkylene-NR ^c R ^d and R ^B is H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^c and R ^d are Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^c and R ^d are H. In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^c is Ci-6 alkyl and R ^d is H.

In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^A and R ^B are Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^A and R ^B are H. In some embodiments, compounds of the disclosure have a structure of formula (le”), wherein R ^A is Ci-6 alkyl and R ^B is H.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I” -A), wherein X is CH2. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein X is CH. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein X is NH. In some embodiments, compounds of the disclosure have a structure of f formula (I’), (I”), or (I”-A), wherein X is O. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I” -A), wherein n is 2 and one of X is O and the other X is CH2.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein m is 0. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein m is 1. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein m is 2. In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein m is 3. In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein m is 4.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein = is a single bond. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein = is a double bond.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein n is 1. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein n is 2.

In some embodiments, compounds of the disclosure have a structure of f formula (F), (F ’), or (I”-A), wherein each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, Ci-6 haloalkyl, halo, -CN, Ci-6 alkyl, C2-6 alkenyl, Ci-6 alkoxy, -S(O)t-Ci-6alkyl, -NR ^e R ^f , and hydroxy.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein each R ¹ is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C3-7 carbocyclyl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R ^la , Ci-6 haloalkyl, halo, -CN, Ci-6 alkyl optionally substituted with hydroxy, C2-6 alkenyl optionally substituted with C3-6 cycloalkyl or phenyl substituted with Co-ealkyl, C2-6 alkynyl- optionally substituted with one or more (e.g., one, two, three, or four) halo, Ci-6 alkoxy optionally substituted with phenyl, -S(O)t-Ci-6alkyl, -C(O)-Ci- 6 alkyl, OS(O)tCi-6haloalkyl, -NRiR ^k and hydroxy.

In some embodiments, compounds of the disclosure have a structure of formula (F), (F ’), or (I”-A), wherein each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, Ci-6 haloalkyl, halo, and Ci-6 alkyl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, and Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein each R ¹ is independently selected from the group consisting of phenyl, 5-9 membered heteroaryl, C3-7 carbocyclyl, Ci-6 haloalkyl, halo, and Ci-6 alkyl, wherein the phenyl and 5-9 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (I”), or (I”-A), wherein each R ¹ is independently selected from the group consisting of 5-9 membered heteroaryl, 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) R ^la , Ci-6 haloalkyl, halo, Ci-6 alkyl optionally substituted with hydroxy, C2-6 alkenyl optionally substituted with C3-6 cycloalkyl or phenyl substituted with Co-ealkyl, C2- 6 alkynyl optionally substituted with one or more (e.g., one, two, three, or four) halo, Ci-6 alkoxy optionally substituted with phenyl, -NR'R ^k , wherein the 5-9 membered heteroaryl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, cyano, phenyl, 3-7 membered heterocyclyl, Ci-6 alkyl, Ci- ealkylene-(3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) halo), Ci-ealkylene substituted with hydroxy, Ci-6 alkylene-NR ^A R ^B , -C(O)-3-6 membered heterocyclyl, hydroxy, Ci-6 haloalkyl, Ci-6 alkoxy, and -C(O)-Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I”), or (I”-A), wherein each R ¹ is independently selected from the group consisting of 5-9 membered heteroaryl, 3-7 membered heterocyclyl, Ci-6 haloalkyl, halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, and -NR ⁱ R ^k

In some embodiments, compounds of the disclosure have a structure of formula (I”), or (I”-A), wherein each R ¹ is selected from the group consisting of halo, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, Ci-6 haloalkyl, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, 5- or 6- membered monocyclic heteroaryl, and 4- or 5-membered heterocyclyl.

In some embodiments, compounds of the disclosure have a structure of formula (I”), or (I”-A), wherein each R ¹ is selected from the group consisting of H, halo, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (!’ ’), or (!’ ’-A), wherein R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 alkoxy, and C3-6 cycloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkynyl, and C3-6 cycloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ² is selected from the group consisting of halo, Ci-6 alkyl, and Ci-6 haloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ² is halo. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ² is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, Co-6 alkylene-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-ealkyl, (Ci-ealkylene- OH), and -NR ^e R ^f ), -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , -(Co-ealkylene)-(O- 3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl benzyl, and -C(O)O-Ci-6 alkyl), and -NR ^A R ^B , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, Co-6 alkylene- (3-10 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-ealkyl, (Ci- ealkylene-OH), -C(O)O-Ci-6 alkyl, and -NR ^e R ^f , -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , -(Co-ealkylene)-(0-3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl benzyl, and -C(O)O-Ci-6 alkyl), and NR ^AA R ^BB , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I” -A), wherein R ³ is selected from the group consisting of Ci-6 alkoxy and -(Co- ealkylene)-O-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(O)O-Ci-6 alkyl), -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (F), (I”), or (I” -A), wherein R ³ is selected from the group consisting of Ci-6 alkoxy and -(Co- ealkylene)-O-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(0)0-Ci-6 alkyl), -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I” -A), wherein R ³ is -NR ^AA R ^BB or Ci -20 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (!’ ’-A), wherein R ³ is C1.20 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ^A and R ^B are each independently H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I” -A), wherein R ³ is -NR ^AA R ^BB .

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ^AA and R ^BB are independently selected from the group consisting of H, Ci-6 alkyl, C1.20 alkylene-NR ^c R ^d , and -(C 0-20 alkylene)-(3-10 membered heterocyclyl), wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, hydroxy, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ^AA and R ^BB are independently selected from the group consisting of H, Ci-6 alkyl, C1.20 alkylene-NR ^c R ^d , and -(Ci -20 alkylene)-(3-5 membered heterocyclyl), wherein the 3-5 membered heterocyclyl is optionally substituted with Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein each R ^c and R ^d are independently, H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ³ is Ci-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ³ is -(Co-ealkylene)-0-(3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(O)O-Ci-6 alkyl).

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ³ is -(Co-ealkylene)-0-(3-9 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, benzyl and -C(O)O-Ci-6 alkyl).

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ⁴ is selected from the group consisting of H, Ci-6 alkyl, and halo.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ⁴ is selected from the group consisting of H, Ci-6 alkyl, C2-6 alkynyl optionally substituted with phenyl or 5-6 membered heteroaryl, and halo.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ⁴ is selected from the group consisting of H, hydroxy, -NR ^e R ^f , Ci-6 alkyl, Ci- 6 alkoxy, and Ci-6 haloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (I”) of (I’ ’-A), wherein R ⁴ is selected from the group consisting of H, hydroxy, -NH2, -NH(CI-6 alkyl), -N(CI-6 alkyl)2, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 haloalkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ⁴ is H.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (!’ ’), or (I’ ’ -A), wherein R ³ and R ⁴ , together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)-C(O)NR ^e R ^f , -C(O)-Ci- eheteroalkyl, -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-C 1-6 alkoxy, -(Co-6 alkylene)-OH, oxo, - C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci- ealkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ⁵ is H or Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein R ⁵ is H. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein R ⁵ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ⁶ is H or Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein R ⁶ is H. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein R ⁶ is Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I” -A), wherein each R ^3a is independently selected from the group consisting of - NR ^A R ^B , CI-6 alkoxy, hydroxy, 3-8 membered heterocyclyl, and -(Co-6 alkylene)-(C3-6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, Ci-e haloalkyl, - C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, Ci-6 alkylene-OH, and Ci-6 alkylene- Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein each R ^3a is independently selected from the group consisting of D, -NR ^A R ^B , Ci-6 alkoxy, hydroxy, 3-10 membered heterocyclyl, and -(Co-6 alkylene)-(C3-6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) D, Ci-6 haloalkyl, -C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, Ci-6 alkylene-OH, and Ci-6 alkylene-Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I” -A), wherein each R ^3a is -NR ^A R ^B . In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I’ ’-A), wherein each R ^3a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, -C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, Ci-6 alkylene-OH, and Ci-6 alkylene-Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein each R ^3a is 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, -C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, Ci-6 alkylene-OH, - C(O)O-Ci-6 alkyl, and Ci-6 alkylene-Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy, -(Co-6 alkylene)-phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 alkylene-NR ^c R ^d .

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein each R ^A and R ^B are independently, for each occurrence, H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, benzyl, and -C(O)OCi-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein each R ^c and R ^d are independently, for each occurrence, H or Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I” -A), wherein each R ^c and R ^d are H.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (!’ ’), or (!’ ’-A), wherein each R ^e and R ^f are H.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein each of R ^s and R ^h are H.

In some embodiments, compounds of the disclosure have a structure of formula (I’), (I”), or (I”-A), wherein R ¹ is H.

In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ^x is Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I’ ’-A), wherein R ^x is halo. In some embodiments, compounds of the disclosure have a structure of formula (I”) or (I”-A), wherein R ^x is D.

In another aspect, provided herein are compounds of formula (1-1”), or a pharmaceutically acceptable salt thereof, wherein: each R ¹ is independently selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, and -CN; n is 0, 1, or 2; each of R ² , R ³ , R ⁴ , and R ⁶ is independently selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, and -CN; and

R ⁵ is Ci-6 alkylene-C(O)NH2, wherein each hydrogen of NH2 is optionally substituted.

In some embodiments, compounds of the disclosure have a structure of formula (I-F), wherein n is 0.

In some embodiments, compounds of the disclosure have a structure of formula (I-F), wherein R ² , R ³ , R ⁴ , and R ⁶ are hydrogen.

In some embodiments, compounds of the disclosure have a structure of formula (I-F), wherein R ⁵ is Ci-6 alkylene-C(O)NH-NH-C(O)-C2-6alkenylene-C(O)O-Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (I-F), wherein R ⁵ is C2 alkylene-C(O)NH-NH-C(O)-C2alkenylene-C(O)OCH3.

In another aspect, provided herein are compounds of formula (II’), or a pharmaceutically acceptable salt thereof, wherein

Ring A is phenyl optionally substituted with one or more (e.g., one, two, three, or four) R ¹ ; each X is independently selected from the group consisting of CH2, CH, NH, and O (any hydrogen atom of the NH2, CH, NRh (when Rh=H) may be substituted with R _x ); each R ^x is independently Ci-6 alkyl or halo when R ^x is substituted on a carbon atom or each R ^x is independently Ci-6 alkyl when R ^x is substituted on a nitrogen atom; m is 0, 1, or 2;

= is a single bond or double bond; n is 1 or 2; each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 haloalkyl, halo, Ci-6 alkyl, Ci-6 alkoxy, -0-(Co-6 alkylene)-phenyl, -S-Ci-ealkyl, -S-Ci-6 haloalkyl, -NR ^e R ^f , and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, Ci- 6 alkyl optionally substituted with 3-7 membered heterocyclyl, Ci-6 alkylene-NR ^A R ^B , Ci-6 haloalkyl, and Ci-6 alkoxy;

R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and C3-6 cycloalkyl;

R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , -0-3-8 membered heterocyclyl optionally substituted with -C(O)O-Ci-6 alkyl, Ci- 6 alkyl optionally substituted with -NR ^c R ^d , -0-5-6 membered heteroaryl, Co-6 alkylene-CN, Co- 6 alkylene-C(O)NR ^e R ^f , and -NR ^A R ^B , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a ;

R ⁴ is selected from the group consisting of H, Ci-6 alkyl, halo, hydroxy, and -NR ^e R ^f ; or R3 and R4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)-C(O)NR ^e R ^f , -C(O)-Ci- eheteroalkyl, -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-C 1-6 alkoxy, -(Co-6 alkylene)-OH, oxo, - C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci- ealkyl;

R ⁵ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and Ci-6 alkyl; each R ^3a is independently selected from the group consisting of Ci-6 alkyl, -NR ^A R ^B , Ci- 6 alkoxy, hydroxy, -C(O)NR ^c R ^d , 3-8 membered heterocyclyl, phenyl, and -(Co-6 alkylene)-(C3- 6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, - C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, Ci-6 alkylene-OH, and Ci-6 alkylene- C1-6 alkoxy, each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, Ci-6 alkyl ene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy, -(Co-6 alkylene)-phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy; each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, benzyl, and -C(O)OCi-6 alkyl, or

R ^c and R ^d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; and each R ^e and R ^f are independently, for each occurrence, H or Ci-6 alkyl.

In another aspect, provided herein are compounds of formula(II”), or a pharmaceutically acceptable salt thereof, wherein

Ring A is phenyl optionally substituted with one or more (e.g., one, two, three, or four) R ¹ ; each X is independently selected from the group consisting of CH2, CH, NH, and O (any hydrogen atom of the NH2, CH, NRh (when Rh=H) may be substituted with R _x ); each R ^x is independently Ci-6 alkyl or halo when R ^x is substituted on a carbon atom or each R ^x is independently Ci-6 alkyl when R ^x is substituted on a nitrogen atom; m is 0, 1, or 2;

= is a single bond or double bond; n is 1 or 2; each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, 3-7 membered heterocyclyl, Ci-6 haloalkyl, halo, Ci-6 alkyl, Ci-6 alkoxy, -0-(Co-6 alkylene)-phenyl, -S-Ci-ealkyl, -S-C1-6 haloalkyl, -NR ^e R ^f , and hydroxy, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each selected from the group consisting of halo, Ci- 6 alkyl optionally substituted with 3-7 membered heterocyclyl, Ci-6 alkylene-NR ^A R ^B , Ci-6 haloalkyl, and Ci-6 alkoxy;

R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, and C3-6 cycloalkyl;

R ³ is selected from the group consisting of Ci-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , - 0-3-8 membered heterocyclyl optionally substituted with -C(O)O-Ci-6 alkyl, C2-6 alkyl optionally substituted with -NR ^c R ^d , -0-5-6 membered heteroaryl, Co-6 alkylene-C(O)NR ^e R ^f , and -NR ^A R ^B , wherein the Ci-6 alkoxy is substituted with one or more (e.g., one, two, three, or four) R ^3a , and wherein R ³ is not -N(H)C(O)CHa or -NH2;

R ⁴ is selected from the group consisting of H, Ci-6 alkyl, halo, hydroxy, and -NR ^e R ^f ; or

R ³ and R ⁴ , together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)-C(O)NR ^e R ^f , -C(O)-Ci- eheteroalkyl, -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-C 1-6 alkoxy, -(Co-6 alkylene)-OH, oxo, - C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci- ealkyl;

R ⁵ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and Ci-6 alkyl; each R ^3a is independently selected from the group consisting of Ci-6 alkyl, -NR ^A R ^B , Ci- 6 alkoxy, hydroxy, -C(O)NR ^c R ^d , 3-8 membered heterocyclyl, phenyl, and -(Co-6 alkylene)-(C3- 6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, - C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, Ci-6 alkylene-OH, and Ci-6 alkylene- C1-6 alkoxy, each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, S(O)2Ci-6 alkyl, -C(O)-Ci-6 alkyl, Ci-6 alkyl ene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo or -C(O)O-Ci-6 alkyl, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy, -(Co-6 alkylene)- phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy; each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, C1-6 alkyl, benzyl, and -C(O)OCi-6 alkyl, or

R ^c and R ^d can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl; and each R ^e and R ^f are independently, for each occurrence, H or C1-6 alkyl.

In some embodiments, the compound of formula (II’) or (II”) is a compound of formula (Ila’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

In some embodiments, the compound of formula (II’) or (II”) is a compound of formula (lib’): (lib ), or a pharmaceutically acceptable salt thereof, wherein: s is 0, 1, 2, or 3; and

R'-R ⁶ are as defined above.

In some embodiments, the compound of formula (II’) or (II”) is a compound of formula (He’): or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein X is CH2. In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein X is NH. In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein X is O.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein m is 0. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein m is 1. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein m is 2.

In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein = is a single bond. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein = is a double bond.

In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein n is 1. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein n is 2.

In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, Ci-6 haloalkyl, halo, Ci-6 alkyl, Ci-6 alkoxy, -S-Ci- ealkyl, -NR ^e R ^f , and hydroxy.

In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein each R ¹ is independently selected from the group consisting of phenyl, 5-6 membered heteroaryl, C3-7 carbocyclyl, Ci-6 haloalkyl, halo, Ci-6 alkyl, wherein the phenyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, Ci-6 alkyl, Ci- 6 alkylene-NR ^A R ^B , Ci-6 haloalkyl, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 alkoxy, and C3- 6 cycloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein R ² is halo. In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein R ² is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IF) or (II”), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , -0-3-8 membered heterocyclyl optionally substituted with -C(O)O-Ci-6 alkyl, and -NR ^A R ^B , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (II”), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , - 0-3-8 membered heterocyclyl optionally substituted with -C(O)O-Ci-6 alkyl, C2-6 alkyl optionally substituted with -NR ^c R ^d , -0-5-6 membered heteroaryl, Co-6 alkylene-C(O)NR ^e R ^f , and -NR ^A R ^B , wherein the Ci-6 alkoxy is substituted with one or more (e.g., one, two, three, or four) R ^3a , and wherein R ³ is not -N(H)C(O)CH3 or -NH2.

In some embodiments, compounds of the disclosure have a structure of formula (II”), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , - O-(3-8 membered heterocycly) optionally substituted with -C(O)O-Ci-6 alkyl, and -NR ^A R ^B , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ³ is selected from the group consisting of Ci-6 alkoxy and 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl, -O-C3-7 cycloalkyl optionally substituted with -NR ^c R ^d , wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ³ is Ci-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ³ is 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ⁴ is selected from the group consisting of H, Ci-6 alkyl, and halo.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ⁴ is H.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R3 and R4, together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 5-10 membered monocyclic or bicyclic ring fused to the phenyl, wherein the 5-10 membered ring comprises at least one heteroatom, wherein the 5-10 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, phenyl, 5-6 membered heteroaryl, -(Co-6 alkylene)-C(O)NR ^e R ^f , -C(O)-Ci- eheteroalkyl, -(Co-6 alkylene)-NR ^c R ^d , -(Co-6 alkylene)-C 1-6 alkoxy, -(Co-6 alkylene)-OH, oxo, - C(O)OH, and -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci- ealkyl.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ⁵ is H or C1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ⁵ is H. In some embodiments, compounds of the disclosure have a structure of formula (IP) or (II”), wherein R ⁵ is C1-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ⁶ is H or C1-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein R ⁶ is H. In some embodiments, compounds of the disclosure have a structure of formula (IP) or (II”), wherein R ⁶ is C1-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IP) or (II”), wherein each R ^3a is independently selected from the group consisting of -NR ^A R ^B , Ci-6 alkoxy, hydroxy, 3-8 membered heterocyclyl, and -(Co-6 alkylene)-(C3-6 cycloalkyl optionally substituted with NR ^c R ^d ), wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C1-6 alkyl, Ci-e haloalkyl, -C(O)OC 1-6 alkyl, Ci-6 alkyelene- C3-7 cycloalkyl, benzyl, C1-6 alkylene-OH, and C 1-6 alkyl ene-C 1-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (IP) or (II”), wherein each R ^3a is -NR ^A R ^B .

In some embodiments, compounds of the disclosure have a structure of formula (IP) or (II”), wherein each R ^3a is 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, C1-6 alkyl, Ci-e haloalkyl, - C(O)OCi-6 alkyl, Ci-6 alkyelene-C3-7 cycloalkyl, benzyl, C1-6 alkylene-OH, and Ci-6 alkylene- C1-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (IP) or (II”), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, C1-6 alkylene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo, 5-6 membered heteroaryl optionally substituted with C1-6 alkyl or C1-6 alkoxy, -(Co-6 alkylene)-phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the C1-6 alkyl, C1-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy. In some embodiments, compounds of the disclosure have a structure of formula (II”), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylene-NR ^c R ^d , 3-6 membered heterocyclyl optionally substituted with oxo or -C(O)O-Ci-6 alkyl, 5-6 membered heteroaryl optionally substituted with Ci-6 alkyl or Ci-6 alkoxy, -(Co-6 alkylene)-phenyl, and -(Co-6 alkylene)-C3-6 cycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkylene and C3-6 cycloalkyl are each optionally substituted with hydroxy.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, Ci-6 alkoxy, and Ci-6 alkylene-NR ^c R ^d .

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein each R ^A and R ^B are independently, for each occurrence, H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, benzyl, and -C(O)OCi-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein each R ^c and R ^d are independently, for each occurrence, H or Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein each R ^c and R ^d are H.

In some embodiments, compounds of the disclosure have a structure of formula (II’) or (II”), wherein each R ^e and R ^f are H.

In another aspect, provided herein are compounds of formula (III”), or a pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from naphthyl and 8-12 membered bicyclic heteroaryl, wherein the naphthyl and 8-12 membered bicyclic are optionally substituted with one or more (e.g., one, two, three, or four) R ¹ ;

Yi is N or CR ⁶ ;

Y ₂ is N or CR ⁴ ; Y ₃ is N or CR ⁵ ;

Y ₄ is N or CR ³ ;

Y ₅ is N or CR ² ; each X is independently selected from the group consisting of CH2, CH, NR ^h , and O (any hydrogen atom of the NH2, CH, NRh (when Rh=H) may be substituted with R _x ), wherein each R ^h is independently H or Ci-6 alkyl;

= is a single bond or double bond; each R ^x is independently Ci-6 alkyl or halo; n is 1 or 2; m is 0, 1, or 2; each R ¹ is independently selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, and -CN;

R ² is selected from the group consisting of halo, Ci-6 alkyl, Ci-6 haloalkyl, and Ci-6 alkoxy;

R ³ is selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, and hydroxy, wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) -NR ^A R ^B or 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl;

R ⁴ is selected from the group consisting of H, Ci-6 alkyl, halo, and hydroxy;

R ⁵ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and Ci-6 alkyl; and each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, and Ci-6 haloalkyl.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein Ring A is naphthyl. In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein Ring

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein at least one of Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ are N. In some embodiments, Y ¹ is N.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein Y ² , Y ³ , Y ⁴ , and Y ⁵ are not N. In some embodiments, Y ² is N.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein Y ¹ , Y ³ , Y ⁴ , and Y ⁵ are not N. In some embodiments, Y ³ is N.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein Y ¹ , Y ² , Y ⁴ , and Y ⁵ are not N. In some embodiments, Y ² and Y ³ are N. In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein Y ¹ , Y ⁴ , and Y ⁵ are not N.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein X is CH2.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein n is 1.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein m is 0.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein R ² is Ci-6 alkyl, e.g., methyl.

In some embodiments, compounds of the disclosure have a structure of formula (IIP ’), wherein R ³ is Ci-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) -NR ^A R ^B , e g., -O-(CH ₂ )2-N(CH ₃ )2.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein R ³ is Ci-6 alkoxy optionally substituted with 3-8 membered heterocyclyl optionally substituted with Ci-ealkyl.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein R ⁴ is H.

In some embodiments, compounds of the disclosure have a structure of formula (III”), wherein R ⁵ is H.

In another aspect, provided herein are compounds of formula (IV”), or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: each R ¹ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, and Ci-6 alkyl; n is 0, 1, or 2;

(A) R ² is Ci-6 alkyl or halo; R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, -C(O)-Ci- ealkyl; -O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) Ci-6 alkyl, -NR ^A R ^B , and nitro, wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a , and wherein if R ³ is hydroxy, nitro, NH2, NHCH3, or N(CHI 2, neither R ⁷ nor R ⁸ is methyl;

R ⁴ is H, Ci-6 alkyl, halo, and hydroxy; or

(B) R ² is selected from the group consisting of H, Ci-6 alkyl, Ci-6 haloalkyl, and Ci- 6 alkoxy;

R ³ and R ⁴ , together with the atoms to which they are attached, combine to form: i) an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5- membered ring has at least one nitrogen connected to the phenyl at the R ³ position or two oxygens, or ii) an aromatic or non-aromatic 6 membered monocyclic ring fused to the phenyl, wherein the 6 membered ring has one and only one nitrogen, the nitrogen connected to the phenyl at the R ³ position, and the remaining atoms in the ring are carbon, wherein the 5 or 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, Ci-6 alkyl optionally substituted with hydroxy or -NR ^c R ^d , -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci-ealkyl;

R ⁵ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁶ is selected from the group consisting of H, halo, and Ci-6 alkyl;

R ⁷ is selected from the group consisting of hydrogen, Ci-6 alkyl optionally substituted with Ci-6 alkoxy, C2-6 alkynyl, Ci-6 haloalkyl, cyano, and 3-8 membered heterocyclyl optionally substituted with Ci-6 alkyl;

R ⁸ is hydrogen or Ci-6 alkyl; each R ^3a is independently selected from the group consisting of Ci-6 alkyl, -NR ^e R ^f , and 3-8 membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, and Ci-6 haloalkyl; each R ^A and R ^B are independently, for each occurrence, selected from the group consisting ofH, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, S(O)2Ci-2 alkyl, -C(O)-unsubstituted Ci- 6 alkyl, 3-6 membered unsaturated heterocyclyl optionally substituted with one oxo, 5-6 membered heteroaryl substituted with Ci-6 alkyl or Ci-6 alkoxy, and pyrazolyl, wherein the Ci-

6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH2, wherein if one of R ^A and R ^B is -C(O)-unsubstituted Ci-6 alkyl, the other of R ^A and R ^B is not H, and wherein R ^A and R ^B are not -(CJfc^NEb or -C^ CHs^NJL; each R ^c and R ^d are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, and -C(O)OCi-6 alkyl, and each R ^e and R ^f are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, and -C(O)OCi-6alkyl, wherein the compound is not a compound represented by: pharmaceutically acceptable salt thereof.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein n is 0.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ² is Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ² is methyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ² is halo. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ² is hydrogen.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, -C(O)-Ci-6alkyl; -O- (3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) Ci-6 alkyl, -NR ^A R ^B , and nitro, wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a , and wherein if R ³ is hydroxy, nitro, NH2, NHCH3, or N(CHa)2, R ⁷ is not methyl; and R ⁴ is H, Ci-6 alkyl, halo, and hydroxy.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is selected from the group consisting of Ci-6 alkoxy, hydroxy, -O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) Ci-6 alkyl, -NR ^A R ^B , and nitro, wherein the Ci-6 alkoxy is optionally substituted with one or more (e.g., one, two, three, or four) R ^3a , and wherein if R ³ is hydroxy, nitro, NH2, NHCH3, or N(CH3)2, R ⁷ is not methyl; and R ⁴ is H, Ci-6 alkyl, halo, and hydroxy. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is Ci-6 alkoxy optionally substituted with one or more (e.g., one, two, three, or four) R ^3a .

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is hydroxy. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is -O-(3-8 membered oxygen-containing heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is -NR ^A R ^B . In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ is and nitro.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁴ is H.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁵ is H.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁶ is H.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁷ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁷ is Ci-6 alkyl optionally substituted with Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁷ is C2-6 alkynyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁷ is Ci-6 haloalkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁷ is cyano. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁷ is 3-8 membered heterocyclyl optionally substituted with Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁸ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ⁸ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ^3a is -NR ^e R ^f . In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ^3a is 3-8 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of halo, hydroxy, Ci-6 alkyl, and Ci-e haloalkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, S(O)2Ci-2 alkyl, -C(O)-unsubstituted Ci-6 alkyl, 3-6 membered unsaturated heterocyclyl optionally substituted with one oxo, 5-6 membered heteroaryl substituted with Ci-6 alkyl or Ci-6 alkoxy, and pyrazolyl, wherein the Ci-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH2.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein each R ^A and R ^B are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, S(O)2Ci-2 alkyl, -C(O)-unsubstituted Ci-6 alkyl, 5-6 membered heteroaryl substituted with Ci-6 alkyl or Ci-6 alkoxy, and pyrazolyl, wherein the Ci-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH2.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ^A is H and R ^B is H. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ^A is H and R ^B is Ci-6 alkyl optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH2. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ^A is H and R ^B is S(O)2Ci-2 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ^A is H and R ^B is 5-6 membered heteroaryl substituted with Ci-6 alkyl or Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein each R ^A is H and R ^B is pyrazolyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein each R ^A is Ci-6 alkyl and R ^B is -C(O)- unsubstituted Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more (e.g., one, two, three, or four) hydroxy and/or one NH2.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ and R ⁴ , together with the atoms to which they are attached, combine to form: an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5- membered ring has at least one nitrogen connected to the phenyl at the R ³ position or two oxygens, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, Ci-6 alkyl optionally substituted with hydroxy or -NR ^c R ^d , -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci-ealkyl. In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ and R ⁴ , together with the atoms to which they are attached, combine to form: an aromatic or non-aromatic 5 membered monocyclic ring fused to the phenyl, wherein the 5- membered ring has at least one nitrogen connected to the phenyl at the R ³ position, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, Ci-6 alkyl optionally substituted with hydroxy or -NR ^c R ^d , -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci-ealkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IV”), wherein R ³ and R ⁴ , together with the atoms to which they are attached, combine to form an aromatic or non-aromatic 6 membered monocyclic ring fused to the phenyl, wherein the 6 membered ring has one and only one nitrogen, the nitrogen connected to the phenyl at the R ³ position, and the remaining atoms in the ring are carbon, wherein the 6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of oxo, Ci-6 alkyl optionally substituted with hydroxy or -NR ^c R ^d , -(Co-6 alkylene)-3-7 membered heterocyclyl optionally substituted with Ci- ealkyl.

In another aspect, provided here are compounds of formula (VI”): or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: optionally substituted phenyl;

X is NR ⁹ or a bond;

Y is NR ⁹ , CH2, or a bond;

R ⁹ is selected from H and Ci-ealkyl; a nitrogen containing 4-6 membered heterocyclylene or 4-6 membered heterocycle fused to phenyl; each of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , and X ⁶ is CH or N, wherein the CH may be substituted with

R ¹ ; wherein ered monocyclic heterocyclylene; each R ¹ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, Ci-6 alkyl, Ci-6 alkoxy, -NR ^e R ^f , 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; n is 0, 1, or 2; each of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of hydrogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, -NR ^e R ^f , Ci-6 alkoxy, and Ci-6 alkyl;

R ⁷ is selected from the group consisting of Ci-6 alkyl optionally substituted with Ci-6 alkoxy, C2-6 alkynyl, Ci-6 haloalkyl, cyano, and 3-8 membered heterocyclyl optionally substituted with Ci-6 alkyl;

R ⁸ is hydrogen; or R ⁷ and R ⁸ may be taken together with the carbon to which they are attached to form a 3-4 membered cycloalkyl or heterocyclyl ring; and each R ^e and R ^f are independently, for each occurrence, selected from the group consisting of H, Ci-6 alkyl, and -C(O)OCi-6alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein phenyl optionally substituted with Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein X is NR ⁹ . In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein X is a bond.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein Y is NR ⁹ . In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein Y is CH2. In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein Y is a bond.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ⁹ is H. In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ⁹ is Ci-ealkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein nitrogen containing 4-6 membered heterocyclylene, e.g., 4- membered heterocyclylene, 5 -membered heterocyclylene, 6-membered heterocyclylene.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein nitrogen containing 4-6 membered heterocyclylene, e.g., 4-5 membered heterocyclylene, 4- membered heterocyclylene, 5 -membered heterocyclylene, 6- membered heterocyclylene, e.g., 6-membered monocyclic heterocyclylene, 6-membered bicyclic heterocyclylene.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ¹ is Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ¹ is 5-6 membered heteroaryl.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein n is 0. In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein n is 1.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein each of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of hydrogen and halo.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ⁷ is Ci-6 alkyl optionally substituted with Ci-6 alkoxy and R ⁸ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ⁷ is methyl and R ⁸ is hydrogen.

In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ⁷ and R ⁸ are taken together with the carbon to which they are attached to form a 3-4 membered cycloalkyl ring. In some embodiments, compounds of the disclosure have a structure of formula (VI”), wherein R ⁷ and R ⁸ are taken together with the carbon to which they are attached to form a 3-4 membered heterocyclyl ring.

In another aspect, provided herein are compounds of formula (VII”): or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from: Z is CH2 or NH, wherein any hydrogen atom of the CH2 or NH may be substituted with

R ¹ ; each R ¹ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, Ci-6 alkyl, Ci-6 alkoxy, -S(O)tCi-6alkyl; -NR ^e R ^f , 3-8 membered heterocyclyl, and 5-6 membered heteroaryl; t is 0, 1, or 2; n is 0, 1, or 2; each of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of hydrogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, -NR ^e R ^f , Ci-6 alkoxy, and Ci-6 alkyl; or R ³ and R ⁴ may be taken together with the atoms to which they are attached to form an aromatic 5- 6 membered monocyclic ring fused to the phenyl to which R ³ and R ⁴ are attached; wherein the 5-6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) Ci-6 alkyl optionally substituted with hydroxy or -NR ^c R ^d ;

R ⁷ is hydrogen or Ci-6 alkyl;

R ⁸ is hydrogen, Ci-6 alkyl, or Ci-ehaloalkyl;

R ⁹ is hydrogen or Ci-6 alkyl;

R ¹⁰ is (5-6 membered heteroarylene)-(Co-6alkylene)-R ⁿ ;

R ¹¹ is 3-7 membered heterocyclyl or -NR ⁸ R ^h ; and

R ¹² and R ¹³ are hydrogen; or

R ⁷ and R ⁹ may be taken together with the atoms to which they are attached to form a 5- 6 membered heterocycle fused to the phenyl to which R ⁹ is attached;

R ⁹ and R ¹⁰ may be taken together with the atoms to which they are attached to form 6- membered heterocycle or cyclohexane ring fused to the phenyl to which R ⁹ and R ¹⁰ are attached;

R ¹² and R ¹³ may be taken together with the atoms to which they are attached to form phenyl ring fused to the ring to which R ¹² and R ¹³ are attached; each R ^c and R ^d are independently H or Ci-6 alkyl; and each R ^e and R ^f are independently selected from the group consisting of H, Ci-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy; each R ^s and R ^h are independently selected from the group consisting of H, Ci-6 alkyl, C3-6 cycloalkyl, 3-7 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy, wherein when R ^s is hydrogen, R ^h is not hydrogen; wherein when R ¹⁰ is (5-6 membered heteroarylene)-(Co-ealkylene)-(3-7 membered heterocyclyl), and R ³ is -NR ^c R ^d , R ⁸ is hydrogen; and wherein when R ^s or R ^h is C3-6 cycloalkyl or 3-7 membered heterocyclyl and R ³ is - NR ^e R ^f , R ^e or R ^f is not 3-7 membered heterocyclyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein ring A is

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein ring A is

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein Z is CH2 wherein the CH2 may be substituted with R ¹ . In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein Z is NH, wherein the NH may be substituted with R ¹ .

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein t is 0.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein n is 0.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from hydrogen and -NR ^e R ^f .

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ³ and R ⁴ are taken together with the atoms to which they are attached to form an aromatic 5-6 membered monocyclic ring fused to the phenyl to which R ³ and R ⁴ are attached, wherein the 5-6 membered ring is optionally substituted with one or more (e.g., one, two, three, or four) Ci-6 alkyl optionally substituted with hydroxy or -NR ^c R ^d .

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ⁷ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VII”), wherein R ⁷ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ⁸ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VII”), wherein R ⁸ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ⁹ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VII”), wherein R ⁹ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ¹¹ is 3-7 membered heterocyclyl. In some embodiments, compounds of the disclosure have a structure of formula (VII”), wherein R ¹¹ is -NR ⁸ R ^h .

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ⁷ and R ⁹ may be taken together with the atoms to which they are attached to form a

5-6 membered heterocycle fused to the phenyl to which R ⁹ is attached.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ⁹ and R ¹⁰ may be taken together with the atoms to which they are attached to form

6-membered heterocycle or cyclohexane ring fused to the phenyl to which R ⁹ and R ¹⁰ are attached.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein R ¹² and R ¹³ may be taken together with the atoms to which they are attached to form phenyl ring fused to the ring to which R ¹² and R ¹³ are attached.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^e and R ^f are independently selected from H and C3-6 cycloalkyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^e and R ^f are independently selected from H and 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy. In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^e and R ^f are independently selected from H and 5-6 membered heteroaryl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^e and R ^f are independently selected from H and Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^s and R ^h are independently selected from H and Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^s and R ^h are independently selected from H and C3-6 cycloalkyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^s and R ^h are independently selected from H and 3-7 membered heterocyclyl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy.

In some embodiments, compounds of the disclosure have a structure of formula (VIP ’), wherein each R ^s and R ^h are independently selected from the group consisting of H and 5-6 membered heteroaryl optionally substituted with one or more (e.g., one, two, three, or four) substituents each independently selected from the group consisting of Ci-6 alkyl, halogen, -OH, -C(O)OCi-6alkyl, and Ci-6 alkoxy.

In another aspect, provided herein are compounds of formula (VIII”) or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein

B is selected from: each R ¹ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, and Ci-6 alkyl; n is 0, 1, or 2; each of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of hydrogen, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, -NR ^e R ^f , NO2, Ci-6 alkoxy, and Ci-6 alkyl; or

R ⁴ and R ⁵ may be taken together with the atoms to which they are attached to form 5- membered heteroaryl fused to the phenyl to which R ⁴ and R ⁵ are attached;

R ⁹ is hydrogen or Ci-6 alkyl; each R ¹⁰ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, -NR ^e R ^f , NO2, Ci-6 alkoxy, Ci-6 alkyl, and C(O)NH(CI-6 alkylene)Ph wherein the Ph is optionally substituted with halogen; m is 0, 1, or 2;

R ⁶ and R ⁹ may be taken together with the atoms to which they are attached to form piperidine ring fused to the phenyl to which R ⁶ is attached; each of R ⁷ and R ⁸ is independently hydrogen, Ci-6 alkyl, or Ci-ehaloalkyl, or R ⁷ and R ⁸ may be taken together with the atom to which they are attached to form 3-4 membered cycloalkyl or heterocyclyl ring; wherein when R ⁹ is methyl, R ⁷ and R ⁸ are not methyl; wherein when R ⁹ is hydrogen, at least one of R ² and R ⁶ is not hydrogen; each of R ^e and R ^f is independently selected from the group consisting of hydrogen, Ci- 6 alkyl, and -C(O)CH2Ph.

In some embodiments, compounds of the disclosure have a structure of formula In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein B is

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein n is 0.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein each of R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ is independently selected from the group consisting of hydrogen, -NR ^e R ^f , NO2, and Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein R ⁴ and R ⁵ may be taken together with the atoms to which they are attached to form 5-membered heteroaryl fused to the phenyl to which R ⁴ and R ⁵ are attached.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein R ⁹ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein R ⁹ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIIF ’), wherein R ¹⁰ is C(O)NH(CI-6 alkylene)Ph wherein the Ph is optionally substituted with halogen.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein m is 0. In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein m is 1.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein R ⁶ and R ⁹ are taken together with the atoms to which they are attached to form piperidine ring fused to the phenyl to which R ⁶ is attached.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein each of R ⁷ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein each of R ⁷ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (VIIF ’), wherein R ⁷ and R ⁸ are taken together with the atom to which they are attached to form 3-4 membered cycloalkyl or heterocyclyl ring.

In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein each of R ⁸ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (VIII”), wherein each of R ⁸ is Ci-6 alkyl. In another aspect, provided herein are compounds of formula (IX”): or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein each R ¹ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, and Ci-6 alkyl; n is 0, 1, or 2;

R ² is Ci-6 alkyl;

R ³ is selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, -NR ^e R ^f , NO2, Ci-6 alkoxy, and Ci-6 alkyl;

R ⁶ is hydrogen or Ci-6 alkyl; and each of R ^e and R ^f is independently selected from hydrogen and Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IX”), wherein n is 0.

In some embodiments, compounds of the disclosure have a structure of formula (IX”), wherein R ² is methyl.

In some embodiments, compounds of the disclosure have a structure of formula (IX”), wherein R ³ is -NR ^e R ^f .

In some embodiments, compounds of the disclosure have a structure of formula (IX”), wherein R ⁶ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (IX”), wherein R ⁶ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (IX”), wherein R ^e and R ^f are hydrogen.

In another aspect, provided herein are compounds of formula (X”)

or a stereoisomer or a pharmaceutically acceptable salt thereof; wherein each R ¹ is independently selected from the group consisting of Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, and Ci-6 alkyl; n is 0, 1, or 2;

R ² is Ci-6 alkyl; and

R ³ is selected from the group consisting of Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, halo, -CN, -NR ^e R ^f , NO2, Ci-6 alkoxy optionally substituted with 3-8 membered heterocyclyl or -NR ^e R ^f ; and

R ⁴ is hydrogen or Ci-6 alkyl;

R ⁵ is hydrogen, Ci-6 alkyl, Ci-ehaloalkyl;

R ⁶ is hydrogen or Ci-6 alkyl; or

R ⁵ and R ⁶ may be taken together with the carbon to which they are attached to form 3- 4 membered cycloalkyl or heterocycle ring; and each of R ^e and R ^f is independently selected from hydrogen and Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein n is 0.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ² is methyl.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ³ is -NR ^e R ^f . In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ³ is Ci-6 alkoxy optionally substituted with -NR ^e R ^f . In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ³ is Ci- 6 alkoxy optionally substituted with 3-8 membered heterocyclyl.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁴ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁴ is Ci-6 alkyl. In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁵ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁵ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁶ is hydrogen. In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁶ is Ci-6 alkyl.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁵ and R ⁶ are taken together with the carbon to which they are attached to form 3-4 membered cycloalkyl ring.

In some embodiments, compounds of the disclosure have a structure of formula (X”), wherein R ⁵ and R ⁶ may be taken together with the carbon to which they are attached to form 3-4 membered heterocycle ring.

In certain aspects the present invention provides a compound of Formula I: or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, or a pharmaceutical composition thereof;

In other aspects the present invention provides a compound of Formula VIII, Formula IX, Formula X, Formula XI, or Formula XIII: or a pharmaceutically acceptable salt, isotopic derivative prodrug, or pharmaceutical composition thereof;

In other aspects the present invention provides a compound of Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVII, Formula XXVIII, or Formula

XXIX:

or a pharmaceutically acceptable salt, isotopic derivative, prodrug, or pharmaceutical composition thereof; wherein: Q ¹ is O or NR ² ;

Q ² is O, NR ² , orCR ³ R ⁴ ;

Q ³ is S, O, or NR ² ;

Q ⁴ is bond, O, NR ² , orCR ³ R ⁴ ; z is 0, 1, 2, or 3; x is 0, 1, 2, 3, or 4; each is an aryl, heteroaryl, heterocycle, cycloalkene, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ and optionally substituted with 1 R ¹¹ substituent; is an aryl, heteroaryl, heterocycle, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ and substituted with 1 R ¹¹ substituent; is an aryl, heteroaryl, heterocycle, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²⁰ ; is a cycloalkyl, aryl, heteroaryl, heterocycle, or bicycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²⁰ and optionally substituted with 1 R ¹¹ substituent; is a tricycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²⁰ ;

X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , and X ⁷ are independently selected from the group consisting of CR ¹⁰ , CH, and N, wherein no more than four of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , and X ⁷ are N;

X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , and X ¹² are independently selected from the group consisting of CH, CR ¹⁰ , CR ¹¹ , and N, wherein no more than four of X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , and X ⁷ are N; each R ¹ is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl; each R ² is independently hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, alkyl-heterocycle, alkyl-heteroaryl, alkyl-aryl, or -C(O)R ⁷ ;

R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl;

R ^3b is alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl; or R ³ and R ⁴ or R ^3b and R ⁴ are combined with the carbon to which they are attached to form a spirocyclopropyl, wherein the spirocyclopropyl group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ⁶ ;

R ⁵ is alkenyl or alkynyl;

R ^5b is haloalkyl; each R ⁶ is independently selected from the group consisting of halogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl; each R ⁷ and R ⁸ is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -NR ⁴ R ¹² , -OR ¹² , and SR ¹² ; each R ¹⁰ is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -alkyl-NR'R ² , - alkyl-OR ² ,

-C(O)R ⁷ , -NR ² C(O)R ⁷ , -OC(O)R ⁷ , -NR'R ² , -OR ² , SR ² , -S(O)R ⁷ , S(O) ₂ R ⁷ , and -P(O)R ⁷ R ⁸ , each of which except hydrogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ;

R ^10b is selected from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -alkyl-NR'R ² , -alkyl-OR ² , -C(O)R ⁷ , - NR ² C(O)R ⁷ , -OC(O)R ⁷ , -NR'R ² , -OR ² , SR ² , -S(O)R ⁷ , S(O) ₂ R ⁷ , and -P(O)R ⁷ R ⁸ , each of which except hydrogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²¹ ; each R ¹² is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl;

R ¹³ , R ¹⁴ , R ¹⁵ , and R ¹⁶ are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, CH2OR ² , and CFFNR'R ² ; or R ¹³ and R ¹⁴ are combined with the carbon to which they are attached to form a spirocyclopropyl; or R ¹⁵ and R ¹⁶ are combined with the carbon to which they are attached to form a spirocyclopropyl;

R ^16b is alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl;

R ¹⁷ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylcycloalkyl, -CH2CH2-OR ² , -CH2CH2-NR ¹ R ² , -alkyl-aryl, -alkyl-heteroaryl, or cycloalkyl;

R ¹⁸ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or - C(O)R ⁷ ; or R ¹⁷ and R ¹⁸ together with the nitrogen to which they are attached form a heterocycle;

R ¹⁹ is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or - C(O)R ⁷ ; each R ²⁰ is independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, oxo, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -alkyl-NR'R ² , -alkyl-OR ² , -C(O)R ⁷ , -NR ² C(O)R ⁷ ,

-OC(O)R ⁷ , -NR'R ² , -OR ² , SR ² , -S(O)R ⁷ , S(O)2R ⁷ , and -P(O)R ⁷ R ⁸ , each of which except hydrogen, cyano, and nitro is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ²² ; each R ²¹ is independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -C(O)R ⁷ , -NR ² C(O)R ⁷ , -OC(O)R ⁷ , -NR'R ² , -OR ² , SR ² , -S(O)R ⁷ , S(O) ₂ R ⁷ , and -P(O)R ⁷ R ⁸ ; and each R ²² is independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, nitro, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, -C(O)R ⁷ , -NR ² C(O)R ⁷ , -OC(O)R ⁷ , -NR'R ² , -OR ² , SR ² , -S(O)R ⁷ , S(O) ₂ R ⁷ , and -P(O)R ⁷ R ⁸ .

The present invention provides a compound of Formula (Z): or a pharmaceutically acceptable salt, prodrug, or pharmaceutical composition thereof. In the compound of Formula (Z), Al 00 may be selected from the group consisting of Formulas (Al), (A2), (A3), (A4), (A5), (A6), (A7), (A8), (A9), (A10), (Al l), (A12), (A13), (A14), (A15), (A16), (A17), (A18), (A19), and (A20): In the compound of Formula (Z), L ¹ may be -CH2-, or may be absent.

In the compound of Formula (Z), L ² may be -CONH-, -NHCO-, -NHSO2-, -SO2NH-, - NH-, -CO-, -NR ¹¹⁴ - or may be absent.

In the compound of Formula (Z), L ³ may be: or may be absent.

In the compound of Formula (Z), L ⁴ may be -CR120R121- or may be absent.

In the compound of Formula (Z), B100 may be:

In the compound of Formula (Z), R ¹⁰¹ may be H, halo, -OH, -CONH2, -OR ¹²⁴ , NR ¹²⁴ R ¹²⁵ , -NO2, -NS(O)2CH3, Ci-Ce alkoxyl, C3-C6 cycloalkoxyl, C3-C6 cycloheteroalkoxyl,

Ci-Ce heteroalkoxyl, -C(O)CH3,

R ¹⁰² may be H, -OH, halo, or an alkyne, including substituted alkynes, for example R ¹⁰³ may be H or halo, or alkyl.

R ¹⁰⁴ may be H, halo, or alkyl.

R ¹⁰⁶ may be H, halo or Ci-Ce alkyl, or a Ci-Ce cycloheteroalkyl.

R ¹⁰⁷ may be H, Me, -COH, -CH2OH, halo, C1-C3 alkyl, C1-C3 heteroalkyl, or C1-C4 cycloheteroalkyl, for example:

R ¹⁰⁸ may be H, halo, CO2H, CONH2, aryl, C3-C6 heteroaryl (for example pyridine), Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, Ci-Ce heteroalkyl, C3-C6 cycloheteroalkyl (for example morpholine), or for example

R ¹⁰⁹ may be H, halo, or Me.

R ¹¹⁰ may be H or Me.

R ¹¹² may be NO2 or NH2.

R ¹¹⁴ may be Me.

R ¹¹⁸ may be

Ruo may be H, Me, halo, cyano, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, Ci-Ce heteroalkyl, C3-C6 cycloheteroalkyl, aryl, or heteroaryl.

R121 may be H.

In alternative aspects of the invention, RI20 and RI21 may together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl or a C3-C6 cycloheteroalkyl.

R122 may be H, Me, halo, aryl, Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloheteroalkyl, for example a phenyl, benzyl, or thiophene or,

R ¹²² may be OR ¹²³ .

R ¹²³ may be aryl, C3-C6 cycloalkyl, or C3-C6 cycloheteroalkyl (for example, phenyl or benzyl).

R ¹²⁴ may be H, -S(O)2CH3, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce heteroalkyl, C3-C6 cycloheteroalkyl, or heteroaryl, or

R ¹²⁵ may be H, C(O)CH3, or may be absent.

In the compound of Formula (Z), each alkoxyl, alkyl, aryl, cycloalkoxyl, cycloalkyl, cycloheteroalkoxyl, cycloheteroalkyl, haloalkyl, heteroalkoxyl, heteroalkyl, and heteroaryl group may be optionally substituted.

Aspects of the invention include salt forms of the compound of Formula (Z). Salt forms may comprise any pharmaceutically acceptable salt, for example hydrochloric acid (HC1), trifluoroacetic acid (TFA), or formic acid (FA).

In preferred embodiments, R ¹⁰⁶ may be -CH3. L ² may be — NHCO-.

L ⁴ may be -CR ¹²⁰ R ¹²¹ -.

R ¹²⁰ may be CH3 and R ¹²¹ may be H.

In alternative aspects, L ⁴ may be -CR ¹²⁰ R ¹²¹ -, and R ¹²⁰ and R ¹²¹ together with the carbon atoms to which they are attached form a (hetero)cycloalkyl of formula (Yl), (Y2), or (Y3):

In further alternative aspects, L ⁴ may be -CR ¹²⁰ R ¹²¹ ., wherein R ¹²⁰ may be CH2F, CHF,

CF3, or may be selected from the group consisting may be of the formula (X6): and R ¹²¹ may be H.

In certain embodiments a compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

In certain embodiments a compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof; In certain embodiments a compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof;

In certain embodiments a compound of the present invention is of Formula:

or a pharmaceutically acceptable salt thereof. In certain embodiments a compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof.

Aspects of the invention provide a composition comprising the compounds according to the invention.

Aspects of the invention provide a pharmaceutically acceptable salt or a prodrug of the compounds of the invention.

Aspects of the invention provide a method of treating a subject afflicted with a viral infection, the method comprising administering to the subject a compound according to the invention.

Aspects of the invention provide a method of preventing a viral infection in a subject, the method comprising administering to the subject a compound according to the invention.

Aspects of the invention provide a method of preventing viral replication in a subject, the method comprising administering to the subject a compound according to the invention. Aspects of the invention provide a method of inhibiting PLpro in the subject, the method comprising administering to the subject a compound according to the invention

EMBODIMENTS OF THE PRESENT INVENTION In certain embodiments a compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , R ¹ , R ⁶ , R ¹⁰ , R ¹¹ , Q ³ , Ring B, and x are as defined herein.

In certain embodiments, are selected from: Non-limiting embodiments of R ¹

In certain embodiments, R ¹ is hydrogen.

In certain embodiments, R ¹ is alkyl.

In certain embodiments, R ¹ is haloalkyl.

In certain embodiments, R ¹ is alkenyl.

In certain embodiments, R ¹ is alkynyl.

In certain embodiments, R ¹ is aryl.

In certain embodiments, R ¹ is heteroaryl.

In certain embodiments, R ¹ is hydrogen.

In certain embodiments, R ¹ is cycloalkyl.

Non-limiting embodiments of R ²

In certain embodiments, R ² is hydrogen.

In certain embodiments, R ² is alkyl.

In certain embodiments, R ² is haloalkyl.

In certain embodiments, R ² is alkenyl.

In certain embodiments, R ² is alkynyl.

In certain embodiments, R ² is aryl.

In certain embodiments, R ² is heteroaryl.

In certain embodiments, R ² is cycloalkyl.

In certain embodiments, R ² is -C(O)R ⁷ .

Non-limiting embodiments of R ³

In certain embodiments, R ³ is hydrogen

In certain embodiments, R ³ is halogen

In certain embodiments, R ³ is alkyl.

In certain embodiments, R ³ is haloalkyl.

In certain embodiments, R ³ is alkenyl.

In certain embodiments, R ³ is alkynyl.

In certain embodiments, R ³ is aryl.

In certain embodiments, R ³ is heteroaryl.

In certain embodiments, R ³ is cycloalkyl. Non-limiting embodiments of R ^3b

In certain embodiments, R ^3b is alkyl.

In certain embodiments, R ^3b is haloalkyl.

In certain embodiments, R ^3b is alkenyl.

In certain embodiments, R ^3b is alkynyl.

In certain embodiments, R ^3b is aryl.

In certain embodiments, R ^3b is heteroaryl.

In certain embodiments, R ^3b is cycloalkyl.

Non-limiting embodiments of R ⁴

In certain embodiments, R ⁴ is hydrogen.

In certain embodiments, R ⁴ is halogen.

In certain embodiments, R ⁴ is alkyl.

In certain embodiments, R ⁴ is haloalkyl.

In certain embodiments, R ⁴ is alkenyl.

In certain embodiments, R ⁴ is alkynyl.

In certain embodiments, R ⁴ is aryl.

In certain embodiments, R ⁴ is heteroaryl.

In certain embodiments, R ⁴ is cycloalkyl.

Non- limiting embodiments of R ⁵

In certain embodiments, R ⁵ is alkenyl.

In certain embodiments, R ⁵ is alkynyl.

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments,

Non- limiting embodiments of R ^5b

In certain embodiments, R ^5b is haloalkyl.

In certain embodiments,

In certain embodiments,

In certain embodiments, R ^5b is -CF3.

Non-limiting embodiments of R ⁶

In certain embodiments, R ⁶ is halogen.

In certain embodiments, R ⁶ is alkyl.

In certain embodiments, R ⁶ is haloalkyl.

In certain embodiments, R ⁶ is alkenyl.

In certain embodiments, R ⁶ is alkynyl.

In certain embodiments, R ⁶ is aryl.

In certain embodiments, R ⁶ is heteroaryl.

In certain embodiments, R ⁶ is cycloalkyl.

Non-limiting embodiments of R ⁷

In certain embodiments, R ⁷ is hydrogen.

In certain embodiments, R ⁷ is alkyl.

In certain embodiments, R ⁷ is haloalkyl.

In certain embodiments, R ⁷ is alkenyl. In certain embodiments, R ⁷ is alkynyl.

In certain embodiments, R ⁷ is aryl.

In certain embodiments, R ⁷ is heteroaryl.

In certain embodiments, R ⁷ is cycloalkyl.

In certain embodiments, R ⁷ is -NR'R ¹² .

In certain embodiments, R ⁷ is -OR ¹² .

In certain embodiments, R ⁷ is SR ¹² .

Non-limiting embodiments of R ⁸

In certain embodiments, R ⁸ is hydrogen.

In certain embodiments, R ⁸ is alkyl.

In certain embodiments, R ⁸ is haloalkyl.

In certain embodiments, R ⁸ is alkenyl.

In certain embodiments, R ⁸ is alkynyl.

In certain embodiments, R ⁸ is aryl.

In certain embodiments, R ⁸ is heteroaryl.

In certain embodiments, R ⁸ is cycloalkyl.

In certain embodiments, R ⁸ is -NR'R ¹² .

In certain embodiments, R ⁸ is -OR ¹² .

In certain embodiments, R ⁸ is SR ¹² .

Non-limiting embodiments of R ¹⁰

In certain embodiments, R ¹⁰ is hydrogen.

In certain embodiments, R ¹⁰ is halogen.

In certain embodiments, R ¹⁰ is alkyl.

In certain embodiments, R ¹⁰ is haloalkyl.

In certain embodiments, R ¹⁰ is cyano.

In certain embodiments, R ¹⁰ is nitro.

In certain embodiments, R ¹⁰ is alkenyl.

In certain embodiments, R ¹⁰ is alkynyl.

In certain embodiments, R ¹⁰ is aryl.

In certain embodiments, R ¹⁰ is heteroaryl.

In certain embodiments, R ¹⁰ is cycloalkyl.

In certain embodiments, R ¹⁰ is -C(O)R ⁷ . In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, R ¹⁰ is -OR ² .

In certain embodiments, R ¹⁰ is SR ² .

In certain embodiments, R ¹⁰ is -S(O)R ⁷ .

In certain embodiments, R ¹⁰ is S(O)2R ⁷ .

In certain embodiments, R ¹⁰ is -P(O)R ⁷ R ⁸ .

Non-limiting embodiments of R ^10b :

In certain embodiments, R ^10b is hydrogen.

In certain embodiments, R ^10b is halogen.

In certain embodiments, R ^10b is alkyl.

In certain embodiments, R ^10b is haloalkyl.

In certain embodiments, R ^10b is cyano.

In certain embodiments, R ^10b is nitro.

In certain embodiments, R ^10b is alkenyl.

In certain embodiments, R ^10b is alkynyl.

In certain embodiments, R ^10b is aryl.

In certain embodiments, R ^10b is heteroaryl.

In certain embodiments, R ^10b is cycloalkyl.

In certain embodiments, R ^10b is -C(O)R ⁷ .

In certain embodiments, R ^10b is -NR ² C(O)R ⁷ .

In certain embodiments, R ^10b is -OC(O)R ⁷ .

In certain embodiments, R ^10b is -NR'R ² .

In certain embodiments, R ^10b is -OR ² .

In certain embodiments, R ^10b is SR ² .

In certain embodiments, R ^10b is -S(O)R ⁷ .

In certain embodiments, R ^10b is S(O)2R ⁷ .

In certain embodiments, R ^10b is -P(O)R ⁷ R ⁸ . Non-limiting embodiments of R ¹¹ :

In certain embodiments,

In certain embodiments,

In certain embodiments,

In certain embodiments, Non-limiting embodiments of R ¹²

In certain embodiments, R ¹² is hydrogen.

In certain embodiments, R ¹² is alkyl.

In certain embodiments, R ¹² is haloalkyl.

In certain embodiments, R ¹² is alkenyl.

In certain embodiments, R ¹² is alkynyl.

In certain embodiments, R ¹² is aryl.

In certain embodiments, R ¹² is heteroaryl.

In certain embodiments, R ¹² is cycloalkyl.

Non-limiting embodiments of R ¹³

In certain embodiments, R ¹³ is hydrogen.

In certain embodiments, R ¹³ is alkyl.

In certain embodiments, R ¹³ is haloalkyl.

In certain embodiments, R ¹³ is alkenyl.

In certain embodiments, R ¹³ is alkynyl.

In certain embodiments, R ¹³ is aryl.

In certain embodiments, R ¹³ is heteroaryl.

In certain embodiments, R ¹³ is cycloalkyl.

Non-limiting embodiments of R ¹⁴

In certain embodiments, R ¹⁴ is hydrogen.

In certain embodiments, R ¹⁴ is alkyl.

In certain embodiments, R ¹⁴ is haloalkyl.

In certain embodiments, R ¹⁴ is alkenyl.

In certain embodiments, R ¹⁴ is alkynyl.

In certain embodiments, R ¹⁴ is aryl.

In certain embodiments, R ¹⁴ is heteroaryl.

In certain embodiments, R ¹⁴ is cycloalkyl.

Non-limiting embodiments of R ¹⁵

In certain embodiments, R ¹⁵ is hydrogen.

In certain embodiments, R ¹⁵ is alkyl. In certain embodiments, R ¹⁵ is haloalkyl.

In certain embodiments, R ¹⁵ is alkenyl.

In certain embodiments, R ¹⁵ is alkynyl.

In certain embodiments, R ¹⁵ is aryl.

In certain embodiments, R ¹⁵ is heteroaryl.

In certain embodiments, R ¹⁵ is cycloalkyl.

Non-limiting embodiments of R ¹⁶

In certain embodiments, R ¹⁶ is hydrogen.

In certain embodiments, R ¹⁶ is alkyl.

In certain embodiments, R ¹⁶ is haloalkyl.

In certain embodiments, R ¹⁶ is alkenyl.

In certain embodiments, R ¹⁶ is alkynyl.

In certain embodiments, R ¹⁶ is aryl.

In certain embodiments, R ¹⁶ is heteroaryl.

In certain embodiments, R ¹⁶ is cycloalkyl.

Non-limiting embodiments of R ^16b

In certain embodiments, R ^16b is alkyl.

In certain embodiments, R ^16b is haloalkyl.

In certain embodiments, R ^16b is alkenyl.

In certain embodiments, R ^16b is alkynyl.

In certain embodiments, R ^16b is aryl.

In certain embodiments, R ^16b is heteroaryl.

In certain embodiments, R ^16b is cycloalkyl.

Non-limiting embodiments of R ¹⁷

In certain embodiments, R ¹⁷ is hydrogen.

In certain embodiments, R ¹⁷ is alkyl.

In certain embodiments, R ¹⁷ is haloalkyl.

In certain embodiments, R ¹⁷ is alkenyl.

In certain embodiments, R ¹⁷ is alkynyl.

In certain embodiments, R ¹⁷ is heteroaryl.

In certain embodiments, R ¹⁷ is -alkylcycloalkyl. In certain embodiments, R ¹⁷ is -CH2CH2-OR ² .

In certain embodiments, R ¹⁷ is -CH2CH2-NR ¹ R ² .

In certain embodiments, R ¹⁷ is -alkyl-aryl.

In certain embodiments, R ¹⁷ is -alkyl-heteroaryl.

In certain embodiments, R ¹⁷ is cycloalkyl.

Non-limiting embodiments of R ¹⁸

In certain embodiments, R ¹⁸ is hydrogen.

In certain embodiments, R ¹⁸ is alkyl.

In certain embodiments, R ¹⁸ is haloalkyl.

In certain embodiments, R ¹⁸ is alkenyl.

In certain embodiments, R ¹⁸ is aryl.

In certain embodiments, R ¹⁸ is heteroaryl.

In certain embodiments, R ¹⁸ is cycloalkyl.

In certain embodiments, R ¹⁸ is -C(O)R ⁷ .

Non-limiting embodiments of R ¹⁹

In certain embodiments, R ¹⁹ is hydrogen.

In certain embodiments, R ¹⁹ is alkyl.

In certain embodiments, R ¹⁹ is haloalkyl.

In certain embodiments, R ¹⁹ is alkenyl.

In certain embodiments, R ¹⁹ is alkynyl.

In certain embodiments, R ¹⁹ is aryl.

In certain embodiments, R ¹⁹ is heteroaryl.

In certain embodiments, R ¹⁹ is cycloalkyl.

In certain embodiments, R ¹⁹ is cycloalkyl.

In certain embodiments, R ¹⁹ is -C(O)R ⁷ .

Non-limiting embodiments of R ²⁰

In certain embodiments, R ²⁰ is hydrogen.

In certain embodiments, R ²⁰ is halogen.

In certain embodiments, R ²⁰ is alkyl.

In certain embodiments, R ²⁰ is haloalkyl.

In certain embodiments, R ²⁰ is cyano. In certain embodiments, R ²⁰ is nitro.

In certain embodiments, R ²⁰ is alkenyl.

In certain embodiments, R ²⁰ is alkynyl.

In certain embodiments, R ²⁰ is aryl.

In certain embodiments, R ²⁰ is heteroaryl.

In certain embodiments, R ²⁰ is cycloalkyl.

In certain embodiments, R ²⁰ is -C(O)R ⁷ .

In certain embodiments, R ²⁰ is -NR ² C(O)R ⁷ .

In certain embodiments, R ²⁰ is -OC(O)R ⁷ .

In certain embodiments, R ²⁰ is -NR'R ² .

In certain embodiments, R ²⁰ is -OR ² .

In certain embodiments, R ²⁰ is SR ² .

In certain embodiments, R ²⁰ is S(O)R ⁷ .

In certain embodiments, R ²⁰ is S(O)2R ⁷ .

In certain embodiments, R ²⁰ is -P(O)R ⁷ R ⁸ .

In certain embodiments, R ²⁰ is heteroaryl

Non-limiting embodiments of R ²¹

In certain embodiments, R ²¹ is heteroaryl

In certain embodiments, R ²¹ is hydrogen.

In certain embodiments, R ²¹ is halogen.

In certain embodiments, R ²¹ is alkyl.

In certain embodiments, R ²¹ is haloalkyl.

In certain embodiments, R ²¹ is cyano.

In certain embodiments, R ²¹ is nitro.

In certain embodiments, R ²¹ is alkenyl.

In certain embodiments, R ²¹ is alkynyl.

In certain embodiments, R ²¹ is aryl.

In certain embodiments, R ²¹ is heteroaryl.

In certain embodiments, R ²¹ is cycloalkyl.

In certain embodiments, R ²¹ is -C(O)R ⁷ .

In certain embodiments, R ²¹ is -NR ² C(O)R ⁷ .

In certain embodiments, R ²¹ is -OC(O)R ⁷ .

In certain embodiments, R ²¹ is -NR'R ² . In certain embodiments, R ²¹ is -OR ² .

In certain embodiments, R ²¹ is SR ² .

In certain embodiments, R ²¹ is S(O)R ⁷ .

In certain embodiments, R ²¹ is S(O)2R ⁷ .

In certain embodiments, R ²¹ is -P(O)R ⁷ R ⁸ .

In certain embodiments, R ²¹ is heteroaryl.

Non-limiting embodiments of R ²²

In certain embodiments, R ²² is hydrogen.

In certain embodiments, R ²² is halogen.

In certain embodiments, R ²² is alkyl.

In certain embodiments, R ²² is haloalkyl.

In certain embodiments, R ²² is cyano.

In certain embodiments, R ²² is nitro.

In certain embodiments, R ²² is alkenyl.

In certain embodiments, R ²² is alkynyl.

In certain embodiments, R ²² is aryl.

In certain embodiments, R ²² is heteroaryl.

In certain embodiments, R ²² is cycloalkyl.

In certain embodiments, R ²² is -C(O)R ⁷ .

In certain embodiments, R ²² is -NR ² C(O)R ⁷ .

In certain embodiments, R ²² is -OC(O)R ⁷ .

In certain embodiments, R ²² is -NR'R ² .

In certain embodiments, R ²² is -OR ² .

In certain embodiments, R ²² is SR ² .

In certain embodiments, R ²² is S(O)R ⁷ .

In certain embodiments, R ²² is S(O)2R ⁷ .

In certain embodiments, R ²² is -P(O)R ⁷ R ⁸ . REPRESENTATIVE COMPOUNDS OF THE PRESENT INVENTION

PHARMACEUTICAL COMPOSITIONS

Also disclosed herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, or four) pharmaceutically acceptable excipients. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, A-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. (See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79, the entirety of the contents of which are incorporated by reference herein).

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

The terms “human,” “patient,” and “subject” are used interchangeably herein. Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more (e.g., one, two, three, or four) symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.

Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences , Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 ^st Edition (Lippincott Williams & Wilkins, 2005).

The compounds and pharmaceutical compositions provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

METHODS OF TREATMENT

Another aspect of the disclosure provides methods of treating patients suffering from a viral infection, e.g., a coronaviral infection. In particular, in certain embodiments, the disclosure provides a method of treating the below medical indications comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound described herein. In one aspect, the compounds described herein are contemplated as PLpro inhibitors. In certain embodiments, the disclosure provides a method of treating a viral infection in a patient in need thereof, comprising inhibiting PLpro by administering a compound described herein.

SARS-CoV-2 is a positive strand RNA betacoronavirus. The genome of SARS-CoV-2 contains 16 nonstructural proteins (Nspl to Nspl6) that are initially expressed as a viral polyprotein (See Thiel, et al., Journal of General Virology 2003, 84 (9), 2305-2315; Barretto, et al, J Virol 2005, 79 (24), 15189-98; and Harcourt, et al., Journal of Virology 2004, 78 (24), 13600-13612, the entirety of the contents of each of which are incorporated by reference herein). During viral replication in coronaviruses, this polyprotein is processed by viral- encoded proteases to facilitate the formation of the membrane-bound replicase complex that carries out viral RNA replication (See Mielech, et al, Journal of Virology 2015, 89 (9), 4907- 4917, the entirety of the contents of which are incorporated by reference herein). One of the main proteases from CoV, the 3C-like protease, is known for its ability to cleave Nsp4-Nspl6. In addition to the 3C-like protease, CoVs can also encode up to two papain-like proteases (PLpros), one of which cleaves Nspl -3. For example, CoVs such as the mouse hepatitis virus (MHV) and other human coronaviruses, including NL63, OC43, HKU1, and 229E, encode for PLP1 and PLP29. For SARS-CoV-2, its genome mirrors that of the Middle East respiratory syndrome CoV (MERS-CoV) and SARS-CoV by coding for a single papain-like protease. Without being limited to a mechanism of action, the dual viral polypeptide cleavage and immune suppression roles of PLpros are potential targets for small molecule antiviral development. PLpro is discussed in Mclain and Vabret, Signal Transduction and Targeted Therapy 2020, 5:223; and Rut et al., Sci. Adv. 2020, 6:eabd4596, the entirety of the contents of each of which are incorporated by reference herein. In some embodiments, the infection is chronic. As used herein, “chronic” refers to an infection that persists for an extended period of time, or recurs. In some embodiments, the infection is acute. As used herein, “acute” refers to an infection that is of short duration.

Methods to quantify viral replication are known in the art. In some embodiments, viral count is determined using a plaque assay. In some embodiments, viral count is determined using a focus forming assay (FFA). In some embodiments, viral count is determined using an endpoint dilution assay. In some embodiments, viral count is determined using an enzyme- linked -63- immunosorbent assay (ELISA). In some embodiments, viral count is determined using Tunable resistive pulse sensing (TRPS) to detect individual virus particles. In some embodiments, viral replication is determined by quantifying the amount or percentage of host cell death, e.g., in vitro, for example, using propidium iodide (PI) to identify dead cells, quantifying the amount of morphologically rounded cells, or by immunofluorescence microscopy for apoptotic markers. In some embodiments, viral count is determined by measuring viral titer or multiplicity of infection (MOI) or by performing a plaque assay, a focus forming assay, and endpoint dilution assay, a viral protein quantification assay (for example, a hemagglutination assay, a bicinchoninic acid assay (BCA), or a single radial immunodiffusion assay (SRID) assay), transmission electron microscopy analysis, a tunable resistive pulse sensing (TRPS) assay, a flow cytometry assay, a quantitative PCR (qPCR) assay, or an Enzyme-linked immunosorbent assay (ELISA). In some embodiments, viral replication is determined by quantification of viral nucleic acid (for example, viral DNA or viral RNA) content.

Methods to quantify viral transmission are known in the art. In some embodiments, viral transmission is quantified using epidemiological modeling (see, e.g., Graw F. et al., (2016) Modeling Viral Spread. Annu Rev Virol, 3(1)). In some embodiments, viral transmission is assessed in vitro, e.g., in cell culture, e.g., using microscopy, e.g., using transmission electron microscopy (TEM).

Methods to quantify viral assembly are known in the art. In some embodiments, viral assembly is determined using statistical modeling (see, e.g., Clement N et al., (2018) Viral Capsid Assembly: A Quantified Uncertainty Approach. J Comp Biol, 25(1)). In some embodiments, viral assembly is determined using biochemical techniques to determine capsid complex formation, e.g., co-immunoprecipitation, e.g., western blotting. In some embodiments, viral assembly is determined by flow cytometry for detection of colocalized viral protein (see, e.g., Stoffel, C.L. et al. (2005). "Rapid Determination of Baculovirus Titer by a Dual Channel Virus Counter" American Biotechnology Laboratory.37 (22): 24-25). Viral genes encode elements necessary for the process of viral infection, a multi- step process, including, for example, attachment to the host cell, penetration, de-envelopment, viral gene transcription cascade, viral protein expression, viral genome replication, viral packaging and assembly, envelopment, transport and maturation, release and egress, and host cell-to-cell transmission. P genes are those genes corresponding to early steps of viral infection, e.g., viral genome replication, y genes are those genes corresponding to late steps of viral infection, e.g., egress. Methods to quantify viral gene expression are known in the art. In some embodiments, viral gene expression is determined using reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR). In some embodiments, RNA sequencing (RNA-Seq) is used to determine viral gene expression. In some embodiments, viral DNA is quantified using a Southern blot. In some embodiments, P gene expression is quantified. In some embodiments, y gene expression is quantified. In some embodiments, P gene expression and y gene expression are quantified. In some embodiments, expression of the entire viral genome is quantified.

Methods to quantify virus release are known in the art. In some embodiments, viral release is determined by biochemical assay, e.g., western blotting, e.g., metabolic labeling (see, e.g., Yadav et al., (2012). “A facile quantitative assay for viral particle genesis reveals cooperativity in virion assembly and saturation of an antiviral protein.” Virology.429(2): 155- 162). In some embodiments, viral release is determined by ELISA. In some embodiments, viral release is determined using electron microscopy, e.g., transmission electron microscopy (TEM). In some embodiments, viral release is determined by infectivity measurements for the detection of virions in a sample, e.g., serum. In some embodiments, viral release is determined by quantification of viral DNA or viral RNA in serum in vivo or culture supernatant in vitro.

Methods of treatment of the present invention can be used as a monotherapy or in combination with one or more (e.g., one, two, three, or four) other therapies (for example, anti- infective agents) that can be used to treat a disease or disorder, for example, an infection. The term “combination,” as used herein, is understood to mean that two or more different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, such that the effects of the treatments on the patient overlap at a point in time. In certain embodiments, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In certain embodiments of either case, the treatment is more effective because of combined administration. For example, the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment. In certain embodiments, delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive. The delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.

Accordingly, in certain embodiments, the subject has received, is receiving, or is scheduled to receive one or more (e.g., one, two, three, or four) other therapies suitable for use in treating the disease or disorder. In certain embodiments, the method of treatment of the present invention further comprises administering to the subject one or more (e.g., one, two, three, or four) other therapies suitable for use in treating a disease or disorder, for example, an infection. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise an agent that ameliorates one or more (e.g., one, two, three, or four) symptoms of infection with an intracellular pathogen. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise surgical removal of an infected tissue.

Accordingly, in certain embodiments, the subject has received, is receiving, or is scheduled to receive one or more (e.g., one, two, three, or four) other therapies suitable for use in treating the disease or disorder. In certain embodiments, the method of treatment of the present invention further comprises administering to the subject one or more (e.g., one, two, three, or four) other therapies suitable for use in treating a disease or disorder, for example, an infection. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise an agent that ameliorates one or more (e.g., one, two, three, or four) symptoms of infection with an intracellular pathogen. In certain embodiments, the one or more (e.g., one, two, three, or four) other therapies comprise surgical removal of an infected tissue.

It is understood that a method of use disclosed herein can be used in combination with an agent, for example, an anti -infective agent that ameliorates one or more (e.g., one, two, three, or four) symptoms of a disease or disorder associated with an intracellular pathogen. For example, a method of use disclosed herein can be used in combination with another antiviral agent.

In some embodiments, the additional therapeutic agents can be therapeutic anti-viral vaccines. SYNTHETIC PROCEDURES

List of Abbreviations

Example 1 : 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(5,6,7,8-tetrahydronap hthalen-l- yl)ethyl)benzamide (Compound 172)

Step 7

Compound 172

Step 1: tert- Butyl 3-((3-(methoxycarbonyl)-4-methylphenyl)amino)azetidine-l- carboxylate (1A-2) To a solution of methyl 5-amino-2-methylbenzoate (1.10 g, 6.66 mmol, 1.1 eq) and tert-butyl 3 -oxoazetidine- 1 -carboxylate (1.00 g, 5.84 mmol, 1.0 eq) in DME (30 mL) was added NaBH(OAc)3 (1.49 g, 7.01 mmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (40 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. /crt-Butyl 3 -((3 -(methoxycarbonyl)-4-methylphenyl)amino)azetidine-l -carboxylate (700 mg, 2.18 mmol, 37% yield) was obtained as a white solid. M - 56 + H ⁺ = 265.2.

Step 2: 5-((l-(tert-Butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenz oic acid (1A-3)

To a solution of tert-butyl 3 -((3 -(methoxy carbonyl)-4-methylphenyl)amino)azeti dine- 1- carboxylate (700 mg, 2.18 mmol, 1.0 eq) in a mixture of H2O (10 mL) and THF (30 mL) was added LiOH.LEO (458 mg, 10.9 mmol, 5.0 eq). The mixture was stirred at 70 °C for 16 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with TMBE (10 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with 2-m ethyl tetrahydrofuran (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenz oic acid (700 mg) as a white solid.

Step 3: /V-Methoxy-/V-methyl-5,6,7,8-tetrahydronaphthalene-l-carboxa mide (1A-5)

To a solution of A,O-dimethylhydroxylamine hydrochloride (775 mg, 7.95 mmol, 2.0 eq) in DCM (15 mL) was added 5,6,7,8-tetrahydronaphthalene-l-carboxylic acid (700 mg, 3.97 mmol, 1.0 eq), followed by HATU (1.81 g, 4.76 mmol, 1.2 eq) and DIEA (1.95 g, 15.1 mmol, 2.63 mL, 3.8 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with saturated aqueous NaHCOs (10 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. A-Methoxy-A-methyl-5,6,7,8-tetrahydronaphthalene-l-carboxami de (440 mg, 2.01 mmol, 51% yield) was obtained as a colorless oil. M + H ⁺ = 220.3 (LCMS); 'H NMR (400 MHz, CDCL) 6 7.15 - 7.01 (m, 3H), 4.00 - 2.96 (m, 7H), 2.85 - 2.68 (m, 4H), 1.81 - 1.77 (m, 3H).

Step 4: l-(5,6,7,8-Tetrahydronaphthalen-l-yl)ethanone (1A-6)

To a solution of /'/-methoxy-/'/-methyl-5, 6,7, 8-tetrahydronaphthalene- l -carboxamide (400 mg, 1.82 mmol, 1.0 eq) in THF (10 mL) at 0 °C was added MeMgBr (3 M in Et2O, 912 pL, 1.5 eq). The resulting mixture was stirred at 20 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. l-(5,6,7,8-Tetrahydronaphthalen-l-yl)ethanone (120 mg, 689 pmol, 38% yield) was obtained as colorless oil. 'H NMR (400 MHz, CDCh) 8 7.49 - 7.41 (m, 1H), 7.24 - 7.12 (m, 2H), 3.00 - 2.92 (m, 2H), 2.88 - 2.76 (m, 2H), 2.60 - 2.52 (m, 3H), 1.85 - 1.70 (m, 4H).

Step 5: l-(5,6,7,8-Tetrahydronaphthalen-l-yl)ethanamine (1A-7)

To a solution of l-(5,6,7,8-tetrahydronaphthalen-l-yl)ethanone (100 mg, 574 pmol, 1.0 eq) in MeOH (6.0 mL) was added NH4OAC (531 mg, 6.88 mmol, 12 eq), followed by NaBHiCN (144 mg, 2.30 mmol, 4.0 eq). The resulting mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give l-(5,6,7,8-tetrahydronaphthalen-l- yl)ethanamine (90.0 mg, 513 pmol, 89% yield) as a colorless oil. M - 17 + H ⁺ = 159.0 (LCMS).

Step 6: tc/7- Butyl 3-((4-methyl-3-((l-(5,6,7,8-tetrahydronaphthalen-l- yl)ethyl)carbamoyl) phenyl)amino)azetidine-l-carboxylate (1A-8)

To a solution of l-(5,6,7,8-tetrahydronaphthalen-l-yl)ethanamine (60.0 mg, 342 pmol, 1.0 eq) and 5-((l-(/er/-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenz oic acid (94.4 mg, 308 pmol, 0.9 eq) in DCM (5.0 mL) were added EDCI (98.4 mg, 514 pmol, 1.5 eq), HOBt (69.4 mg, 514 pmol, 1.5 eq) and TEA (69.3 mg, 685 pmol, 95.3 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. /c/7- Butyl 3-((4-methyl-3-((l-(5,6,7,8-tetrahydro naphthalen-l-yl)ethyl)carbamoyl) phenyl)amino)azetidine-l -carboxylate (80.0 mg, 162 pmol, 47%) was obtained as a yellow solid. M + Na ⁺ = 486.1 (LCMS); ¹ H NMR (400 MHz, CD3OD) 8 7.23 (d, J= 7.1 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.03 - 6.95 (m, 2H), 6.56 - 6.49 (m, 2H), 5.43 - 5.36 (m, 1H), 4.61 - 4.58 (m, 1H), 4.29 - 4.17 (m, 3H), 3.74 - 3.69 (m, 2H), 3.10 - 3.02 (m, 1H), 2.83 - 2.77 (m, 3H), 2.21 - 2.18 (m, 3H), 1.95 - 1.87 (m, 2H), 1.83 - 1.77 (m, 2H), 1.48 (m, 11H). Step 7: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(5,6,7,8-tetrahydronap hthalen-l-yl)ethyl) benzamide (Compound 172)

To a solution of tert-butyl 3-((4-methyl-3-((l-(5,6,7,8-tetrahydronaphthalen-l-yl)ethyl) carbamoyl)phenyl)amino)azetidine-l -carboxylate (60.0 mg, 129 pmol, 1.0 eq) in DCM (8.0 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL, 313 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(azetidin-3-ylamino)-2-methyl-A-(l-(5,6,7,8- tetrahydronaphthalen-l-yl)ethyl)benzamide (22.7 mg, 47.6 pmol, 37% yield, TFA salt) as a yellow solid. M + H ⁺ = 364.3 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 7.22 - 7.18 (m, 1H), 7.10 - 7.00 (m, 2H), 6.98 - 6.94 (m, 1H), 6.58 - 6.53 (m, 1H), 6.50 - 6.48 (m, 1H), 5.41 - 5.38 (m, 1H), 4.50 - 4.45 (m, 1H), 4.38 - 4.32 (m, 2H), 3.96 - 3.89 (m, 2H), 3.12 - 2.98 (m, 1H), 2.82 - 2.76 (m, 3H), 2.21 - 2.18 (m, 3H), 1.92 - 1.84 (m, 2H), 1.82 - 1.76 (m, 2H), 1.46 - 1.42 (m, 3H).

Example 2: 5-(Azetidin-3-ylamino)-/V-(l-(2,3-dihydrobenzo[/>] [l,4]dioxin-5-yl)ethyl)-2- methylbenzamide (Compound 168)

Step 5

2A-5 Compound 168

Step 1: /V-Methoxy-/V-methyl-2,3-dihydrobenzo[/>][l,4]dioxine-5-c arboxamide (2A-2)

To a solution of 2,3-dihydro-l,4-benzodioxine-5-carboxylic acid (1.00 g, 5.55 mmol, 1.0 eq) and 7V,O-dimethylhydroxylamine hydrochloride (596 mg, 6.11 mmol, 1.1 eq) in DCM (20 mL) were added TEA (1.69 g, 16.7 mmol, 2.32 mL, 3.0 eq), EDCI (1.28 g, 6.66 mmol, 1.2 eq) and HOBt (900 mg, 6.66 mmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (20 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. A-Methoxy-A-methyl-2,3- dihydrobenzo[Z>][F,4]dioxine-5-carboxamide (600 mg, 2.69 mmol, 48% yield) was obtained as a white solid. M + H ⁺ = 224.0 (LCMS).

Step 2: l-(2,3-Dihydrobenzo[/>][l,4]dioxin-5-yl)ethanone (2A-3)

A mixture of 7V-methoxy-7V-methyl-2,3-dihydrobenzo[Z>][F,4]dioxine-5-c arboxamide (200 mg, 896 pmol, 1.0 eq) in THF (3.0 mL) was degassed and purged with N2 three times, and to this mixture was added MeMgBr (3 M in Et2O, 388 pL, 1.3 eq) at 0 °C. The mixture was warmed to 20 °C and stirred at the same temperature for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product l-(2,3-dihydrobenzo[Z>][l,4]dioxin-5-yl)ethanone (150 mg), which was used in the next step without any further purification.

Step 3: l-(2,3-Dihydrobenzo[/>][l,4]dioxin-5-yl)ethanamine (2A-4)

To a solution of l-(2,3-dihydrobenzo[Z>][l,4]dioxin-5-yl)ethanone (100 mg, 561 pmol, 1.0 eq) in MeOH (1.0 mL) was added NFLOAc (519 mg, 6.73 mmol, 12 eq), followed by NaBFLCN (141 mg, 2.24 mmol, 4.0 eq) at 20 °C. The mixture was stirred at the same temperature for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected as a main peak. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product l-(2,3- dihydrobenzo[Z>][l,4]dioxin-5-yl)ethanamine (150 mg), which was used in the next step without any further purification. M + H ⁺ = 180.0 (LCMS).

Step 4: tert-Butyl-((3-((l-(2,3-dihydrobenzo[/>] [l,4]dioxin-5-yl)ethyl)carbamoyl)-4- methylphenyl)amino)azetidine-l-carboxylate (2A-5)

To a solution of l-(2,3-dihydrobenzo[Z>][l,4]dioxin-5-yl)ethanamine (130 mg, 725 pmol, 1.1 eq) and 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenz oic acid (202 mg, 659 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (267 mg, 2.64 mmol, 367 pL, 4.0 eq), EDCI (379 mg, 1.98 mmol, 3.0 eq) and HOBt (267 mg, 1.98 mmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. /crt-Butyl-((3- ((l-(2,3-dihydrobenzo [Z>][l,4]dioxin-5-yl)ethyl)carbamoyl)-4-methylphenyl)amin o)azetidine -1 -carboxylate (123 mg, 263 pmol, 40% yield) was obtained as a white oil. M + H ⁺ = 468.0 (LCMS).

Step 5: 5-(Azetidin-3-ylamino)-/V-(l-(2,3-dihydrobenzo[/>] [l,4]dioxin-5-yl)ethyl)-2- methylbenzamide (Compound 168)

To a solution of tert-butyl 3-((3-((l-(2,3-dihydrobenzo[Z>][l,4]dioxin-5-yl)ethyl)car bamoyl)-4- methylphenyl)amino)azetidine-l -carboxylate (20.0 mg, 42.8 pmol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 316 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(azetidin-3-ylamino)-7V-(l-(2,3-dihydrobenzo[Z>][l,4] dioxin-5-yl)ethyl)-2-methylbenzamide (12.0 mg, 24.6 pmol, 58% yield, TFA salt) as a white solid. M + H ⁺ = 368.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.54 - 8.47 (m, 1H), 7.04 (d, J= 8.1 Hz, 1H), 6.88 - 6.86 (m, 1H), 6.81 - 6.73 (m, 2H), 6.59 - 6.54 (m, 2H), 5.48 - 5.40 (m, 1H), 4.53 - 4.45 (m, 1H), 4.39 - 4.30 (m, 4H), 4.27 - 4.24 (m, 2H), 3.96 - 3.91 (m, 2H), 2.22 (s, 3H), 1.46 (d, J= 7.0 Hz, 3H).

Example 3: (l?)-5-Acetyl-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzamid e (Compound 155)

Compound 155

Step 1: 5-Acetyl-2-methylbenzoic acid (3A-2)

To a solution of 5-bromo-2-methylbenzoic acid (300 mg, 1.40 mmol, 1.0 eq) in THF (10 mL) was added w-BuLi (2.5 M in hexane, 1.12 mL, 2.0 eq) at -78 °C. The mixture was stirred at - 78 °C for 30 min. To the mixture was added a solution of A-methoxy-A-methylacetamide (158 mg, 1.53 mmol, 163 pL, 1.1 eq) in THF (3.0 mL). The mixture was stirred at -78 °C for 1 h, then warmed to 20 °C and stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into HC1 (1 M aqueous, 10 mL) and extracted with MTBE (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-acetyl-2-methylbenzoic acid (70.0 mg), which was used in the next step without any further purification. M + H ⁺ = 179.1 (LCMS); 'H NMR (400 MHz, DMSO ) 5 13.1 (br d, J= 5.4 Hz, 1H), 8.3 (d, J= 2.0 Hz, 1H), 8.0 (dd, J= 8.0, 2.0 Hz, 1H), 7.5 (d, J= 8.0 Hz, 1H), 2.6 (s, 6H).

Step 2: (l?)-5-Acetyl-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzamid e (Compound 155)

To a solution of 5-acetyl-2-methylbenzoic acid (60.0 mg, 337 pmol, 1.0 eq) in DCM (3.0 mL) were added (R)- 1 -(naphthal en-l-yl)ethanamine (57.7 mg, 337 pmol, 53.9 pL, 1.0 eq), EDCI (77.5 mg, 404 pmol, 1.2 eq), HOBt (54.6 mg, 404 pmol, 1.2 eq) and TEA (102 mg, 1.01 mmol, 141 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 35% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (A)-5-Acetyl-2-methyl-A-(l-(naphthalen-l-yl)ethyl)benzamide (11.5 mg, 34.5 pmol, 10% yield) was obtained as a white solid. M + H ⁺ = 332.1 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 8 8.3 (d, J= 8.4 Hz, 1H), 7.9 - 8.0 (m, 3H), 7.8 (d, J= 8.1 Hz, 1H), 7.6 - 7.7 (m, 2H), 7.5 - 7.5 (m, 2H), 7.4 (d, J= 8.0 Hz, 1H), 6.1 (q, J= 6.9 Hz, 1H), 2.5 - 2.6 (m, 3H), 2.4 (s, 3H), 1.7 (d, J= 7.0 Hz, 3H).

Example 4: (7?)-5-Hydroxy-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzami de (Compound 101)

4A-1 Compound 101

Step 1: (7?)-5-Hydroxy-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzami de (Compound 10 1)

A mixture of (R)- 1 -(naphthal en-l-yl)ethanamine (56.3 mg, 329 pmol, 52.6 pL, 1.0 eq) and 5- hydroxy-2-methylbenzoic acid (50.0 mg, 329 pmol, 1.0 eq) in DCM (3.0 mL) were added HATU (250 mg, 657 pmol, 2.0 eq) and DIEA (127 mg, 986 pmol, 172 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile) to give (A)-5-hydroxy-2-methyl-A-(l-(naphthalen- l-yl)ethyl) benzamide (50.2 mg, 164 pmol, 50% yield) as a white solid. M + H ⁺ = 306.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.19 (br d, J= 8.3 Hz, 1H), 7.91 - 7.76 (m, 2H), 7.60 - 7.40 (m, 4H), 6.97 (d, J= 8.3 Hz, 1H), 6.78 (s, 1H), 6.73 (br d, J= 8.3 Hz, 1H), 6.09 (br s, 2H), 2.29 (s, 3H), 1.76 (br d, J= 5.7 Hz, 3H).

Example 5: (7?)-5-Methoxy-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzami de (Compound 136)

Step 1

5A-1 Compound 136

Step 1: (7?)-5-Methoxy-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzami de (Compound 136 )

To a mixture of (R)- 1 -(naphthal en-l-yl)ethanamine (50 mg, 292 pmol, 47.0 pL, 1.0 eq) and 5- methoxy-2-methylbenzoic acid (48.6 mg, 292 pmol, 1.0 eq) in DCM (2.0 mL) were added EDCI (67.2 mg, 350 pmol, 1.2 eq), HOBt (47.4 mg, 350 pmol, 1.2 eq) and TEA (88.6 mg, 876 pmol, 100 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 45% - 75% B over 8 min; mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile). (A)-5-Methoxy-2-methyl- A-(l -(naphthal en-l-yl)ethyl)benzamide (36.1 mg, 112 pmol, 38% yield) was obtained as a white solid. M + H ⁺ = 320.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.24 (d, J= 8.4 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63 - 7.43 (m, 4H), 7.09 (d, J= 8.3 Hz, 1H), 6.87 - 6.78 (m, 2H), 6.19 - 6.08 (m, 1H), 3.74 (s, 3H), 2.35 (s, 3H), 1.80 (d, J= 6.7 Hz, 3H). Example 6: (l?)-2-Chloro-5-methoxy-/V-(l-(naphthalen-l-yl)ethyl)benzami de (Compound 132)

Step 1

6A-1 Compound 132

Step 1: (l?)-2-Chloro-5-methoxy-/V-(l-(naphthalen-l-yl)ethyl)benzami de (Compound 132 )

To a mixture of (R)- 1 -(naphthal en-l-yl)ethanamine (60.0 mg, 350 pmol, 56.0 pL, 1.0 eq) and 2-chloro-5-methoxybenzoic acid (65.4 mg, 350 pmol, 1.0 eq) in DCM (3.0 mL) were added EDCI (80.6 mg, 420 pmol, 1.2 eq) and HOBt (56.8 mg, 420 pmol, 1.2 eq) and TEA (106 mg, 1.05 mmol, 146 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 50% - 80% B over 8 min; mobile phase A: water (10 mM NH4HCO3), mobile phase B: acetonitrile). (A)-2-Chloro-5-methoxy- A-(l -(naphthal en-l-yl)ethyl)benzamide (56.3 mg, 161 pmol, 46% yield) was obtained as a white solid. M + H ⁺ = 340.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.23 (d, J= 8.5 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.63 - 7.42 (m, 4H), 7.25 (d, J= 8.9 Hz, 1H), 7.22 (d, J= 3.0 Hz, 1H), 6.88 (dd, J= 3.1, 8.8 Hz, 1H), 6.14 (q, J= 6.9 Hz, 1H), 3.79 (s, 3H), 1.82 (d, J = 6.8 Hz, 3H).

Example 7: (/?)-/c/7-Butyl (2-(4-methyl-3-((l-(naphthalen-l- yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (Compound 158)

7A-1 7A-2

Step 3

7A-3 Compound 158

Step 1: Methyl 5-(2-((terCbutoxycarbonyl)amino)ethoxy)-2-methylbenzoate (7A-2)

A mixture of tert-butyl (2-hydroxyethyl)carbamate (2.43 g, 15.0 mmol, 2.33 mL, 1.0 eq), methyl 5-hydroxy-2-methylbenzoate (2.50 g, 15.0 mmol, 1.0 eq) and PPhi (4.34 g, 16.6 mmol, 1.1 eq) in THF (30 mL) was degassed and purged with N2 three times. To the mixture was added DIAL) (3.35 g, 16.6 mmol, 3.22 mL, 1.1 eq) dropwise at 20 °C. The resulting mixture was stirred at 70 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/2. Methyl 5-(2-((tert- butoxycarbonyl)amino)ethoxy)-2-methylbenzoate (2.50 g, 8.08 mmol, 54% yield) was obtained as a yellow oil. M + Na ⁺ = 332.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.43 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 2.8, 8.3 Hz, 1H), 5.11 - 4.95 (m, 1H), 4.02 (s, 2H), 3.88 (s, 3H), 3.53 (br d, J= 5.1 Hz, 2H), 2.51 (s, 3H), 1.45 (s, 9H).

Step 2: 5-(2-((terCButoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (7A-3)

To a solution of methyl 5-(2-((te/7-butoxycarbonyl)amino)ethoxy)-2-methylbenzoate (1.60 g, 5.17 mmol, 1.0 eq) in a mixture of MeOH (8.0 mL) and THF (24 mL) was added NaOH (2 M aqueous, 10 mL, 4.0 eq). The mixture was stirred at 70 °C for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, H2O (30 mL) was added, and the mixture was washed with MTBE (15 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5- (2-((ter/-butoxycarbonyl) amino)ethoxy)-2-methyl benzoic acid (1.1 g), which was used in the next step without any further purification. M + Na ⁺ = 318.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 13.49 (br s, 1H), 9.33 (s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 7.28 (br s, 1H), 7.00 - 6.92 (m, 1H), 6.70 (t, J = 8.4 Hz, 2H), 5.18 - 5.11 (m, 1H), 2.64 - 2.54 (m, 2H), 2.00 - 1.90 (m, 1H), 1.87 - 1.72 (m, 3H).

Step 3: (l?)-tert-Butyl (2-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy) ethy l)carbamate (Compound 158)

To a solution of 5-(2-((ter/-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (50.0 mg, 169 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (34.8 mg, 203 pmol, 32.5 pL, 1.2 eq) in DCM (3.0 mL) were added TEA (51.4 mg, 508 pmol, 70.7 pL, 3.0 eq), EDCI (48.7 mg, 254 pmol, 1.5 eq) and HOBt (34.3 mg, 254 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were washed with brine (3.0 mL x 3), dried over ISfeSCU, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.5). (A)-tert-Butyl (2-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl) phenoxy)ethyl)carbamate (77.2 mg, 143 pmol, 84% yield) was obtained as a white oil. M - 56 + H ⁺ = 393.0 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.24 (d, J= 8.6 Hz, 1H), 7.89 (d, J= 7.8 Hz, 1H), 7.83 (d, J= 8.3 Hz, 1H), 7.62 - 7.45 (m, 4H), 7.09 (d, J= 8.4 Hz, 1H), 6.85 - 6.77 (m, 2H), 6.18 - 6.09 (m, 1H), 5.98 - 5.91 (m, 1H), 4.94 (br d, J= 4.9 Hz, 1H), 3.98 - 3.90 (m, 2H), 3.52 - 3.43 (m, 2H), 2.35 (s, 3H), 1.81 (d, J= 6.7 Hz, 3H), 1.44 (s, 9H).

Example 8: (l?)-5-(2- Aminoethoxy )-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzamide (Compound 159)

Compound 158 Compound 159

Step 1 : (l?)-5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)ethyl )benzamide (Compound 159)

To a mixture of (A)-terLbutyl (2-(4-methyl-3-((l -(naphthal en-l-yl)ethyl) carbamoyl)phenoxy)ethyl)carbamate (20.0 mg, 44.6 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-5-(2-Aminoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)ethyl)b enzamide (6.21 mg, 16.1 pmol, 36% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 349.1 (LCMS); flT NMR (400 MHz, CD ₃ OD) 8 8.26 (d, J= 8.4 Hz, 1H), 7.91 (d, J= 7.8 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.70 - 7.44 (m, 4H), 7.17 (d, J= 8.5 Hz, 1H), 6.97 (dd, J= 2.8, 8.4 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.06 (q, J = 7.0 Hz, 1H), 4.59 (br s, 2H), 4.28 - 4.11 (m, 2H), 3.33 (d, J= 5.1 Hz, 2H), 2.27 (s, 3H), 1.71 (d, J= 6.9 Hz, 3H).

Example 9: (7?)-5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthalen- l- yl)ethyl)benzamide (Compound 160)

Step 1

Compound 159 Compound 160

Step 1 : (7?)-5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthalen- l-yl)ethyl)benzami de (Compound 160)

To a solution of (A)-5-(2-aminoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)ethyl)b enzamide (20.0 mg, 57.4 pmol, 1.0 eq, HC1 salt) in MeOH (3.0 mL) was added TEA (900 pL), followed by the addition of formaldehyde (9.32 mg, 115 pmol, 8.55 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBH ₃ CN (7.21 mg, 115 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) at 25 °C and extracted with EtOAc (3.0 mL x 3). The combined organic layers were washed with brine (3.0 mL x 3), dried over NajSCh, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-5-(2-(Dimethylamino)ethoxy)-2- methyl-A-(l -(naphthal en-l-yl)ethyl)benzamide (15.9 mg, 42.2 pmol, 74% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 377.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.85 (br d, J= 7.8 Hz, 1H), 8.25 (d, J= 8.3 Hz, 1H), 7.90 (d, J= 8.3 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.63 (d, J= 6.8 Hz, 1H), 7.60 - 7.43 (m, 3H), 7.18 (d, J= 8.4 Hz, 1H), 6.98 (dd, J= 2.8, 8.4 Hz, 1H), 6.93 (d, J= 2.7 Hz, 1H), 6.11 - 5.97 (m, 1H), 4.35 - 4.25 (m, 2H), 3.61 - 3.51 (m, 2H), 2.95 (s, 6H), 2.28 (s, 3H), 1.71 (d, J= 6.8 Hz, 3H).

Example 10: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-(oxetan-3-ylox y)benzamide

(Compound 152)

Compound 152

Step 1: Methyl 2-methyl-5-(oxetan-3-yloxy)benzoate (10A-1)

To a solution of methyl 5 -hydroxy -2 -methylbenzoate (150 mg, 903 pmol, 1.0 eq) and 3- iodooxetane (199 mg, 1.08 mmol, 1.2 eq) in DMF (4 mL) was added CS2CO3 (588 mg, 1.81 mmol, 2.0 eq). The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 2-methyl-5-(oxetan-3-yloxy) benzoate (1.10 g), which was used in the next step without any further purification.

Step 2: 2-Methyl-5-(oxetan-3-yloxy)benzoic acid (10A-2)

To a solution of methyl 2-methyl-5-(oxetan-3-yloxy)benzoate (80.0 mg, 360 pmol, 1.0 eq) in a mixture of THF (3.0 mL) and H2O (1.0 mL) was added LiOH.LEO (45.3 mg, 1.08 mmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material completely consumed, and desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with petroleum ether (3.0 mL x 2). The aqueous phase was adjusted to pH 4 with HC1 (1 M aqueous) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-methyl-5-(oxetan-3-yloxy)benzoic acid (60.0 mg) as a colorless oil, which was used in the next step without any further purification. M + H ⁺ = 209.2 (LCMS).

Step 3: (l?)-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-(oxetan-3-ylox y)benzamide (Compo und 152)

To a solution of 2-methyl-5-(oxetan-3-yloxy)benzoic acid (50.0 mg, 240 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (41.1 mg, 240 pmol, 38.4 pL, 1.0 eq) in DCM (3.0 mL) were added TEA (48.6 mg, 480 pmol, 2.0 eq), EDCI (55.2 mg, 288 pmol, 1.2 eq) and HOBt (38.9 mg, 288 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (EtOAc/petroleum ether = 2/1) to give (A)-2-methyl-A-(l-(naphthalen-l-yl)ethyl)-5-(oxetan-3-yloxy) benzamide (12.2 mg, 33.2 pmol) as a white solid. M + H ⁺ = 362.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.22 (d, J = 8.4 Hz, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.84 (d, J= 8.1 Hz, 1H), 7.66 - 7.43 (m, 4H), 7.10 - 7.04 (m, 1H), 6.66 - 6.62 (m, 1H), 6.62 - 6.56 (m, 1H), 6.18 - 6.06 (m, 1H), 5.98 - 5.88 (m, 1H), 5.16 - 5.05 (m, 1H), 4.93 - 4.82 (m, 2H), 4.72 - 4.62 (m, 2H), 2.40 - 2.31 (m, 3H), 1.84 - 1.75 (m, 3H).

Example 11 : (l?)-5-(Azetidin-3-yloxy)-2-methyl-/V-(l-(naphthalen-l-yl)et hyl)benzamide (Compound 141)

Compound 141

Step 1: tert- Butyl 3-(3-(methoxycarbonyl)-4-methylphenoxy)azetidine-l-carboxyla te (11A-1)

To a stirred solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) in DMF (10 mL) were added CS2CO3 (1.18 g, 3.61 mmol, 2.0 eq) and tert-butyl 3-iodoazetidine- 1-carboxylate (613 mg, 2.17 mmol, 1.2 eq). The mixture was stirred at 110 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl 3-(3-(methoxycarbonyl)-4- methylphenoxy)azetidine- 1-carboxylate (450 mg, 1.40 mmol, 78% yield) was obtained as a colorless oil. 'H NMR (400 MHz, CD ₃ C1) 8 7.29 (s, 1H), 7.19 - 7.17 (d, J= 8.4 Hz, 1H), 6.87 - 6.84 (m, 1H), 4.93 - 4.89 (m, 1H), 4.35 - 4.31 (m, 2H), 4.03 - 4.01 (m, 2H), 3.91 (s, 3H), 2.54 (s, 3H), 1.47 (s, 9H).

Step 2: 5-((l-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)-2-methylbenzoi c acid (11A-2)

To a stirred solution of tert-butyl 3 -(3 -(methoxy carbonyl)-4-methylphenoxy)azeti dine- 1- carboxylate (200 mg, 622 pmol, 1.0 eq) in a mixture of THF (5.0 mL) and H2O (1.0 mL) was added LiOH.H2O (52.2 mg, 1.24 mmol, 2.0 eq) at 20 °C for 2 h then at 70 °C for another 14 h. Another 10.0 mg of LiOH.H2O was added and the reaction mixture was stirred at 70 °C for another 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and washed with TBME (5.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with DCM (3.0 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product 5-((l-(tert-butoxy carbonyl)azetidin-3-yl)oxy)-2-methylbenzoic acid (150 mg, 488 pmol, 78% yield) as a colorless oil, which was used in the next step without any further purification. M - H“ = 306.1 (LCMS).

Step 3: (l?)-tert-Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy)a zeti dine-l-carboxylate (11A-3)

To a mixture of 5 - (l-tert-butoxycarbonylazetidin-3-yl) oxy-2-methyl-benzoic acid (90.0 mg, 292 pmol, 1.0 eq) in DCM (5.0 mL) was added (U?)-l-(l-naphthyl)ethanamine (55.2 mg, 322 pmol, 51.6 pL, 1.1 eq), followed by TEA (88.9 mg, 879 pmol, 122 pL, 3.0 eq) and T3P (280 mg, 439 pmol, 261 pL, 50% in EtOAc, 1.5 eq). The resulting mixture was stirred at 20 °C for 1.5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (3.0 mL). The product was extracted with DCM (8.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. (7?)-tert-Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy)a zetidine-l-carboxylate (120 mg, 261 pmol, 89% yield) was obtained as a colorless oil. M + H ⁺ = 461.4 (LCMS). Step 4: (l?)-tert-Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy)a zeti dine-l-carboxylate (Compound 141)

To a mixture of (/ )-/c77-butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy) azeti dine-l-carboxylate (50.0 mg, 109 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtO Ac (4 M, 10 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-tert-Butyl3-(4-methyl-3-((l -(naphthal en-l-yl)ethyl)carbamoyl)phenoxy)azeti dine-l- carboxylate (14.0 mg, 38.8 pmol, 36% yield) was obtained as a white solid. M + H ⁺ = 361.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.27 - 8.21 (m, 1H), 7.94 - 7.89 (m, 1H), 7.85 - 7.78 (m, 1H), 7.64 - 7.45 (m, 4H), 7.20 - 7.16 (m, 1H), 6.84 - 6.79 (m, 1H), 6.77 - 6.71 (m, 1H), 6.10 - 6.00 (m, 1H), 5.15 - 5.06 (m, 1H), 4.55 - 4.43 (m, 2H), 4.13 - 4.04 (m, 2H), 2.31 - 2.20 (m, 3H), 1.76 - 1.65 (m, 3H).

Example 12: (/?)-/c/7-Butyl 4-(4-methyl-3-((l-(naphthalen-l- yl)ethyl)carbamoyl)phenoxy)piperidine-l-carboxylate (Compound 164)

12A-2 Compound 164

Step 1: tert-Butyl 4-(3-(methoxycarbonyl)-4-methylphenoxy)piperidine-l-carboxyl ate (12A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (200 mg, 1.20 mmol, 1.0 eq) in THF (20 mL) were added tert-butyl 4-hydroxypiperidine-l -carboxylate (266 mg, 1.32 mmol, 1.1 eq) and PPhs (379 mg, 1.44 mmol, 1.2 eq), followed by DIAD (316 mg, 1.56 mmol, 304 pL, 1.3 eq) at 0 °C under a N2 atomsphere. The resulting mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. /crt-Butyl 4-(3-(m ethoxy carbonyl)-4-methyl phenoxy) piperidine- 1 -carboxylate (200 mg, 572 pmol, 48% yield) was obtained as a yellow oil. ^T H NMR (400 MHz, CDCI3) 8 7.48 - 7.45 (m, 1H), 7.18 - 7.12 (m, 1H), 7.00 - 6.95 (m, 1H), 4.50 - 4.44 (m, 1H), 3.92 - 3.87 (m, 3H), 3.74 - 3.65 (m, 2H), 3.40 - 3.31 (m, 2H), 2.55 - 2.50 (m, 3H), 1.96 - 1.86 (m, 2H), 1.80 - 1.69 (m, 2H), 1.51 - 1.46 (m, 9H).

Step 2: 5-((l-(tert-Butoxycarbonyl)piperidin-4-yl)oxy)-2-methylbenzo ic acid (12A-2)

To a stirred solution of tert-butyl 4-(3-methoxycarbonyl-4-methyl-phenoxy)piperidine-l- carboxylate (120 mg, 343 pmol, 1.0 eq) in a mixture of THF (6.0 mL) and H2O (2.0 mL) was added LiOH.H2O (36.0 mg, 859 pmol, 2.5 eq) at 20 °C for 8 h and then at 70 °C for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with MTBE (5.0 mL x 3). The aqueous was acidified to pH 5 with HC1 (1 M aqueous) and the product was extracted with DCM (5.0 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-methylbenzo ic acid (85.0 mg) as a colorless oil, which was used in the next step without any further purification. M - H“ = 334.2 (LCMS).

Step 3: (R)-tert-Butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy) piperidine-l-carboxylate (Compound 164)

To a suspension of (U?)-l-(l-naphthyl)ethanamine (65.1 mg, 380 pmol, 60.8 pL, 1.5 eq) in DCM (5.0 mL) were added 5-[(l-tert-butoxycarbonyl-4-piperidyl)oxy]-2-methyl-benzoic acid (85.0 mg, 253 pmol, 1.0 eq) and TEA (76.9 mg, 760 pmol, 106 pL, 3.0 eq), followed by EDCI (72.9 mg, 380 pmol, 1.5 eq) and HOBt (51.4 mg, 380 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, Ry = 0.5). (A)-/er/-Butyl 4-(4-methyl-3-((l -(naphthal en-1- yl)ethyl)carbamoyl)phenoxy)piperidine-l -carboxylate (110 mg, 218 pmol, 86% yield) was obtained as a white solid. M - 56+ H ⁺ = 433.1; 'H NMR (400 MHz, CDCh) 6 8.26 - 8.22 (m, 1H), 7.91 - 7.88 (m, 1H), 7.86 - 7.81 (m, 1H), 7.60 (s, 5H), 7.10 - 7.06 (m, 1H), 6.85 (s, 1H), 4.39 - 4.33 (m, 1H), 3.71 - 3.62 (m, 2H), 3.31 - 3.23 (m, 2H), 2.36 - 2.33 (m, 3H), 1.83 - 1.78 (m, 4H), 1.47 - 1.46 (m, 9H), 1.31 - 1.20 (m, 3H).

Example 13: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-(piperidin-4-y loxy)benzamide

(Compound 162)

Step 1

Compound 164 Compound 162

Step 1 : (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-(piperidin-4-y loxy)benzamide (Compound 162)

To a mixture of (/?)-/c/7-butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenoxy) piperidine- 1 -carboxylate (80.0 mg, 164 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCI/EtOAc (4 M, 40.9 pL). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated at 30 °C under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-2-Methyl-A-(l -(naphthal en-l-yl)ethyl)-5-(piperidin-4-yloxy) benzamide (40.0 mg, 103 pmol, 63% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 389.1; 'H NMR (400 MHz, CD ₃ OD) 8 8.29 - 8.13 (m, 1H), 7.92 - 7.83 (m, 1H), 7.82 - 7.73 (m, 1H), 7.62 - 7.57 (m, 1H), 7.57 - 7.53 (m, 1H), 7.53 - 7.49 (m, 1H), 7.49 - 7.45 (m, 1H), 7.45 - 7.42 (m, 1H), 7.15 - 7.09 (m, 1H), 6.97 - 6.90 (m, 1H), 6.87 - 6.84 (m, 1H), 6.04 - 5.94 (m, 1H), 4.64 - 4.56 (m, 1H), 3.29 (br d, J= 3.2 Hz, 2H), 3.19 - 3.09 (m, 2H), 2.24 - 2.20 (m, 3H), 2.14 - 2.01 (m, 2H), 2.01 - 1.83 (m, 2H), 1.69 - 1.62 (m, 3H). Example 14: (l?)-2-Methyl-5-(methylsulfonamido)-/V-(l-(naphthalen-l- yl)ethyl)benzamide (Compound 100) ep

14A-3 Compound 100

Step 1: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-nitrobenzamide (14A-2)

To a solution of 2-methyl-5-nitrobenzoic acid (1.00 g, 5.52 mmol, 1.0 eq) and (R)-l- (naphthalen-l-yl)ethanamine (940 mg, 5.52 mmol, 880 pL, 1.0 eq) in DCM (20 mL) were added TEA (1.12 g, 11.0 mmol, 1.54 mL, 2.0 eq) and T3P (10.5 g, 16.6 mmol, 10.0 mL, 50% in EtOAc, 3.0 eq) at 0 °C. The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (7?)-2-Methyl-7V-(l-(naphthalen-l-yl)ethyl)-5- nitrobenzamide (1.50 g, 4.49 mmol, 81% yield) as a white solid. M + H ⁺ = 335.2 (LCMS).

Step 2: (l?)-5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzamide (14A-3)

To a solution of (R)-2-methyl-A-(l -(naphthal en-l-yl)ethyl)-5 -nitrobenzamide (1.00 g, 2.99 mmol, 1.0 eq), 10% palladium on carbon (200 mg) in a mixture of EtOAc (20 mL) and MeOH (20 mL) was degassed and purged with EE for three times, then the mixture was stirred at 20 °C for 16 h under EE (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (5.0 mL x 3). The combined filtrates were concentrated under vacuum to give (A)-5-amino-2-methyl-7V-(l-(naphthalen-l- yl)ethyl)benzamide (800 mg, 2.58 mmol, 86% yield) as a white solid. M + H ⁺ = 305.2 (LCMS).

Step 3: (l?)-2-Methyl-5-(methylsulfonamido)-/V-(l-(naphthalen-l-yl)e thyl)benzamide (Co mpound 100)

To a solution of (A)-5-amino-2-methyl-7V-(l -(naphthal en-l-yl)ethyl)benzamide (100 mg, 329 pmol, 1.0 eq) in Py (2.0 mL) was added MsCl (41.4 mg, 361 pmol, 28 pL, 1.1 eq) at 0 °C .The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (A)-2-Methyl-5-(methylsulfonamido)-7V-(l- (naphthalen-l-yl)ethyl)benzamide (38.5 mg, 100 pmol, 30% yield) as a white solid. M + H ⁺ = 383.1 (LCMS); ^X H NMR (400 MHz, CDCh) 8 8.21 (d, J= 8.5 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.61 - 7.42 (m, 4H), 7.17 - 7.09 (m, 3H), 6.80 (br s, 1H), 6.17 - 6.06 (m, 2H), 2.88 (s, 3H), 2.37 (s, 3H), 1.83 - 1.73 (m, 3H)

Example 15: (7?)-5-((LH-Pyrazol-4-yl)amino)-2-methyl-/V-( l-(naphthalen-l- yl)ethyl)benzamide (Compound 121) p

15A-3 Compound 121 Step 1: 2-Methyl-5-((l-(tetrahydro-2Z/-pyran-2-yl)-LH-pyrazol-4-yl)a mino)benzoic acid (15A-2)

To a stirred solution of methyl 5 -amino-2-m ethylbenzoate (50.0 mg, 303 pmol, 1.0 eq) and 4- bromo-l-(tetrahydro-2J/-pyran-2-yl)-lJ/-pyrazole (83.9 mg, 363 pmol, 1.2 eq) in dioxane (2.0 mL) were added /BuXphos Pd G3 (24.0 mg, 30.3 pmol, 0.1 eq) and sodium Lbutanolate (145 mg, 1.51 mmol, 5.0 eq) under a N2 atmosphere. The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and washed with MTBE (3.0 mL x 2). The aqueous was acidified to pH 6 with HC1 (1 M aqueous) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 2-methyl-5-((l- (tetrahydro-2J/-pyran-2-yl)-U/-pyrazol-4-yl)amino)benzoic acid (100 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 302.3 (LCMS).

Step 2: 2-Methyl-\-((/?)-l-(naplithalen-l-yl)etliyl)-5-(( l-(tetrahydro-2//-pyran-2-yl)-l//- pyrazol-4-yl)amino)benzamide (15A-3)

To a stirred solution of 2-methyl-5-(( l -(tetrahydro-27/-pyran-2-yl)- l7/-pyrazol-4-yl)amino) benzoic acid (130 mg, 431 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (111 mg, 647 pmol, 104 pL, 1.5 eq) in DCM (5 mL) were added EDCI (124 mg, 647 pmol, 1.5 eq) and HOBt (87.4 mg, 647 pmol, 1.5 eq), followed by TEA (131 mg, 1.29 mmol, 180 pL, 3.0 eq). The mixture was stirred at 20 °C for 2 h. TLC indicated that the starting material was completely consumed. The mixture was poured into water (5.0 mL) and extratced with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.2). 2-Methyl-7V-((/?)-l-(naphthalen-l-yl)ethyl)-5-((l-(tetrahydr o-2J/-pyran-2-yl)- U/-pyrazol-4-yl)amino)benzamide (90.0 mg, 198 pmol, 46% yield) was obtained as a yellow oil.

Step 3: (/?)-5-(( l//-I’yrazol-4-yl)aniino)-2-niethyl-\-( l-(napht halen-l-yl (ethyl (benzamide (Compound 121)

To a stirred solution of 2-methyl-M((/?)- l -(naphthalen- l -yl)ethyl)-5-(( l -(tetrahydro-27/- pyran-2-yl)-lJ/-pyrazol-4-yl)amino)benzamide (90.0 mg, 198 pmol, 1.0 eq) in MeOH (2.0 mL) was added 4-methylbenzenesulfonic acid hydrate (113 mg, 594 pmol, 3.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 40 mm, 10 pm); flow rate: 60 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B : acetonitrile). ( *) -5 -((1 //-Pyrazol -4-yl )ami no)-2-methyl -A-( 1 -(naphthal en- 1 - yl)ethyl)benzamide (30.0 mg, 80.7 pmol, 41% yield) was obtained as a white solid. M + H ⁺ = 371.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 12.57 (br s, 1H), 8.83 (d, J= 8.1 Hz, 1H), 8.23 (d, J= 8.3 Hz, 1H), 8.01 - 7.92 (m, 1H), 7.84 (d, J= 8.1 Hz, 1H), 7.68 - 7.45 (m, 6H), 7.37 (br s, 1H), 6.96 (d, J= 8.3 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 2.4, 8.2 Hz, 1H), 5.89 (quin, J= 7.1 Hz, 1H), 2.14 (s, 3H), 1.55 (d, J= 6.8 Hz, 3H).

Example 16: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-(thiazol-2-yla mino)benzamide (Compound 107)

Step 1

14A-3 Compound 107

Step 1: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-(thiazol-2-yla mino)benzamide (Co mpound 107)

To a mixture of (A)-5-amino-2-methyl-A-(l-(naphthalen-l-yl)ethyl)benzamide (100 mg, 329 pmol, 1.5 eq) and 2-chlorothiazole (26.2 mg, 219 pmol, 1.0 eq) in propan-2-ol (2.0 mL) was added TSOH.H2O (62.5 mg, 329 pmol, 1.5 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: water (10 mM bflLHCOs), mobile phase B: acetonitrile). (R)- 2-Methyl-A-(l-(naphthalen-l-yl)ethyl)-5-(thiazol-2-ylamino)b enzamide (16.8 mg, 43.4 pmol, 20% yield) was as an off-white solid. M + H ⁺ = 388.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.25 (d, J= 8.3 Hz, 1H), 7.90 (d, J= 8.2 Hz, 1H), 7.83 (d, J= 8.2 Hz, 1H), 7.62 - 7.43 (m, 5H), 7.33 - 7.27 (m, 2H), 7.20 (d, J = 3.5 Hz, 1H), 7.16 (d, J= 8.2 Hz, 1H), 6.59 (d, J= 3.7 Hz, 1H), 6.19 - 6.10 (m, 1H), 6.02 (br d, J= 8.4 Hz, 1H), 2.40 (s, 3H), 1.82 (d, J= 6.7 Hz, 3H).

Example 17: (7?)-5-((2-Methoxypyridin-3-yl)amino)-2-methyl-/V-(l-(naphth alen-l- yl)ethyl) benzamide (Compound 115)

17A-2 Step 3

Compound 115

Step 1: Methyl 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoate (17A-1)

A mixture of methyl 5-amino-2-methylbenzoate (400 mg, 2.42 mmol, 1.2 eq), 3-bromo-2- methoxypyridine (379 mg, 2.02 mmol, 1.0 eq) and CS2CO3 (1.31 g, 4.04 mmol, 2.0 eq) in dioxane (6.0 mL) was degassed and purged with N2 three times. To the mixture were added Pd2(dba)3 (185 mg, 202 pmol, 0.1 eq) and Xantphos (234 mg, 404 pmol, 0.2 eq) at 20 °C. The resulting mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. Methyl 5-((2- methoxypyridin-3-yl)amino)-2-methylbenzoate (400 mg, 1.47 mmol, 73% yield) was obtained as a yellow solid. M + H ⁺ = 273.3 (LCMS). Step 2: 5-((2-Methoxypyridin-3-yl)amino)-2-methylbenzoic acid (17A-2)

To a solution of methyl 5-((2-methoxypyridin-3-yl)amino)-2-methylbenzoate (400 mg, 1.47 mmol, 1.0 eq) in a mixture of MeOH (9.0 mL) and THF (27 mL) was added LiOH.ThO (185 mg, 4.41 mmol, 3.0 eq). The mixture was stirred at 70 °C for 5 h. TLC indicated that most of the starting material still remained. The mixture was allowed to cool to room temperature and NaOH (58.75 mg, 1.47 mmol, 1.0 eq) was added. The resulting mixture was stirred at 70 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (18 mL) and the mixture was washed with petroleum ether (6.0 mL x 5). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-((2-methoxypyridin-3-yl)amino)-2- m ethylbenzoic acid (210 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 259.3 (LCMS).

Step 3: (l?)-5-((2-Methoxypyridin-3-yl)amino)-2-methyl-/V-(l-(naphth alen-l-yl)ethyl) benzamide (Compound 115)

To a solution of (7?)-l-(naphthalen-l-yl)ethanamine (66.3 mg, 387 pmol, 1.0 eq) and 5-((2- methoxypyridin-3-yl)amino)-2-methylbenzoic acid (100 mg, 387 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (206 mg, 2.03 mmol, 283 pL, 3.0 eq), EDCI (325 mg, 1.69 mmol, 2.5 eq) and HOBt (229 mg, 1.69 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.6). (7?)-5-((2-Methoxypyridin-3-yl)amino)-2-methyl-7V-(l-(naphth alen-l-yl)ethyl) benzamide (90.0 mg, 219 pmol, 57% yield) was obtained as a yellow solid. M + H ⁺ = 412.2 (LCMS); ^X H NMR (400 MHz, CDCh) 8 8.28 - 8.21(m, 1H), 7.92 - 7.81 (m, 2H), 7.69 - 7.63 (m, 1H), 7.61 - 7.42 (m, 4H), 7.30 - 7.15 (m, 1H), 7.20 - 7.15 (m, 1H), 7.13 - 7.06 (m, 2H), 6.78 - 5.72 (m, 1H), 6.19 -6.12 (m, 1H), 6.01 - 5.92 (m, 2H), 4.03 (s, 3H), 2.38 (s, 3H), 1.77 - 1.84 (m, 3H). Example 18: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-((2-oxo-l,2-di hydropyridin-3- yl)amino)benzamide (Compound 119)

Compound 115 Compound 119

Step 1: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-((2-oxo-l,2-di hydropyridin-3- yl)amino)benzamide (Compound 119)

A mixture of (7?)-5-((2-methoxypyridin-3-yl)amino)-2-methyl-7V-(l-(naphth alen-l-yl)ethyl) benzamide (45 mg, 109 pmol, 1.0 eq) in DCM (5.0 mL) was degassed and purged with N2 three times. To the mixture was added BBr ₃ (219 mg, 875 pmol, 8.0 eq) in DCM (2 mL) at - 78°C. The mixture was stirred at 20°C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue. The residue was diluted with MeOH (2 mL) and basified to pH 8 using NH3.H2O (37% aqueous). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (7?)-2-Methyl-7V-(l -(naphthal en-1- yl)ethyl)-5-((2-oxo-l,2-dihydropyridin-3-yl)amino)benzamide (11.5 mg, 28.8 pmol, 26% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 398.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.32 - 8.19 (m, 1H), 7.98 - 7.77 (m, 2H), 7.69 - 7.43 (m, 4H), 7.25 - 7.10 (m, 4H), 6.98 - 6.78 (m, 1H), 6.32 - 6.21 (m, 1H), 6.13 - 5.93 (m, 1H), 2.34 - 2.24 (m, 3H), 1.79 - 1.59 (m, 3H).

Example 19: 5-(/V-(l-Amino-3-hydroxypropan-2-yl)acetamido)-2-methyl-/V-( (l?)-l- (naphthalen-l-yl)ethyl)benzamide (Compound 165)

Step 1

1A-3 19A-1

Compound 165

Step 1: (R)-tert-butyl 3-((4-methyl-3-((l-(naphthalen-l-yl)ethyl)carbamoyl)phenyl) amino)azetidine-l-carboxylate (19A-1)

To a solution of 5-(( l -(/c/7-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (100 mg, 326 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (61.5 mg, 359 pmol, 1.1 eq) in DCM (5.0 mL) were added TEA (99.1 mg, 979 pmol, 136 pL, 3.0 eq), EDCI (75.1 mg, 392 pmol, 1.2 eq) and HOBt (52.9 mg, 392 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude product (R)-tert-butyl 3-((4-methyl-3-((l-(naphthalen-l- yl)ethyl)carbamoyl)phenyl)amino)azetidine-l -carboxylate (150 mg), which was used in the next step without any further purification. M + H ⁺ = 460.4 (LCMS).

Step 2: (/? Her/- Butyl 3-( \-(4-ni el hy l-3-(( 1 -( 11a ph t halen- 1 -y l ) ethyl) carbamoyl) phenyl) acetamido)azetidine-l-carboxylate (19A-2)

To a solution of (/?)-/c77-butyl 3 -((4-methyl-3-((l -(naphthal en-l-yl) ethyl) carbamoyl) phenyl) amino)azetidine-l -carboxylate (40.0 mg, 87.0 pmol, 1.0 eq) and acetyl chloride (7.52 mg, 95.7 pmol, 6.83 pL, 1.1 eq) in DCM (1.0 mL) was added pyridine (6.88 mg, 87.0 pmol, 7.03 pL, 1.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (1.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (R)-tert- butyl 3-CV-(4-methyl-3-(( l -(naphthal en-l-yl) ethyl) carbamoyl) phenyl) acetamido)azetidine- 1-carboxylate (38.2 mg), which was used in the next step without any further purification. M + H ⁺ = 502.4 (LCMS).

Step 3: 5-(/V-(l-Amino-3-hydroxypropan-2-yl)acetamido)-2-methyl-/V-( (l?)-l-(naphthale n-l-yl)ethyl)benzamide (Compound 165)

To a solution of (/ )-/c/7-butyl 3-(7V-(4-methyl-3-((l-(naphthalen-l-yl) ethyl) carbamoyl) phenyl) acetamido)azetidine- 1-carboxylate (10.0 mg, 19.9 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (154 mg, 1.35 mmol, 100 pL). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (1.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(7V-(l-Amino-3-hydroxypropan-2- yl)acetamido)-2-methyl-A-((R)-l-(naphthalen-l-yl)ethyl)benza mide (3.00 mg, 6.58 pmol, 33% yield, HC1 salt) was obtained as a yellow gum. M + H ⁺ = 420.1 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 8 8.25 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.81 (d, J= 8.4 Hz, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.60 - 7.42 (m, 3H), 7.03 (d, J = 8.2 Hz, 1H), 6.79 - 6.66 (m, 2H), 6.05 (q, J= 7.3 Hz, 1H), 4.20 (dd, J= 4.0, 11.2 Hz, 1H), 4.04 - 3.89 (m, 2H), 3.23 (br dd, J= 3.5, 13.1 Hz, 1H), 3.04 - 2.90 (m, 1H), 2.22 (s, 3H), 2.01 (d, = 4.4 Hz, 3H), 1.70 (dd, J = 2.8, 6.9 Hz, 3H).

Example 20: (7?)-5-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-lH-indole-6-carb oxamide

(Compound 153) ,

Step 1

Step 2

15A-1 20A-1

Step 1: Methyl 5-amino-4-iodo-2-methylbenzoate (20A-1)

To a solution of methyl 5-amino-2-methylbenzoate (15.0 g, 90.8 mmol, 1.0 eq) in AcOH (80 mL) was added NIS (22.5 g, 99.9 mmol, 1.1 eq). The mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was consumed. The reaction mixture was poured into H2O (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. Methyl 5-amino-4-iodo-2-methylbenzoate (2.40 g, 9.18 mmol, 89% yield) was obtained as a brown oil. M + H ⁺ = 293.0 (LCMS).

Step 2: Methyl 5-amino-2-methyl-4-((trimethylsilyl)ethynyl)benzoate (20A-2)

A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (3.00 g, 10.3 mmol, 1.0 eq), TEA (2.09 g, 20.6 mmol, 2.87 mL, 2.0 eq), Pd(PPh ₃ ) ₂ C12 (217 mg, 309 pmol, 0.03 eq), Cui (19.6 mg, 103 pmol, 0.01 eq) and ethynyltrimethyl silane (1.52 g, 15.5 mmol, 2.14 mL, 1.5 eq) in a mixture of toluene (80 mL) and H2O (40 mL) was degassed and purged with N2 for three times. The resulting mixture was stirred at 70 °C for 3 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. Methyl 5-amino-2-methyl-4- ((trimethylsilyl)ethynyl)benzoate (2.40 g, 9.18 mmol, 89% yield) was obtained as a brown oil. M + H ⁺ = 262.1 (LCMS). Step 3: Methyl 5-methyl-l//-indole-6-carboxylate (20A-3)

A mixture of methyl 5-amino-2-methyl-4-((trimethylsilyl)ethynyl)benzoate (1.00 g, 3.83 mmol, 1.0 eq), Cu(OAc)2 (1.39 g, 7.65 mmol, 2.0 eq) in DCE (50 mL) was degassed and purged with N2 for three times, and then the mixture was stirred at 130 °C for 1 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. Methyl 5-methyl- lJT-indole-6-carboxylate (500 mg, 2.64 mmol, 18% yield) was obtained as a yellow solid. M + H ⁺ = 190.1 (LCMS).

Step 4: 5-Methyl-l//-indole-6-carboxylic acid (20A-4)

To a solution of methyl 5-methyl-lJ/-indole-6-carboxylate (40.0 mg, 211 pmol, 1.0 eq) in a mixture of EtOH (2.0 mL) and THF (2.0 mL) was added NaOH (2 M aqueous, 529 pL, 5.0 eq). The mixture was stirred at 20 °C for 30 min. The mixture was stirred at 80 °C for 3 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and washed with MTBE (3.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 5-methyl-lJT- indole-6-carboxylic acid (30.0 mg, 171 pmol, 81% yield) as a white solid, which was used in the next step without any further purification.

Step 5: (/ )-5- I el Iiy l- X -( 1 -( na ph t Iialen- 1 -y 1 )et hy 1 )- 1 //-indole-6-ca rboxa ni ide (Compoun d 153)

To a solution of 5-methyl-lJ/-indole-6-carboxylic acid (30.0 mg, 171 pmol, 1.0 eq) and ( ?)-l- (naphthalen-l-yl)ethanamine (35.2 mg, 206 pmol, 33.0 pL, 1.2 eq) in DCM (2.0 mL) were added EDCI (39.4 mg, 206 pmol, 1.2 eq), HOBt (30.1 mg, 223 pmol, 1.3 eq) and TEA (52.0 mg, 514 pmol, 72.0 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1 : 1, R/= 0.6). (7?)-5-Methyl-7V-(l-(naphthalen-l-yl)ethyl)-U/-indole-6-carb oxamide (13.2 mg, 35.8 pmol, 21% yield) was obtained as a yellow solid. M + H ⁺ = 329.0 (LCMS); ¹ HNMR (400 MHz, CDCh) 8 8.29 (d, J = 8.5 Hz, 1H), 8.18 - 8.09 (m, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.83 (d, J= 8.1 Hz, 1H), 7.62 - 7.45 (m, 4H), 7.43 (s, 1H), 7.38 - 7.33 (m, 1H), 7.22 - 7.17 (m, 1H), 6.49 - 6.39 (m, 1H), 6.22 - 6.13 (m, 1H), 6.02 (br d, J= 8.4 Hz, 1H), 2.53 (s, 3H), 1.82

(d, J = 6.8 Hz, 3H).

Example 21: (l?)-tert-Butyl((5-methyl-6-((l-(naphthalen-l-yl)ethyl)carba moyl)-lH- indol-2-yl)methyl)carbamate (Compound 189)

Step 4

Compound 189

Step 1: Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)prop-l-yn-l-yl)-2-m ethyl benzoate (21A-1)

To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (1.00 g, 3.44 mmol, 1.0 eq), tert- butyl prop-2-yn-l-ylcarbamate (533 mg, 3.44 mmol, 1.0 eq), Cui (262 mg, 1.37 mmol, 0.4 eq) and Pd(PPh3)2Ch (482 mg, 687 pmol, 0.2 eq) was added TEA (10 mL) under a N2 atmosphere. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (20 mL) and extracted with DCM (15 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-amino-4-(3-((/c/7-butoxycarbonyl)amino)prop- l -yn- l -yl)-2 -methyl benzoate (1.50 g, 4.71 mmol, 51% yield) was obtained as a white solid. M + H ⁺ = 319.2 (LCMS); ¹ HNMR (400 MHz, CDCh) 6 7.13 - 7.10 (m, 1H), 4.86 - 4.78 (m, 1H), 4.23 - 4.17 (m, 2H), 3.89 - 3.85 (m, 3H),

2.45 - 2.40 (m, 3H), 1.48 (s, 9H).

Step 2: Methyl 2-(((/c/7-biitoxyc:irboiiyl):iiiiino)nietliyl)-5-nietliyl-l //-indole-6- carboxylate (21A-2)

To a solution of methyl 5-amino-4-(3-((/er/-butoxycarbonyl)amino)prop-l-yn-l-yl)-2 -methyl benzoate (500 mg, 1.57 mmol, 1.0 eq) in DCE (30 mL) was added Cu(OAc)2 (713 mg, 3.93 mmol, 2.5 eq). The mixture was stirred at 130 °C for 1 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The hot reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(((/c77-butoxycarbonyl) amino)methyl)-5-methyl- I T/-indole-6-carboxylate (1.10 g,

3.46 mmol, 73% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCh) 8 9.08 - 9.00 (m, 1H), 8.06 - 8.01 (m, 1H), 7.38 (s, 1H), 6.29 - 6.24 (m, 1H), 4.40 - 4.36 (m, 2H), 3.91 - 3.89 (m, 3H), 2.67 (s, 3H), 1.49 (s, 9H).

Step 3: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methyl-l //-indole-6-carboxylic acid (21A-3)

To a solution of methyl 2-(((ter/-butoxycarbonyl)amino)methyl)-5-methyl-UT-indole-6- carboxylate (800 mg, 2.51 mmol, 1.0 eq) in a mixture of THF (10 mL) and MeOH (3.0 mL) was added NaOH (2 M in aqueous, 8.0 mL, 6.4 eq). The mixture was stirred at 20 °C for 1 h and then was stirred at 60 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and washed with MTBE (10 mL x 2). The aqueous was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with DCM (15 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 2-(((/c77- butoxycarbonyl) amino)methyl)-5-methyl-U/-indole-6-carboxylic acid (750 mg, 1.97 mmol, 78% yield) as a red solid, which was used in the next step without any further purification. M -H" = 303.1 (LCMS); ^X H NMR (400 MHz, CDCh) 6 8.46 - 8.40 (m, 1H), 7.81 - 7.77 (m, 1H), 6.79 - 6.76 (m, 1H), 6.33 - 6.30 (m, 1H), 3.27 - 3.08 (m, 2H), 2.07 - 2.05 (m, 3H), 1.46 - 1.40 (m, 9H).

Step 4: (l?)-tert-Butyl((5-methyl-6-(( l-(naphthalen-l-yl)ethyl)carbamoyl)-lH-indol-2- yl)methyl)carbamate (Compound 189)

To a solution of (A)-l-(naphthalen-l-yl)ethanamine (186 mg, 1.08 mmol, 174 pL, 1.1 eq) and 2-(((/ert-butoxycarbonyl)amino)methyl)-5-methyl-lZ7-indole-6 -carboxylic acid (300 mg, 986 pmol, 1.0 eq) in DCM (8.0 mL) were added TEA (299 mg, 2.96 mmol, 412 pL, 3.0 eq), EDCI (283 mg, 1.48 mmol, 1.5 eq) and HOBt (200 mg, 1.48 mmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 40 mm, 10 pm); flow rate: 30 mL/min; gradient: 45% - 75% B over 8 min; mobile phase A: 0.04% aqueous NH4HCO3, mobile phase B: acetonitrile). (A)-terLButyl((5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamo yl)-lZ/-indol-2- yl)methyl) carbamate (280 mg, 612 pmol, 62% yield) was obtained as a white solid. M + H ⁺ = 458.1 (LCMS); 'H NMR (400 MHz,CDCh) 8 8.89 - 8.82 (m, 1H), 8.32 - 8.26 (m, 1H), 7.92

- 7.87 (m, 1H), 7.85 - 7.81 (m, 1H), 7.62 - 7.45 (m, 4H), 7.34 - 7.28 (m, 2H), 6.22 - 6.12 (m, 2H), 6.04 - 5.98 (m, 1H), 5.07 - 5.00 (m, 1H), 4.35 - 4.30 (m, 2H), 2.53 - 2.50 (m, 3H), 1.84

- 1.79 (m, 3H), 1.48 - 1.44 (m, 9H).

Example 22: (/?)-2-(Aniinoniethyl)-5-methyl- \-( l-(naphthalen-l-yl)ethyl)-l //-indole-6- carboxamide (Compound 148)

Compound 189 Compound 148

Step 1: (/?)-2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)ethyl)- lE/-indole-6- carboxamide (Compound 148)

To a stirred solution of (R)-terLbutyl ((5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-lZ7- indol-2-yl) methyl)carbamate (220 mg, 481 pmol, 1.0 eq) in DCM (8.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.00 mL, 112 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-2-(Aminomethyl)-5-methyl-7V-(l-(naphthalen-l-yl)ethyl)-l J/-indole-6-carboxamide (150 mg, 420 pmol, 87% yield, TFA salt) was obtained as a pink powder. M + H ⁺ = 358.1 (LCMS); ^X H NMR (400 MHz, CD ₃ OD) 8 8.29 (d, J= 8.6 Hz, 1H), 7.92 (d, J= 7.9 Hz, 1H), 7.82 (d, J=

8.3 Hz, 1H), 7.66 (d, J= 7.1 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.55 - 7.46 (m, 2H), 7.38 (d, J =

5.4 Hz, 2H), 6.51 (s, 1H), 6.14 - 6.01 (m, 1H), 4.26 (s, 2H), 2.42 (s, 3H), 1.73 (d, J= 6.9 Hz, 3H).

Example 23: (l?)-2-(Azetidin-3-yl)-5-methyl-/V-(l-(naphthalen-l-yl)ethyl )-LH-indole-6- carboxamide (Compound 156)

Step 4

23A-4

Compound 156

Step 1: /c/7- Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)azeti dine-l- carboxylate (23 A- 1)

To a stirred solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq) in THF (6.0 mL) were added /c/V-butyl 3 -ethynylazetidine-1 -carboxylate (243 mg, 1.34 mmol, 1.3 eq), Pd(PPh3)4 (23.8 mg, 20.6 pmol, 0.02 eq), Cui (3.93 mg, 20.6 pmol, 0.02 eq) and TEA (261 mg, 2.58 mmol, 358.63 pL, 2.5 eq). Then the mixture was degassed and purged with N2 three times and stirred at 20 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1 : 1, R/= 0.7). /c/V-Butyl 3-((2-amino-4-(methoxycarbonyl)-5- methylphenyl)ethynyl)azetidine-l -carboxylate (300 mg, 871 pmol, 85% yield) was obtained as a yellow oil. ^X H NMR (400 MHz, CDCh) 8 7.29 (s, 1H), 7.14 (s, 1H), 4.17 - 3.99 (m, 5H), 3.87 (s, 3H), 2.44 (s, 3H), 1.49 - 1.41 (m, 9H).

Step 2: Methyl 2-( l-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-lZ/-indole-6- carboxylat e (23A-2)

To a solution of /c/V-butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl) ethynyl) azetidine- 1 -carboxylate (160 mg, 465 pmol, 1.0 eq) in DCE (10 mL) was added Cu(OAc)2 (169 mg, 929 pmol, 2.0 eq). The mixture was stirred at 130 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product methyl 2-(l-(terLbutoxycarbonyl)azetidin-3-yl)-5-methyl-U/-indole-6 - carboxylate (130 mg) as a brown oil, which was used in the next step without any further purification. Step 3: 2-( l-(tert-Butoxycarbonyl)azetidin-3-yl)-5-methyl-lZ/-indole-6- carboxylic acid (23A-3)

To a solution of methyl 2-( l -(/c/7-butoxycarbonyl)azetidin-3-yl)-5-methyl- l7/-indole-6- carboxylate (80.0 mg, 42.1 pmol, 1.0 eq) in a mixture of EtOH (2.0 mL) and THF (2.0 mL) was added NaOH (2 M aqueous, 2.0 mL, 24 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and washed with MTBE (3.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(l-(terLbutoxycarbonyl)azeti din-3 -yl)-5 -methyl- U/-indole-6-carboxylic acid (80.0 mg) as a white oil, which was used in the next step without any further purification. M - 56 + H ⁺ = 275.2 (LCMS).

Step 4: Butyl 3-(5-methyl-6-(( l-(naphthalen-l-yl)ethyl)carbamoyl)-TH-indol-2- yl)azetidine-l-carboxylate (23A-4)

To a solution of 2-(l-(terLbutoxycarbonyl)azetidin-3-yl)-5-methyl-U/-indole-6 -carboxylic acid (100 mg, 303 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (57.0 mg, 333 pmol, 53.3 pL, 1.1 eq) in DCM (4.0 mL) were added EDCI (69.6 mg, 363 pmol, 1.2 eq), HOBt (49.1 mg, 363 pmol, 1.2 eq) and TEA (91.9 mg, 909 pmol, 126 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1 : 1, R/= 0.6). (/ )-/c77-Butyl 3-(5-methyl-6-((l- (naphthalen-l-yl)ethyl)carbamoyl)-U/-indol -2 -yl)azeti dine- 1 -carboxylate (50.0 mg, 103 pmol, 34% yield) was obtained as a white solid. M + H ⁺ = 484.1 (LCMS).

Step 5: (/?)-2-(Azelidin-3-yI)-5-nielIiyl- \-( 1 -( naplitlialen- 1 -yl )elliyl )- 1 //-indole-6-carboxa mide (Compound 156)

To a solution of (/ )-/c 7-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-U/-indol - 2-yl)azetidine-l -carboxylate (50.0 mg, 103 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HClZEtOAc (4 M, 1.0 mL). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-2-(Azetidin-3-yl)-5-methyl-A-(l-(naphthalen-l-yl)ethyl)- l//-indole-6- carboxamide (5.95 mg, 14.2 pmol, 14% yield, HC1 salt) was obtained as a white gum. M + H ⁺ = 384.1 (LCMS); ^X H NMR (400 MHz, CD ₃ OD) 8 8.28 (d, = 8.3 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.82 (d, J= 8.1 Hz, 1H), 7.66 (d, J= 7.0 Hz, 1H), 7.62 - 7.43 (m, 3H), 7.34 (d, J= 13.0 Hz, 2H), 6.46 (s, 1H), 6.07 (q, J= 6.7 Hz, 1H), 4.48 - 4.23 (m, 5H), 2.42 (s, 3H), 1.73 (d, J= 7.0 Hz, 3H).

Example 24: (7?)-2-((Dimethylamino)methyl)-l-(hydroxymethyl)-5-methyl-/V -(l- (n:iplitli:ilen-l-yl)etliyl)-l//-indole-6-carboxaniide (Compound 192)

Compound 148 Compound 192

Step 1: (7?)-2-((Dimethylamino)methyl)-l-(hydroxymethyl)-5-methyl-/V -(l-(naphthalen- l-yl)ethyl)-l//-indole-6-carboxamide (Compound 192)

To a solution of (A)-2-(aminomethyl)-5-methyl-A-(l-(naphthalen-l-yl)ethyl)-l/ /-indole-6- carboxamide (90.0 mg, 252 pmol, 1.0 eq) in MeOH (6.0 mL) was added TEA (50.0 pL), followed by the addition of formaldehyde (2.94 g, 36.3 mmol, 2.70 mL, 37% purity in water, 144 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBH ₃ CN (134 mg, 2.13 mmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (200 x 40 mm, 10 pm); flow rate: 50 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (A)-2-((Dimethylamino)methyl)-l-(hydroxymethyl)-5-methyl- A-(l -(naphthal en-l-yl)ethyl)-l//-indole-6-carboxamide (22.3 mg, 48.1 pmol, 19% yield, FA salt) was obtained as a white solid. M + H ⁺ = 416.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.78 - 8.73 (m, 1H), 8.30 - 8.25 (m, 1H), 8.21 - 8.18 (m, 1H), 7.98 - 7.94 (m, 1H), 7.86 - 7.81 (m, 1H), 7.68 - 7.65 (m, 1H), 7.63 - 7.49 (m, 4H), 7.32 - 7.28 (m, 1H), 6.35 - 6.33 (m, 1H), 5.98 - 5.90 (m, 1H), 5.62 - 5.54 (m, 2H), 3.65 - 3.60 (m, 2H), 2.35 - 2.33 (m, 3H), 2.20 - 2.14 (m, 6H), 1.63 - 1.57 (m, 3H). Example 25: (l?)-5-Methyl-2-(morpholinomethyl)-/V-(l-(naphthalen-l-yl)et hyl)-LH- indole-6-carboxamide (Compound 206)

Compound 206 Step 1: Methyl 4-iodo-2-methyl-5-(2,2,2-trifluoroacetamido)benzoate (25A-1)

To a stirred solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq) and TEA (125 mg, 1.24 mmol, 172 pL, 1.2 eq) in THF (3.5 mL) was added dropwise a solution of TFAA (238 mg, 1.13 mmol, 158 pL, 1.1 eq) in THF (1.0 mL) at -15 °C. The mixture was stirred at the same temperature for 1 h then at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude methyl 4-iodo-2-methyl-5-(2,2,2-trifluoroacetamido)benzoate (400 mg) as a yellow solid which was used the next step without any further purification. M - H“ = 386.0 (LCMS).

Step 2: Methyl 5-methyl-2-(morpholinomethyl)-l//-indole-6-carboxylate (25A-2)

To a mixture of Cui (4.92 mg, 25.8 pmol, 0.04 eq) and Pd(PPh3)2Ch (2.27 mg, 3.23 pmol, 0.005 eq) in DMF (4.5 mL) were added methyl 4-iodo-2-methyl-5-(2,2,2-trifluoroacetamido) benzoate (250 mg, 646 pmol, 1.0 eq), morpholine (113 mg, 1.29 mmol, 114 pL, 2.0 eq), prop- 2-yn-l-ol (54.3 mg, 969 pmol, 57.2 pL, 1.5 eq) and K2CO3 (179 mg, 1.29 mmol, 2.0 eq) followed by DMF (2.0 mL) under a N2 atmosphere. The mixture was stirred at 80 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was cooled to room temperature and diluted with MTBE (10 mL). The resulting mixture was washed with saturated aqueous NaHCCL (5.0 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl

5-methyl-2-(morpholinomethyl)-lZ/-indole-6-carboxylate (170 mg, 85% yield) was obtained as a yellow oil.

Step 3: 5-Methyl-2-(niorpholinoniethyl)- 1 //-indole-6-carboxylic acid (25A-3)

To a solution of methyl 5-methyl-2-(morpholinomethyl)-lZ/-indole-6-carboxylate (170 mg, 590 pmol, 1.0 eq) in a mixture of THF (10 mL) and H2O (2.5 mL) was added NaOH (2 M aqueous, 7.37 mL, 25 eq). The mixture was stirred at 20 °C for 1 h then at 70 °C for 16 h. LCMS indicated that half of the starting material remained and another NaOH (2 M aqueous, 5.0 mL) aqueous was added, and the mixture was stirred another 5 h. The reaction mixture was allowed to cool to room temperature and washed with MTBE (10 mL). The aqueous was acidified to pH 5 with HC1 (I M aqueous) and extracted with DCM (5.0 mL x 5). The organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 5-methyl-2- (morpholinomethyl)-U/-indole-6-carboxylic acid (175 mg, 90% purity) as a brown gum.

Step 4: (/?)-5-Methyl-2-(niorpholinoniethyl)-\-( 1 -(naphthalen- 1 -yl)ethyl)-l //-indole-6- carboxamide (Compound 206)

To a mixture of 5-methyl-2-(morpholinomethyl)-lZ7-indole-6-carboxylic acid (140 mg, 510 pmol, 1.0 eq) and R)-l -(naphthal en-l-yl)ethanamine (87.4 mg, 510 pmol, 81.7 pL, 1.0 eq) in DCM (2.0 mL) were added EDCI (147 mg, 766 pmol, 1.5 eq) and HOBt (103 mg, 766 pmol, 1.5 eq), followed by TEA (155 mg, 1.53 mmol, 213 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20%

- 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (R)-5- Methyl-2-(morpholinomethyl)-A-(l -(naphthal en-l-yl)ethyl)-U/-indole-6-carboxamide (18.4 mg, 43.0 pmol, 8% yield, FA salt) was obtained as a white solid. M + H ⁺ = 428.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 9.43 - 9.32 (m, 1H), 8.41 - 8.37 (m, 1H), 8.32 - 8.25 (m, 1H), 7.93

- 7.87 (m, 1H), 7.86 - 7.79 (m, 1H), 7.63 - 7.44 (m, 4H), 7.37 - 7.31 (m, 2H), 6.35 - 6.27 (m, 1H), 6.22 - 6.12 (m, 1H), 6.07 - 5.96 (m, 1H), 3.84 - 3.69 (m, 6H), 2.63 - 2.49 (m, 7H), 1.82 (d, J = 6.8 Hz, 3H).

Example 26: l-(N:iphth:ilen-l-yl)ethyl)-l//-benzo| |imidazole-6-carbox:imide

(Compound 125)

Step 1

4A-1 Compound 125

Step 1: l-(Naphthalen-l-yl)ethyl)-LH-benzo[J|imidazole-6-carboxamide (Compo und 125)

To a solution of (A)-l-(naphthalen-l-yl)ethanamine (100 mg, 584 pmol, 1.0 eq) and 1H- benzo[ ]imidazole-6-carboxylic acid (94.7 mg, 584 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (118 mg, 1.17 mmol, 163 pL, 2.0 eq), EDCI (134 mg, 701 pmol, 1.2 eq) and HOBT (94.7 mg, 701 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (4.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (A)-A-(l-(Naphthalen-l-yl)ethyl)-17T- benzo[t ]imidazole-6-carboxamide (40.7 mg, 121 pmol, 21% yield) was obtained as a white solid. M + H ⁺ = 316.3 (LCMS); ¹ H NMR (400 MHz, CDCh) 6 8.11 - 8.07 (m, 2H), 7.84 - 7.78 (m, 1H), 7.76 (s, 1H), 7.71 - 7.66 (m, 1H), 7.56 - 7.48 (m, 2H), 7.44 - 7.31 (m, 4H), 7.14 - 7.02 (m, 1H), 6.11 - 6.02 (m, 1H), 1.77 - 1.65 (m, 3H).

Example 27: (l?)-5-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-LH-benzo[J]imida zole-6- carboxamide (Compound 102)

Step 1

27A-1 Compound 102

Step 1: (l?)-5-Methyl-/V-( l-(naphthalen-l-yl)ethyl)-lZ/-benzo[J|imidazole-6-carboxamid e

(Compound 102)

To a mixture of (R)- 1 -(naphthal en-l-yl)ethanamine (40.3 mg, 235 pmol, 37.6 pL, 1.0 eq) and 5-methyl-U/-benzo[J]imidazole-6-carboxylic acid (50.0 mg, 235 pmol, 1.0 eq, HC1 salt) in DCM (3.0 mL) were added EDCI (67.6 mg, 353 pmol, 1.5 eq), HOBt (47.7 mg, 353 pmol, 1.5 eq) and TEA (71.4 mg, 705 pmol, 98.2 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: l 0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (R)- 5-Methyl-A-(l-(naphthalen-l-yl)ethyl)-17/-benzo[ ]imidazole-6-carboxamide (16.1 mg, 48.0 pmol, 20% yield) as a white solid. M + H ⁺ = 330.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 12.42 (s, 1H), 8.95 - 8.78 (m, 1H), 8.26 (d, J= 8.4 Hz, 1H), 8.23 - 8.17 (m, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.84 (br d, J= 7.9 Hz, 1H), 7.69 - 7.49 (m, 4H), 7.47 (s, 1H), 7.34 (s, 1H), 6.00 - 5.86 (m, 1H), 2.44 - 2.36 (m, 3H), 1.60 (d, J= 7.0 Hz, 3H). Example 28: (/ )-2-(Ani inonielIiyl)-5-metIiyl-X-( 1 -( naplillialen- 1 -yl )elhyl )- 1 //- benzo[ |imidazole-6-carboxamide (Compound 128)

Compound 128

Step 1: Methyl 2-methyl-4,5-dinitrobenzoate (28A-2)

To a solution of methyl 2-methyl-4-nitrobenzoate (1.00 g, 5.12 mmol, 1.0 eq) in H2SO4 (10 mL, 98% purity) was added KNO3 (596 mg, 5.89 mmol, 1.2 eq) at 0 °C. The resulting mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into ice water (20 mL) and neutralized with saturated aqueous NaHCO, to adjust the pH to 7. The product was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 2-methyl-4,5-dinitrobenzoate (700 mg, 2.91 mmol, 57% yield) was obtained as a yellow solid. 'H NMR (400 MHz, DMSO- d ₆ ) 6 8.54 (s, 1H), 8.26 (s, 1H), 3.98 - 3.84 (m, 3H), 2.73 - 2.58 (m, 3H). Step 2: Methyl 4,5-diamino-2-methylbenzoate (28A-3)

To a solution of methyl 2-methyl-4,5-dinitrobenzoate (1.50 g, 6.25 mmol, 1.0 eq) and 10% palladium on carbon (100 mg) in a mixture of MeOH (20 mL) and dioxane (20 mL) was degassed and purged with H2 for three times. The mixture was stirred at 20 °C for 16 h under H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (2.0 mL><3). The combined filtrates were concentrated under vacuum to give methyl 4,5-diamino-2-methylbenzoate (600 mg, 3.33 mmol, 53% yield) as a brown solid. M + H ⁺ = 181.2 (LCMS).

Step 3: Methyl 4-amino-5-(2-((terCbutoxycarbonyl)amino)acetamido)-2-methylb enzoate (28A-4)

To a solution of methyl 4,5-diamino-2-methylbenzoate (170 mg, 943 pmol, 1.0 eq) and 2- ((/c/7-butoxycarbonyl)amino)acetic acid (165 mg, 943 pmol, 1.0 eq) in THF (5.0 mL) was added DCC (389 mg, 1.89 mmol, 382 pL, 2.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/50 to 1/5. Methyl 4-amino-

5-(2-((/c77-butoxycarbonyl)amino)acetamido)-2-methylbenzo ate (200 mg, 593 pmol, 63% yield) was obtained as a white solid. M + H ⁺ = 338.3 NMR (400 MHz, CDCL) 8 8.09 (br s, 1H), 7.85 - 7.72 (m, 1H), 6.67 - 6.56 (m, 1H), 5.43 (br s, 1H), 4.01 - 3.91 (m, 2H), 3.84 - 3.73 (m, 3H), 2.56 - 2.37 (m, 3H), 1.54 - 1.43 (m, 9H).

Step 4: Methyl 2-(((/c/7-biitoxyc:irbonyl):iinino)methyl)-5-methyl-l//-benz o| |iniidazole-

6-carboxylate (28A-5)

To a solution of methyl 4-amino-5-(2-((terLbutoxycarbonyl)amino)acetamido)-2- methylbenzoate (100 mg, 296 pmol, 1.0 eq) in AcOH (1.0 mL). The resulting mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product methyl 2-(((/c77-butoxycarbonyl )amino)methyl )-5-methyl- 17/-benzo[t/]imidazole-6- carboxylate (90.0 mg) as a colorless oil, which was used in the next step without any further purification. M + H ⁺ = 320.3 (LCMS).

Step 5: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methyl-lH-benzo[J|i midazole-6-carbo xylic acid (28A-6)

To a solution of methyl 2-(((/c77-butoxy carbonyl)amino)methyl)-5-m ethyl- l//-benzo[t/] imidazole-6-carboxylate (90.0 mg, 282 pmol, 1.0 eq) in a mixture of THF (9.0 mL) and H2O (3.0 mL) was added NaOH (2 M aqueous, 423 pL, 3.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10.0 mL) and washed with MTBE (5.0 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(((terLbutoxycarbonyl)amino)methyl)-5-methyl-U/-benzo[J]im idazole-6- carboxylic acid (90.0 mg) as a colorless oil, which was used in the next step without any further purification. M + H ⁺ = 306.3 (LCMS).

Step 6: (l?)-tert-Butyl ((5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-lH-benzo[ J]i midazol-2-yl)methyl)carbamate (28A-7)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (33.7 mg, 197 pmol, 31.5 pL, 1.0 eq) and 2-(((ter/-butoxycarbonyl)amino)methyl)-5-methyl-lJT-benzo[J] imidazole-6-carboxylic acid (60.0 mg, 197 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (59.7 mg, 590 pmol, 82.1 pL, 3.0 eq), EDCI (45.2 mg, 236 pmol, 1.2 eq) and HOBt (31.9 mg, 236 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1 : 1, R/= 0.5). (/?)-/c/7-Butyl ((5-methyl-6-((l- (naphthalen-l-yl)ethyl)carbamoyl)-U/-benzo[J]imidazol-2-yl)m ethyl) carbamate (40.0 mg, 87.0 pmol, 44% yield) was obtained as a white solid. M + H ⁺ = 459.4 (LCMS).

Step 7: (7?)-2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)ethyl)- lH-benzo[J|imidaz ole-6-carboxamide (Compound 128)

To a stirred solution of (R)-terLbutyl ((5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-UT- benzo[d]imidazol-2-yl)methyl)carbamate (40.0 mg, 87.0 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile).

(A)-2-(Aminomethyl)-5-methyl-A-(l -(naphthalen- 1 -yl)ethyl)- 1 J/-benzo[t ]imidazole-6- carboxamide (9.70 mg, 20.5 pmol, 24% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 359.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.32 (d, J= 8.7 Hz, 1H), 7.95 (d, J= 8.2 Hz, 1H), 7.86 (d, J= 8.3 Hz, 1H), 7.69 (d, J= 13 Hz, 1H), 7.65 - 7.50 (m, 4H), 7.47 (s, 1H), 6.12 (q, J= 6.7 Hz, 1H), 4.42 (s, 2H), 2.50 (s, 3H), 1.77 (d, J= 7.0 Hz, 3H).

Example 29: (l?)-5-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-LH-benzo[J]imida zole-6- carboxamide (Compound 131)

29A-4 29A-5

Compound 131

Step 1: tert- Butyl 3-((2-amino-5-(methoxycarbonyl)-4-methylphenyl)carbamoyl)aze tidin e-l-carboxylate (29A-1)

To a solution of methyl l-(tert-butoxycarbonyl)azetidine-3 -carboxylic acid (223 mg, 1.11 mmol, 1.0 eq) in DMF (1.5 mL) were added pyridine (1.5 mL) and CDI (185 mg, 1.11 mmol, 1.0 eq). The mixture was stirred at 45 °C for 30 min. Then to the mixture was added methyl 4,5-diamino-2-methyl-benzoate (200 mg, 1.11 mmol, 1.0 eq), the resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by lash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 3- ((2-amino-5-(methoxycarbonyl)-4-methylphenyl)carbamoyl)azeti dine-l-carboxylate (400 mg, 1.10 mmol, 50% yield) was obtained as a white solid. M -100 + H ⁺ = 264.3 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.14 (s, 1H), 7.86 - 7.69 (m, 1H), 6.54 (s, 1H), 5.64 (s, 2H), 3.96 (br s, 4H), 3.71 (s, 3H), 3.54 - 3.42 (m, 1H), 2.40 (s, 3H), 1.39 (s, 9H).

Step 2: Methyl 2-( l-(tert-biitoxyc:irbonyl):izetidiii-3-yl)-5-methyl-l//-benzo | |iniidazole- 6-carboxylate (29A-2)

To a solution of tert-butyl 3-((2-amino-5-(methoxycarbonyl)-4-methylphenyl) carbarn oyl)azeti dine- 1 -carboxylate (400 mg, 1.10 mmol, 1.0 eq) in AcOH (0.5 mL) was stirred at 70 °C for 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1 : 1, R/= 0.4). Methyl 2-(l-(ter/-butoxy carbonyl) azetidin-3-yl)-5-methyl-l/7-benzo[t/]imidazole-6-carboxy late (350 mg, 1.01 mmol, 92% yield) was obtained as a yellow oil. M + H ⁺ = 346.3 (LCMS).

Step 3: Methyl 2-(l-(tert-butoxycarbonyl)azetidin-3-yl)-5-methyl-l-((2-(tri methylsilyl)et hoxy)methyl)- 1 //-benzo |7| ini idazole-6-carboxylate (29A-3)

To a solution of methyl 2-( l -(/c/7-butoxycarbonyl)azetidin-3-yl)-5-methyl- l//- benzo[t/]imidazole-6-carboxylate (200 mg, 420 pmol, 1.0 eq) in DMF (6.0 mL) was added sodium hydride (25.2 mg, 631 pmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. To the mixture was added SEM-C1 (105 mg, 631 pmol, 112 pL, 1.5 eq), the resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10: 1, R/ = 0.5). Methyl 2-(l -(/c/V-butoxy carbonyl)azetidin-3-yl)-5-methyl-l-((2-(trimethylsilyl)ethox y)methyl)-l/7-benzo[t/]imidazole -6-carboxylate (150 mg, 315 pmol, 75% yield) was obtained as a yellow oil. M + H ⁺ = 476.3 (LCMS).

Step 4: 2-(l-(tert-Butoxycarbonyl)azetidin-3-yl)-5-methyl-l-((2-(tri methylsilyl)ethoxy)me thyl)-l //-benzo p/| ini idazole-6-carboxylic acid (29A-4)

To a solution of methyl 2-(l-(terLbutoxycarbonyl)azetidin-3-yl)-5-methyl-l-((2- (trimethylsilyl)ethoxy)methyl)-l//-benzo[t/]imidazole-6-carb oxylate (80.0 mg, 42.1 pmol, 1.0 eq) in a mixture of EtOH (2.0 mL) and THF (2.0 mL) was added NaOH (2 M aqueous, 2.0 mL, 24 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and washed with MTBE (3.0 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (I M aqueous). The product was extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-( l -(/m-butoxy carbonyl )azeti din-3 -yl)- 5-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lZ7-benzo[J] imidazole-6-carboxylic acid (80.0 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 462.4 (LCMS).

Step 5: (/?)-tert-Butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-l-((2-(t rimet hylsilyl)ethoxy)methyl)-TH-benzo[J]imidazol-2-yl)azetidine-l -carboxylate (29A-5) To a solution of 2-(l-(ter/-butoxycarbonyl)azetidin-3-yl)-5-methyl-l-((2-(tri methylsilyl) ethoxy )methyl)- l//-benzo[t/]imidazole-6-carboxylic acid (70.0 mg, 152 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (26.0 mg, 152 pmol, 24.0 pL, 1.0 eq) in DCM (4.0 mL) were added EDCI (34.9 mg, 182 pmol, 1.2 eq), HOBt (24.6 mg, 182 pmol, 1.2 eq) and TEA (46.0 mg, 455 pmol, 63.0 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10:1, R/= 0.7). (/?)-/c/7-Butyl 3-(5-methyl-6-((l- (naphthalen-l-yl)ethyl)carbamoyl)-l-((2-(trimethylsilyl)etho xy)methyl)-UT- benzo[d]imidazol-2-yl)azetidine-l -carboxylate (70.0 mg, 114 pmol, 75% yield) was obtained as a yellow solid.

Step 6: (/? Her/- Butyl 3-(5-methyl-6-(( l-(naphthalen-l-yl)ethyl)carbamoyl)-l//-benzo[J]i midazol-2-yl)azetidine-l-carboxylate (29A-6)

To a solution of (/?)-/c/7-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-l-((2- (trimethylsilyl)ethoxy)methyl)- l7/-benzo[r/]imidazol-2-yl)azetidine- l -carboxylate (65.0 mg, 106 pmol, 1.0 eq) in DMF (1.0 mL) were added ethane-l,2-diamine (28.6 mg, 476 pmol, 31.84 pL, 4.5 eq) and TBAF (1 M in THF, 317 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (2.0 mL) and extracted with EtOAc (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10: 1, R/ = 0.6). (/?)-/c77-Butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)ethyl) carbamoyl)- 17/-benzo[t/]imidazol-2-yl)azetidine- l -carboxylate (50.0 mg, 103 pmol, 98% yield) was obtained as a yellow solid. M + H ⁺ = 485.4 (LCMS).

Step 7: (/?)-2-( Azel id i n-3-y 1 )-5-m et hy l- X -( 1 -( 11 a p hl ha 1 en- 1 -y 1 )et hyl )- 1 //-benzo p/| im idazo le-6-carboxamide (Compound 131)

To a solution of (A)-tert-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)ethyl)carbamoyl)-U/-benzo [J]imidazol-2-yl)azetidine-l -carboxylate (50.0 mg, 103 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (A)-2-(Azetidin-3-yl)-5-methyl-A-(l-(naphthalen-l-yl)ethyl)- 17/-benzo [ ]imidazole-6-carboxamide (11.0 mg, 28.5 pmol, 28% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 385.1 (LCMS); 'H NMR (400 MHz, CD3OD) 8 8.93 (br d, J= 7.9 Hz, 1H), 8.29 (d, J= 8.5 Hz, 1H), 7.92 (d, J= 8.6 Hz, 1H), 7.83 (d, J= 8.1 Hz, 1H), 7.66 - 7.43 (m, 6H), 6.18 - 5.96 (m, 1H), 4.55 - 4.41 (m, 5H), 2.48 (s, 3H), 1.74 (d, J= 7.0 Hz, 3H).

Example 30: l-(n:iphth:ilen-l-yl)ethyl)-l//-ind:izole-6-c:irboxamide (Compound

124)

Step 1

4A-1 Compound 124

Step 1: (/?)- V-(l-(naphthaleii-l-yl)ethyl)-l//-ind:izole-6-carbox:iinide (Compound 124)

To a solution of (A)-l-(naphthalen-l-yl)ethanamine (100 mg, 584 pmol, 1.0 eq) and 1H- indazole-6-carboxylic acid (94.7 mg, 584 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (118 mg, 1.17 mmol, 163 pL, 2.0 eq), T3P (2.23 g, 3.50 mmol, 2.08 mL, 50% in EtOAc, 6.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (A)-A-(l -(Naphthal en-l-yl)ethyl)-l JT-indazole-6- carboxamide (28.2 mg, 89.4 pmol, 15% yield) was obtained as a white solid. M + H ⁺ = 316.2 (LCMS); ¹ HNMR (400 MHz, CDCI3) 58.21 - 8.19 (m, 1H), 8.15 - 8.09 (m, 1H), 8.03 (s, 1H), 7.93 - 7.84 (m, 2H), 7.78 - 7.75 (m, 1H), 7.64 - 7.61 (m, 1H), 7.55 - 7.43 (m, 4H), 6.48 - 6.46 (m, 1H), 6.22 - 6.14 (m, 1H), 1.84 - 1.83 (d, J= 4, 3H), Example 31: (/?)-5-Methyl-\-( l-(ii:iplitli:ileii-l-yl)etliyl)-l//-iiid:izole-6-c:irboxaii iide

(Compound 142)

Step 3

Compound 142

Step 1: Methyl 5-methyl-l//-ind:izole-6-carboxylate (31A-2)

To a solution of 6-bromo-5-methyl-17/-indazole (200 mg, 948 pmol, 1.0 eq) in MeOH (3.0 mL) were added Pd(dppf)C12 (139 mg, 190 pmol, 0.2 eq) and TEA (767 mg, 7.58 mmol, 1.10 mL, 8.0 eq) under a N2 atmosphere. The mixture was degassed and purged with CO three times. The resulting mixture was stirred at 70 °C for 16 h under a CO (50 psi) atmosphere. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Methyl 5 -methyl- UT-indazole-6- carboxylate (150 mg, 789 pmol, 83% yield). M + H ⁺ = 191.1 (LCMS).

Step 2: 5-Methyl-l//-indazole-6-carboxylic acid (31A-3)

To a solution of methyl 5-methyl-lJ/-indazole-6-carboxylate (100 mg, 526 pmol, 1.0 eq) in a mixture of THF (3.0 mL) and H2O (1.0 mL) was added LiOH (66.2 mg, 1.58 mmol, 3.0 eq). The mixture was stirred at 20 °C for 18 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. H2O (5.0 mL) was added and the mixture was washed with MTBE (2.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 5- methyl- l#-indazole-6-carboxylic acid (70.0 mg, 397 pmol, 76% yield) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 177.2 (LCMS).

Step 3: (/ )-5- I el hy l- \ -( 1 -( na phi halen- 1 -y 1 )el hy 1 )- 1 //-indazole-6-ca r bo xa in ide (Compou nd 142)

To a solution of 5-methyl-U/-indazole-6-carboxylic acid (30.0 mg, 170 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (29.2 mg, 170 pmol, 27.3 pL, 1.0 eq) in DCM (2.0 mL) were added EDCI (39.2 mg, 204 pmol, 1.2 eq), HOBt (27.6 mg, 204 pmol, 1.2 eq) and TEA (34.5 mg, 341 pmol, 47.4 pL, 2.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 45% - 90% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (A)-5-Methyl-A-(l- (naphthalen-l-yl)ethyl)-U/-indazole-6-carboxamide (8.51 mg, 25.8 pmol, 16% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 330.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.00 (br d, J= 7.8 Hz, 1H), 8.29 (d, J= 8.5 Hz, 1H), 8.10 (br s, 1H), 7.92 (d, J= 7.9 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.66 (d, J= 7.1 Hz, 1H), 7.63 - 7.46 (m, 5H), 6.09 (quin, J= 7.1 Hz, 1H), 2.43 (s, 3H), 1.74 (d, J= 7.0 Hz, 3H).

Example 32: (l?)-6-Methyl-/V-(l-(naphthalen-l-yl)ethyl)quinoline-7-carbo xamide (Compound 150)

OH benzenesulfonate TEA

H ₂ SO _4I H ₂ O,

Step 1 Step 2

32A-1 32A-2

Compound 150

Step 1: 7-Bromo-6-methylquinoline (32A-2)

To a mixture of 3-bromo-4-methyl-aniline (18.0 g, 96.8 mmol, 1.0 eq) and sodium 3- nitrobenzenesulfonate (26.1 g, 116 mmol, 1.2 eq) in H2SO4 (60 mL, 98% purity) and H2O (25 mL) was added propane-1, 2, 3-triol (26.7 g, 290 mmol, 21.7 mL, 3.0 eq). The mixture was stirred at 130 °C for 2 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and neutralized with K2CO3 to pH 8. The product was extracted with EtOAc (30 mL x 5). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 7-Bromo-6-methylquinoline (10.4 g, 46.8 mmol, 48% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCL) 8 8.87 - 8.85 (m, 1H), 8.63 - 8.56 (m, 1H), 8.01 - 7.96 (m, 1H), 7.62 - 7.58 (m, 1H), 7.41 - 7.35 (m, 1H), 2.60 - 2.56 (m, 3H).

Step 2: Methyl 6-methylquinoline-7-carboxylate (32A-3)

To a solution of 7-bromo-6-methylquinoline (6.00 g, 27.0 mmol, 1.0 eq) and TEA (10.9 g, 108 mmol, 15.0 mL, 4.0 eq) in MeOH (50 mL) was added Pd(dppf)C12 (1.98 g, 2.70 mmol, 0.1 eq). The mixture was stirred at 70 °C for 16 h under a CO (50 psi) atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 6-methylquinoline-7-carboxylate (6.00 g, 29.8 mmol, 37% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCL) 6 8.98 - 8.89 (m, 1H), 8.72 - 8.64 (m, 1H), 8.14 - 8.06 (m, 1H), 7.71 - 7.63 (m, 1H), 7.49 - 7.39 (m, 1H), 4.16 - 3.89 (m, 3H), 2.85 - 2.68 (m, 3H).

Step 3: 6-Methylquinoline-7-carboxylic acid (32A-4)

To a solution of methyl 6-methylquinoline-7-carboxylate (300 mg, 1.49 mmol, 1.0 eq) in a mixture of THF (8.0 mL), H2O (4.0 mL) and MeOH (2.0 mL) was added LiOH.TbO (125 mg, 2.98 mmol, 2.0 eq). The mixture was stirred at 20 °C for 30 min, then at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (8.0 mL) and washed with MTBE (8.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (8.0 mL x 6). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 6- methylquinoline-7-carboxylic acid (270 mg, 1.44 mmol, 97% yield) as a white solid, which was used in the next step without any further purification. M - H“ = 186.1 (LCMS).

Step 4: (l?)-6-Methyl-/V-(l-(naphthalen-l-yl)ethyl)quinoline-7-carbo xamide (Compound 150)

To a solution of (R)- 1 -(naphthal en-l-yl)ethanamine (89.2 mg, 521 pmol, 83.0 pL, 1.5 eq) and 6-methylquinoline-7-carboxylic acid (65.0 mg, 347 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (70.3 mg, 694 pmol, 96.7 pL, 2.0 eq) and T3P (331 mg, 521 pmol, 310 pL, 50% purity in EtOAc, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.5). (R)- 6-Methyl-7V-(l-(naphthalen-l-yl)ethyl) quinoline-7-carboxamide (26.0 mg, 76.4 pmol, 22% yield) was obtained as a white solid. M + H ⁺ = 341.1 (LCMS); 'H NMR (400 MHz, CDCL) 8 8.82 (br d, J= 2.1 Hz, 1H), 8.32 - 8.23 (m, 1H), 8.12 - 7.98 (m, 2H), 7.90 (d, J= 8.0 Hz, 1H), 7.86 - 7.79 (m, 1H), 7.67 - 7.57 (m, 3H), 7.57 - 7.44 (m, 2H), 7.44 - 7.36 (m, 1H), 6.36 - 6.14 (m, 2H), 2.69 - 2.59 (m, 3H), 1.90 - 1.80 (m, 3H). Example 33: (l?)-6-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-2-oxo-l,2-dihydr oquinoline-7- carboxamide (Compound 167)

Step 3 Step 4

33A-3 Compound 167

Step 1: 7-(Methoxycarbonyl)-6-methylquinoline 1-oxide (33A-1)

To a mixture of methyl 6-methylquinoline-7-carboxylate (240 mg, 1.19 mmol, 1.0 eq) in DCM (5.0 mL) was added m-CPBA (308 mg, 1.43 mmol, 80% purity, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction was poured into saturated aqueous Na2SO3 (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried and concentrated under vacuum to give 7-(methoxycarbonyl)-6- methylquinoline 1-oxide (300 mg, 968 pmol, 81% yield) as a yellow solid. M + H ⁺ = 218.1 (LCMS); ^X H NMR (400 MHz, CDCh) 8 9.33 - 9.23 (m, 1H), 8.56 - 8.46 (m, 1H), 7.80 - 7.70 (m, 1H), 7.69 - 7.60 (m, 1H), 7.38 - 7.30 (m, 1H), 4.04 - 3.91 (m, 3H), 2.82 - 2.70 (m, 3H).

Step 2: Methyl 2-chloro-6-methylquinoline-7-carboxylate (33A-2)

To a solution of 7-(methoxycarbonyl)-6-methylquinoline 1-oxide (230 mg, 1.06 mmol, 1.0 eq) in DCM (8.0 mL) was added POCL (244 mg, 1.59 mmol, 148 pL, 1.5 eq) at 0 °C, followed by DMF (39.0 mg, 529 pmol, 40.7 pL, 0.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. Saturated aqueous NazCO, solution was added to the reaction mixture slowly at 0 °C to adjust the pH to 8. The resulting mixture was separated and the aqueous phase was extracted with DCM (10 mL x 5). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum to afford the crude product which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-chloro-6-methylquinoline-7-carboxylate (120 mg, 509 pmol, 48% yield) was obtained as a white solid. M + H ⁺ = 236.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.69 - 8.62 (m, 1H), 8.17 - 7.96 (m, 1H), 7.77 - 7.59 (m, 1H), 7.47 (d, J= 8.5 Hz, 1H), 3.98 (s, 3H), 2.80 - 2.70 (m, 3H).

Step 3: 6-Methyl-2-oxo-l,2-dihydroquinoline-7-carboxylic acid (33A-3)

To a solution of methyl 2-chloro-6-methylquinoline-7-carboxylate (120 mg, 509 pmol, 1.0 eq) in dioxane (5.0 mL) was added HC1 (6 M in aqueous, 962 pL, 11 eq). The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, diluted with H2O (3.0 mL) and acidified to pH 5 with NaOH (2 M aqueous). The product was extracted with EtOAc (8.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product 6-methyl-2-oxo-l,2- dihydroquinoline-7-carboxylic acid (160 mg, 472 pmol, 93% yield) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 204.0 (LCMS); 'H NMR (400 MHz, DMS0- _e ) 8 11.83 - 11.74 (m, 1H), 7.91 - 7.83 (m, 1H), 7.81 - 7.76 (m, 1H), 7.58 - 7.54 (m, 1H), 6.63 - 6.52 (m, 1H), 1.25 - 1.20 (m, 3H).

Step 4: (l?)-6-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-2-oxo-l,2-dihydr oquinoline-7- carboxamide (Compound 167)

To a solution of (R)- 1 -(naphthal en-l-yl)ethanamine (75.8 mg, 443 pmol, 70.9 pL, 1.5 eq) and 6-methyl-2-oxo-l,2-dihydroquinoline-7-carboxylic acid (100 mg, 295 pmol, 1.0 eq) in DCM (10 mL) were added TEA (89.6 mg, 886 pmol, 123 pL, 3.0 eq), EDCI (84.9 mg, 443 pmol, 1.5 eq) and HOBt (59.9 mg, 442 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 65% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-6-Methyl-A-(l-(naphthalen- l-yl)ethyl)-2-oxo-l,2-dihydroquinoline-7-car b oxamide (8.00 mg, 21.9 pmol, 7% yield) was obtained as a white solid. M + H ⁺ = 357.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 8 11.84 - 11.57 (m, 1H), 9.13 - 8.98 (m, 1H), 8.37 - 8.13 (m, 1H), 8.00 - 7.93 (m, 1H), 7.91 - 7.80 (m, 2H), 7.65 - 7.47 (m, 5H), 7.29 - 7.21 (m, 1H), 6.54 - 6.44 (m, 1H), 5.98 - 5.87 (m, 1H), 2.30 - 2.24 (m, 3H), 1.62 - 1.53 (m, 3H).

Example 34: (l?)-6-Methyl-/V-(l-(naphthalen-l-yl)ethyl)benzo[J| [l,3]dioxole-5- carboxamide (Compound 145)

Compound 145

Step 1: 6-Methylbenzo[ |[l,3]dioxole-5-carbaldehyde (34A-2)

To a solution of 5-methylbenzo[ ][l,3]dioxole (200 mg, 1.47 mmol, 175 pL, 1.0 eq) in DCM (2.0 mL) was added dichloro(methoxy)methane (338 mg, 2.94 mmol, 260 pL, 2.0 eq) at 0 °C. The mixture was stirred at 0 °C for 15 min and a solution of TiCh (334 mg, 1.76 mmol, 1.2 eq) in DCM (2.0 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed. The mixture was poured into H2O (10 mL) and extracted with MTBE (10 mL x 2). The combined organic layers were dried and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/100 to 1/50. 6- Methylbenzo[d][l,3]dioxole-5-carbaldehyde (220 mg, 1.34 mmol, 91% yield) was obtained as a yellow solid. ^X H NMR (400 MHz, CDCh) 5 10.24 - 10.05 (m, 1H), 7.29 (s, 1H), 6.70 (s, 1H), 6.03 (s, 2H), 2.62 (s, 3H).

Step 2: 6-Methylbenzo[J][l,3]dioxole-5-carboxylic acid (34A-3)

To a stirred solution of 6-rnethylbenzo[d][l,3]dioxole-5-carbaldehyde (200 mg, 1.22 mmol, 1.0 eq), Na^PCh (43.9 mg, 366 pmol, 0.3 eq), and H2C>2 (177 mg, 1.82 mmol, 150 pL, 35% purity in H2O, 1.5 eq) in a mixture of acetonitrile (1.5 mL) and H2O (0.6 mL) was added a solution of NaCICb (154 mg, 1.71 mmol, 1.4 eq) in H2O (2.0 mL) dropwise to maintain the temperature between 0 °C and 10 °C. The resulting mixture was stirred at 20 °C for 1.5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous Na2SO3 (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude 6-methylbenzo[d][l,3]dioxole-5-carboxylic acid (220 mg) as a white solid.

Step 3: (l?)-6-Methyl-/V-(l-(naphthalen-l-yl)ethyl)benzo[J] [l,3]dioxole-5-carboxamide (Compound 145)

To a stirred solution of 6-methylbenzo[d][l,3]dioxole-5-carboxylic acid (61.0 mg, 339 pmol, 1.0 eq) and (R)- 1 -(naphthal en-l-yl)ethanamine (63.8 mg, 372 pmol, 59.6 pL, 1.1 eq) in DCM (5.0 mL) were added TEA (103 mg, 1.02 mmol, 141 pL, 3.0 eq) and T3P (323 mg, 508 pmol, 302 pL, 50% purity in EtOAc, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was poured into H2O (2.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.3). (A)-6-Methyl-A-(l-(naphthalen-l-yl)ethyl)benzo[ ][l,3]dioxole-5-carboxamide (37.5 mg, 106 pmol, 31% yield) was obtained as a white solid. M + H ⁺ = 334.0 (LCMS); NMR (400 MHz, CDCh) 8 8.30 - 8.18 (m, 1H), 7.92 - 7.86 (m, 1H), 7.85 - 7.80 (m, 1H), 7.63 - 7.44 (m, 4H), 6.81 - 6.75 (m, 1H), 6.68 - 6.60 (m, 1H), 6.17 - 6.05 (m, 1H), 5.94 - 5.84 (m, 3H), 2.41 - 2.32 (m, 3H), 1.83 - 1.74 (m, 3H).

Example 35: /V-(5-Amino-2-methylphenyl)-2-(naphthalen-l-yl)propanamide (Compound 163)

Step 1: Ethyl 2-(naphthalen-l-yl)propanoate (35A-2)

To a stirred solution of ethyl 2-(naphthalen-l-yl)acetate (500 mg, 2.33 mmol, 1.0 eq) in DMF (10 mL) was added sodium hydride (112 mg, 2.80 mmol, 60% purity, 1.2 eq) in portions at 0 °C. The mixture was stirred at the same temperature for 15 min. lodomethane (364 mg, 2.57 mmol, 160 pL, 1.1 eq) was added dropwise. After the addition was complete, the resulting mixture was stirred at 0 °C for another 15 min. TLC indicated that that the starting material was completely consumed. The mixture was poured into H2O (20 mL) and extracted with MTBE (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give ethyl 2-(naphthalen-l-yl)propanoate (450 mg, 1.97 mmol, 84% yield) as a yellow oil, which was used in the next step without any further purification.

Step 2: 2-(Naphthalen-l-yl)propanoic acid (35A-3)

To a stirred solution of ethyl 2-(naphthalen-l-yl)propanoate (200 mg, 876 pmol, 1.0 eq) in a mixture of EtOH (5.0 mL) and THF (5.0 mL) was added NaOH (2 M aqueous, 1.31 mL, 3.0 eq). The mixture was stirred at 20 °C for 1 h and then at 70 °C for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (20 mL) and washed with MTBE (15 mL x 3). The aqueous was acidified to pH 5 using HC1 (1 M aqueous) and extracted with EtOAc (5 mL x 2). The combined organic layers were dried and concentrated in vacuum to give 2-(naphthalen-l- yl)propanoic acid (180 mg, 90% purity) as a yellow solid. 'H NMR (400 MHz, CDCL) 8 8.22 - 8.05 (m, 1H), 7.94 - 7.87 (m, 1H), 7.85 - 7.79 (m, 1H), 7.61 - 7.45 (m, 4H), 4.64 - 4.52 (m, 1H), 1.74 - 1.68 (m, 3H).

Step 3: /V-(2-Methyl-5-nitrophenyl)-2-(naphthalen-l-yl)propanamide (35A-4)

To a stirred solution of 2-(naphthalen-l-yl)propanoic acid (100 mg, 499 pmol, 1.0 eq) and 2- methyl-5-nitroaniline (83.6 mg, 549 pmol, 209 pL, 1.1 eq) in DCM (5.0 mL) was added TEA (152 mg, 1.50 mmol, 209 pL, 3.0 eq), followed by T3P (636 mg, 999 pmol, 594 pL, 50% purity in EtOAc, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H2O (10 mL) and extracted with MTBE (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether =1/3, R/ = 0.3). 7V-(2-Methyl-5- nitrophenyl)-2-(naphthalen-l-yl)propanamide (90.0 mg, 269 pmol, 54% yield) was obtained as a yellow solid. M + H ⁺ = 335.1 (LCMS).

Step 4: /V-(5-Amino-2-methylphenyl)-2-(naphthalen-l-yl)propanamide (Compound 163)

To a stirred solution of A-(2-methyl-5-nitrophenyl)-2-(naphthalen-l-yl)propanamide (60.0 mg, 179 pmol, 1.0 eq) in a mixture of MeOH (10 mL) and H2O (2.5 mL) was added iron powder (50.1 mg, 897 pmol, 5.0 eq), followed by NH4CI (48.0 mg, 897 pmol, 5.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 x 40 mm, 10 pm); flow rate: 60 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-(5-Amino-2- methylphenyl)-2-(naphthalen-l-yl)propanamide (8.11 mg, 26.4 pmol, 15% yield) was obtained as a yellow solid. M + H ⁺ = 305.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.32 - 8.20 (m, 1H), 7.93 - 7.88 (m, 1H), 7.85 - 7.79 (m, 1H), 7.66 - 7.62 (m, 1H), 7.61 - 7.54 (m, 1H), 7.54 - 7.46 (m, 2H), 6.90 - 6.84 (m, 1H), 6.75 - 6.70 (m, 1H), 6.53 - 6.47 (m, 1H), 4.73 - 4.62 (m, 1H), 1.87 - 1.82 (m, 3H), 1.77 - 1.63 (m, 3H).

Example 36: 5-Amino-/V-(cyano(naphthalen-l-yl)methyl)-2-methylbenzamide (Compound 195)

Step 1 Step 2

36A-1 36A-2

36A-3 Compound 195

Step 1: 2-Amino-2-(naphthalen-l-yl)acetonitrile (36A-2)

To a solution of sodium cyanide (158 mg, 3.20 mmol, 1.0 eq) in MeOH (3.0 mL) was NFL,. FLO (1.82 g, 13.1 mmol, 2.00 mL, 25% purity, 4.1 eq), NH4CI (171 mg, 3.20 mmol, 1.0 eq) and 1- naphthaldehyde (500 mg, 3.20 mmol, 435 pL, 1.0 eq). The mixture was stirred at 20 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were concentrated under vacuum to give the crude product 2-amino-2-(naphthalen-l-yl)acetonitrile (450 mg), which was used in the next step without any further purification. M - 17+ H ⁺ = 166.1 (LCMS).

Step 2: /V-(Cyano(naphthalen-l-yl)methyl)-2-methyl-5-nitrobenzamide (36A-3)

To a solution of 2-amino-2-(naphthalen-l-yl)acetonitrile (100 mg, 549 pmol, 1.0 eq) and 2- methyl-5-nitrobenzoic acid (99.4 mg, 549 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (166 mg, 1.65 mmol, 229 pL, 3.0 eq), EDCI (263 mg, 1.37 mmol, 2.5 eq) and HOBt (185 mg, 1.37 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) at 25 °C and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 7V-(cyano(naphthalen-l-yl)methyl)-2-methyl-5-nitrobenzamide (170 mg), which was used in the next step without any further purification. M + H ⁺ = 346.1 (LCMS).

Step 3: 5-Amino-/V-(cyano(naphthalen-l-yl)methyl)-2-methylbenzamide (Compound 195)

To a solution of 7V-(cyano(naphthalen-l-yl)methyl)-2-methyl-5-nitrobenzamide (170 mg, 492 pmol, 1.0 eq) in a mixture of MeOH (6.0 mL) and H2O (2.0 mL) were added iron powder (137 mg, 2.46 mmol, 5.0 eq) and NH4CI (132 mg, 2.46 mmol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (8.0 mL) at 25 °C and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Amino-7V-(cyano(naphthalen-l-yl)methyl)-2- methylbenzamide (33.3 mg, 102 pmol, 21% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 316.2 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 8 9.73 (d, J= 8.0 Hz, 1H), 8.09 - 8.01 (m, 3H), 7.85 (d, J= 7.1 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.56 - 7.49 (m, 1H), 7.70 - 7.46 (m, 1H), 7.15 - 7.02 (m, 2H), 6.97 - 6.86 (m, 2H), 2.24 - 2.17 (m, 3H).

Example 37: 5-Amino-/V-(2-fluoro-l-(naphthalen-l-yl)ethyl)-2-methylbenza mide (Compound 200)

Step 3 Step 4

37A-4 Compound 200

Step 1: 2-Fluoro-l-(naphthalen-l-yl)ethanone (37A-2)

To a solution of iodosylbenzene (1.55 g, 7.05 mmol, 1.2 eq) and hydrogen fluoride (4.07 g, 23.5 mmol, 8.66 mL, 70% purity in TEA, 4.0 eq) in DCE (10 mL) was added 1 -(naphthal en- l-yl)ethanone (1.00 g, 5.88 mmol, 1.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NaHCO, (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 2-Fluoro-l-(naphthalen-l-yl)ethanone (270 mg, 1.43 mmol, 24% yield) was obtained as a yellow solid. M + H ⁺ = 189.1 (LCMS). Step 2: 2-Fluoro-l-(naphthalen-l-yl)ethanamine (37A-3)

To a solution of 2-fluoro-l -(naphthal en-l-yl)ethenone (130 mg, 691 pmol, 1.0 eq) in MeOH (15 mL) were added NT OAc (1.28 g, 16.6 mmol, 24 eq) and NaBHiCN (347 mg, 5.53 mmol, 8.0 eq). The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.1). 2-Fluoro-l -(naphthal en-l-yl)ethanamine (150 mg, crude) was obtained as a yellow oil. M + H ⁺ = 190.2 (LCMS).

Step 3: \-( 2- 1 1110 ro- 1 -(naphthalen-1 -yl)ethyl)-2-methyl-5-nitrobenzamide (37A-4)

To a solution of 2-fluoro-l -(naphthal en-l-yl)ethanamine (273 mg, 1.44 mmol, 1.0 eq) and 2- methyl-5-nitrobenzoic acid (287 mg, 1.59 mmol, 1.1 eq) in DMF (10 mL) were added TEA (438 mg, 4.33 mmol, 602 pL, 3.0 eq), EDCI (691 mg, 3.61 mmol, 2.5 eq) and HOBt (487 mg, 3.61 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 7V-(2-Fluoro- l-(naphthalen-l-yl)ethyl)-2-methyl-5-nitrobenzamide (180 mg, 511 pmol, 35% yield) was obtained as a brown solid. M + H ⁺ = 353.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.23 (d, J = 2.0 Hz, 1H), 8.21 - 8.09 (m, 2H), 7.90 (dd, J= 8.1, 15.6 Hz, 2H), 7.67 - 7.60 (m, 2H), 7.57 (br d, = 7.7 Hz, 1H), 7.51 (d, = 7.8 Hz, 1H), 7.39 (d, J= 8.4 Hz, 1H), 6.51 (br d, J= 8.2 Hz, 1H), 6.42 - 6.21 (m, 1H), 5.19 - 4.85 (m, 2H), 2.55 (s, 3H).

Step 4: 5-Amino-/V-(2-fluoro-l-(naphthalen-l-yl)ethyl)-2-methylbenza mide (Compound 200)

To a solution of 7V-(2-fluoro-l -(naphthal en-l-yl)ethyl)-2-methyl-5-nitrobenzamide (100 mg, 284 pmol, 1.0 eq) in a mixture of MeOH (10 mL) and H2O (2.5 mL) were added iron powder (79.2 mg, 1.42 mmol, 5.0 eq) and NH4CI (75.9 mg, 1.42 mmol, 5.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-Amino-7V-(2-fluoro-l -(naphthal en-l-yl)ethyl)-2- methyl benzamide (26.8 mg, 83.0 pmol, 29% yield) was obtained as a white solid. M + H ⁺ = 323.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.18 (d, J= 8.6 Hz, 1H), 7.89 (dd, J= 8.1, 17.4

Hz, 2H), 7.67 - 7.45 (m, 4H), 6.99 (d, J= 8.1 Hz, 1H), 6.71 (s, 1H), 6.65 (br d, J= 7.7 Hz, 1H), 6.37 - 6.18 (m, 2H), 5.13 - 4.85 (m, 2H), 2.33 (s, 3H).

Example 38: 5-Amino-/V-(2,2-difluoro-l-(naphthalen-l-yl)ethyl)-2-methylb enzamide

(Compound 185)

38A-4 Compound 185

Step 1: (Zi)-2-Methyl-/V-(naphthalen-l-ylmethylene)propane-2-sulfina mide (38A-1)

To a solution of 2-methylpropane-2-sulfinamide (1.55 g, 12.8 mmol, 1.0 eq) in DCM (25 mL) were added Q1SO4 (4.09 g, 25.6 mmol, 3.93 mL, 2.0 eq) and 1 -naphthaldehyde (2.00 g, 12.8 mmol, 1.74 mL, 1.0 eq). The mixture was stirred at 20 °C for 48 h. LCMS indicated that 53% of the starting material remained and 30% of the desired mass was detected. The reaction mixture was poured into H2O (25 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. (£)-2-Methyl-A-(naphthalen-l- ylmethylene)propane-2-sulfinamide (2.00 g, 3.01 mmol, 23% yield) was obtained as a yellow oil. M + H ⁺ = 260.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 9.17 (s, 1H), 9.07 - 9.02 (m, 1H), 8.08 - 8.01 (m, 2H), 7.96 - 7.92 (m, 1H), 7.70 - 7.63 (m, 1H), 7.62 - 7.54 (m, 2H), 1.34 (s, 9H).

Step 2: /V-(2,2-Difluoro-l-(naphthalen-l-yl)ethyl)-2-methylpropane-2 -sulfinamide (38A- 2)

To a solution of (£)-2-methyl-A-(naphthalen-l-ylmethylene)propane-2-sulfinam ide (500 mg, 1.93 mmol, 1.0 eq) and (difluoromethyl)trimethylsilane (718 mg, 5.78 mmol, 3.0 eq) in THF (6.0 mL) was added Z-BuOK (1 M in THF, 5.78 mL, 3.0 eq). The mixture was degassed and purged with N2 three times, stirred at -70 °C for 10 min, then stirred at 20 °C for another 30 min under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. N- (2,2-Difluoro-l -(naphthal en-l-yl)ethyl)-2-methylpropane-2-sulfinamide (270 mg, 819 pmol, 43% yield) was obtained as a brown oil. M + H ⁺ = 312.1 (LCMS).

Step 3: 2,2-Difluoro-l-(naphthalen-l-yl)ethanamine hydrochloride (38A-3)

To a solution of A-(2,2-difluoro-l-(naphthalen-l-yl)ethyl)-2-methylpropane-2- sulfinamide (100 mg, 321 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 °C for 20 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude product 2,2-difluoro-l -(naphthal en-l-yl)ethanamine hydrochloride (100 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 208.2 (LCMS).

Step 4: /V-(2,2-Difluoro-l-(naphthalen-l-yl)ethyl)-2-methyl-5-nitrob enzamide (38A-4)

To a solution of 2,2-difluoro-l -(naphthal en-l-yl)ethanamine (100 mg, 410 pmol, 1.0 eq, HC1 salt) and 2-methyl-5-nitrobenzoic acid (81.8 mg, 451 pmol, 1.1 eq) in DCM (5.0 mL) were added TEA (125 mg, 1.23 mmol, 171 pL, 3.0 eq), EDCI (157 mg, 821 pmol, 2.0 eq) and HOBt (111 mg, 821 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. A-(2,2-Difluoro-l -(naphthal en-l-yl)ethyl)-2- methyl-5-nitrobenzamide (60.0 mg, 1.62 mmol, 39% yield) was obtained as a white solid. M + H ⁺ = 371.2 (LCMS).

Step 5: 5-Amino-A-(2,2-difluoro-l-(naphthalen-l-yl)ethyl)-2-methylbe nzamide (Compou nd 185)

To a solution of A-(2,2-difluoro-l -(naphthal en-l-yl)ethyl)-2-methyl-5 -nitrobenzamide (50.0 mg, 135 pmol, 1.0 eq) in MeOH (5.0 mL) were added H2O (1.0 mL), iron powder (37.7 mg, 675 pmol, 5.0 eq) and NH4CI (36.1 mg, 675 pmol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (6.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- Amino-A-(2,2-difluoro- 1 -(naphthal en- 1 -yl)ethyl)-2-methylbenzamide was obtained as a white solid. M + H ⁺ = 341.0 (LCMS); 'H NMR (400 MHz, DMSO ) 6 10.13 - 9.65 (m, 1H), 9.49 (br d, J= 8.8 Hz, 1H), 8.31 - 8.23 (m, 1H), 8.04 - 7.94 (m, 2H), 7.80 - 7.74 (m, 1H), 7.69 - 7.53 (m, 3H), 7.34 - 7.19 (m, 2H), 7.15 (s, 1H), 6.71 - 6.66 (m, 1H), 6.59 - 6.52 (m, 1H), 2.29 - 2.19 (m, 3H).

Example 39: 5-Amino-2-methyl-/V-(2,2,2-trifluoro-l-(naphthalen-l-yl)ethy l)benzamide (Compound 183)

39A-1 39A-2

Compound 183

Step 1: 2-Methyl-5-nitro-/V-(2,2,2-trifluoro-l-(naphthalen-l-yl)ethy l)benzamide (39A-2)

To a solution of 2-methyl-5-nitrobenzoic acid (88.5 mg, 488 pmol, 1.1 eq), 2,2,2-trifluoro-l- (naphthalen-l-yl)ethanamine (100 mg, 444 pmol, 1.0 eq) in DMF (10 mL) was added DIEA (172 mg, 1.33 mmol, 232 pL, 3.0 eq). The mixture was stirred at 25 °C for 5 min then HATU (186 mg, 488 pmol, 1.1 eq) was added. The resulting mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H2O (5.0 mL) and dried under vacuum to give 2-methyl-5-nitro-7V-(2,2,2-trifluoro-l-(naphthalen-l-yl)ethy l)benzamide (120 mg, 309 pmol, 70% yield) as a white solid. M + H ⁺ = 389.1 (LCMS); 'H NMR (400 MHz, CDCL) 8 8.27 - 8.15 (m, 3H), 7.96 (t, J= 6.9 Hz, 2H), 7.75 - 7.65 (m, 2H), 7.63 - 7.51 (m, 2H), 7.42 (d, J= 8.1 Hz, 1H), 6.89 - 6.78 (m, 1H), 6.44 (br d, J= 9.3 Hz, 1H), 2.54 (s, 3H).

Step 2: 5-Amino-2-methyl-/V-(2,2,2-trifluoro-l-(naphthalen-l-yl)ethy l)benzamide (Compound 183)

To a stirred solution of 2-methyl-5-nitro-7V-(2,2,2-trifluoro-l-(naphthalen-l-yl)ethy l) benzamide (110 mg, 283 pmol, 1.0 eq) in a mixture of MeOH (10 mL) and H2O (2.5 mL) was added iron powder (79.0 mg, 1.42 mmol, 5.0 eq), followed by NH4CI (75.8 mg, 1.42 mmol, 5.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature. The suspension was filtered through a pad of Celite and the combined filtrates were poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 (100 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 50% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 5-amino-2-methyl-7V-(2,2,2- trifluoro-1 -(naphthal en-l-yl)ethyl)benzamide (39.7 mg, 110 pmol, 39% yield) as a white solid. M + H ⁺ = 359.0 (LCMS); 'H NMR (400 MHz, CDCL) 6 8.24 (d, J= 8.6 Hz, 1H), 7.95 - 7.89 (m, 2H), 7.65 (dt, J=1.4, 8.6 Hz, 2H), 7.61 - 7.55 (m, 1H), 7.54 - 7.47 (m, 1H), 6.99 (d, J =8.9 Hz, 1H), 6.88 - 6.73 (m, 1H), 6.69 - 6.58 (m, 2H), 6.36 (br d, J= 9.5 Hz, 1H), 3.60 (br s, 2H), 2.29 (s, 3H).

Example 40: 5-Amino-2-methyl-/V-(3-(naphthalen-l-yl)oxetan-3-yl)benzamid e

(Compound 191)

40A-4 Compound 191

Step 1: 2-Methyl-/V-(3-(naphthalen-l-yl)oxetan-3-yl)propane-2-sulfin amide (40A-2)

To a solution of 1 -bromonaphthalene (886 mg, 4.28 mmol, 595 pL, 1.5 eq) in THF (10 mL) was added w-BuLi (2.5 M in hexane, 1.60 mL, 1.4 eq) dropwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred at -78 °C for 1 h, then a solution of 2-m ethyl -N- (oxetan-3-ylidene)propane-2-sulfmamide (500 mg, 2.85 mmol, 1.0 eq) in THF (5.0 mL) was added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH4CI (20 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-Methyl-7V-(3 -(naphthal en-1 -yl)oxetan-3-yl)propane- 2-sulfinamide (450 mg, 1.48 mmol, 52% yield) was obtained as a yellow gum.

Step 2: 3-(Naphthalen-l-yl)oxetan-3-amine (40A-3)

To a solution of 2-methyl-7V-(3 -(naphthal en-1 -yl)oxetan-3-yl)propane-2-sulfmamide (250 mg, 824 pmol, 1.0 eq) in MeOH (3.0 mL) was added HCl/dioxane (6 M, 1.0 mL) at 0°C. The resulting mixture was stirred at 0 °C for 10 min. LCMS indicated that the starting material was completely consumed, and the desired product was detected. The reaction mixture was concentrated under vacuum to give 3-(l-naphthyl)oxetan-3-amine (190 mg, 806 pmol, 98% yield, HC1 salt) as a white solid, which was used in the next step without any further purification.

Step 3: 2-Methyl-/V-(3-(naphthalen-l-yl)oxetan-3-yl)-5-nitrobenzamid e (40A-4)

To a solution of 2-methyl-5-nitrobenzoic acid (84.5 mg, 467 pmol, 1.1 eq) and 3 -(naphthal en- l-yl)oxetan-3 -amine (100 mg, 424 pmol, 1.0 eq, HC1 salt) in DMF (10 mL) was added DIE A (164 mg, 1.27 mmol, 222 pL, 3.0 eq). After stirring for 5 min, HATU (177 mg, 467 pmol, 1.1 eq) was added. The resulting mixture was stirred at 25 °C for 3 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was poured into H2O (20 mL), and a precipitate was formed. The mixture was filtered and the solid was washed H2O (5.0 mL) and dried under vacuum to give 2-methyl-7V-(3-(naphthalen-l-yl)oxetan-3-yl)-5- nitrobenzamide (150 mg, 414 pmol, 98% yield) as a white solid. ^T H NMR (400 MHz, CDCL) 8 8.12 (br d, J= 2.4 Hz, 2H), 8.01 - 7.93 (m, 1H), 7.89 (d, J= 8.3 Hz, 1H), 7.77 (d, J= 13 Hz, 1H), 7.56 (s, 3H), 7.42 (br d, J= 8.8 Hz, 1H), 7.33 (br d, J= 9.1 Hz, 1H), 6.65 (br s, 1H), 5.61 - 5.42 (m, 4H), 2.37 (s, 3H).

Step 4: 5-Amino-2-methyl-/V-(3-(naphthalen-l-yl)oxetan-3-yl)benzamid e (Compound 191)

To a stirred solution of 2-methyl-7V-(3-(naphthalen-l-yl)oxetan-3-yl)-5-nitrobenzamid e (80.0 mg, 221 pmol, 1.0 eq) in a mixture of MeOH (8.0 mL) and H2O (2.0 mL) was added iron powder (61.7 mg, 1.10 mmol, 5.0 eq), followed by NH4CI (59.0 mg, 1.10 mmol, 5.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The suspension was filtered through a pad of Celite and filtrate was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 5-amino-2-methyl-7V-(3-(naphthalen-l- yl)oxetan-3-yl)benzamide (19.1 mg, 56.6 pmol, 26% yield) as a white solid. M + H ⁺ = 333.0 (LCMS); 'H NMR (400 MHz, CDCL) 6 7.94 (dd, J= 3.6, 5.9 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.76 (d, J= 7.1 Hz, 1H), 7.59 - 7.46 (m, 3H), 7.43 - 7.36 (m, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.69 - 6.53 (m, 3H), 5.50 (d, J= 6.6 Hz, 2H), 5.46 - 5.39 (m, 2H), 2.14 (s, 3H). Example 41: 5-(2-Ani inoetlioxy )-2-metIiyl-X-( 1 -(naplit halen- 1 - yl)cyclopropyl)benzamide (Compound 281)

Compound 281

Step 1: 2-(Naphthalen-l-yl)propan-2-ol (41A-1)

A mixture of 1 -(naphthal en-l-yl)ethanone (10.0 g, 58.8 mmol, 1.0 eq) in THF (100 mL) was degassed and purged with N2 three times. To this mixture was added methyl lithium (1.6 M in Et20, 73.4 mL, 2.0 eq) dropwise to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 2 h and warmed to 25 °C stirring for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 2-(Naphthalen- l-yl)propan-2-ol (4.00 g, 21.3 mmol, 36% yield) was obtained as a white solid. M - 18 + H ⁺ = 169.1 (LCMS). Step 2: l-(2-Azidopropan-2-yl)naphthalene (41A-2)

A mixture of 2-(naphthalen-l-yl)propan-2-ol (1.00 g, 5.37 mmol, 1.0 eq), FeCL (87.1 mg, 537 prnol, 0.1 eq) in DCM (10 mL) was degassed and purged with N2 three times. To the mixture was added TMSN3 (1.24 g, 10.7 mmol, 1.41 mL, 2.0 eq) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 2 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was filtered to give a residue which was purified by column chromatography using a gradient of DCM. 1 -(2- Azidopropan -2- yl)naphthalene (1.00 g, 4.73 mmol, 88% yield) was obtained as a colorless oil.

Step 3: 2-(Naphthalen-l-yl)propan-2-amine (41A-3)

To a solution of l-(2-azidopropan-2-yl)naphthalene (1.00 g, 4.73 mmol, 1.0 eq) in trifluoroethanol (2.0 mL) was added 10% palladium on carbon (100 mg) at 25 °C in one portion. After degassing and purging with H2 three times, the mixture was stirred at 25 °C for 1 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrated was concentrated under vacuum to give the crude product 2-(naphthalen-l-yl)propan- 2-amine (500 mg, 2.70 mmol, 63% yield), which was used in the next step without any further purification. M - 17 + H ⁺ = 169.1 (LCMS).

Step 4: tert-Butyl (( 5-ni el Iiyl-6-(( 2-( na phi halen- 1 -y 1 )propa n-2-yI )car ba in oy 1 )- 1 //-indol-2- yl)methyl)carbamate (41A-4)

To a solution of 2-(naphthalen-l-yl)propan-2-amine (100 mg, 540 pmol, 1.0 eq) and 2-(((tert- butoxycarbonyl)amino)methyl)-5-methyl-17/-indole-6-carboxyli c acid (197 mg, 648 pmol, 1.2 eq) in DCM (3.0 mL) were added HATU (308 mg, 810 pmol, 1.5 eq), DIEA (209 mg, 1.62 mmol, 3.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1 : 1, R/ = 0.3). / -Butyl ((5- methyl-6-((2-(naphthalen-l-yl)propan-2-yl)carbamoyl)-U/-indo l-2-yl)methyl)carbamate (100 mg, 212 pmol, 39% yield) was obtained as a yellow oil. M + H ⁺ = 472.2 (LCMS). Step 5: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide

(Compound 281)

To a stirred solution of tert-butyl ((5-methyl-6-((2-(naphthalen-l-yl)propan-2-yl)carbamoyl)- U/-indol-2-yl)methyl)carbamate (100 mg, 212 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-Aminoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl ) benzamide (45.3 mg, 119 pmol, 56% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 372.1 (LCMS); ^T H NMR (400 MHz, DMSO-t/e) 6 11.25 - 11.07 (m, 1H), 8.83 - 8.75 (m, 2H), 8.49 - 8.23 (m, 3H), 7.94 (dd, J= 3.1, 6.4 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.1 Hz, 1H), 7.52 - 7.45 (m, 3H), 7.29 (d, J = 5.0 Hz, 2H), 6.43 (s, 1H), 4.17 (br d, J= 5.8 Hz, 2H), 2.14 (s, 3H), 1.89 (s, 6H).

Example 42: 2-(Am inomethyl )-5-met hyl-\-(napht halen- 1-yl methyl )-l//-indole-6- carboxamide (Compound 241)

Step 2

Compound 241

Step 1: tert- Butyl ((5-methyl-6-((naphthalen-l-ylmethyl)carbamoyl)-lH-indol-2- yl)methyl)carbamate (42A-1) To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methyl-U/-indole-6- carboxylic acid (120 mg, 394 pmol, 1.0 eq) and 5 naphthalen-l-ylmethanamine (62.0 mg, 394 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (120 mg, 1.18 mmol, 165 pL, 3.0 eq), EDCI (189 mg, 986 pmol, 2.5 eq) and HOBt (133 mg, 986 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/100 to 1/1. tert-Butyl ((5- methyl-6-((naphthalen-l-ylmethyl)carbamoyl)-l/Z-indol-2-yl)m ethyl)carbamate (60.0 mg, 73.1 pmol, 19% yield) was obtained as a yellow solid. M + H ⁺ = 444.2 (LCMS).

Step 2: 2-( A in in 0111 et hy 1 )-5-m et hy l- X -( na p hl Ii alen- 1 -y 1 in et hy 1 )- 1 //-i ndole-6-ca r boxa in id e (Compound 241)

To a stirred solution of tert-butyl ((5-methyl-6-((naphthalen-l-ylmethyl)carbamoyl)-U/-indol- 2-yl)methyl)carbamate (60.0 mg, 73.1 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- (Aminomethyl)-5-methyl-A-(naphthalen-l-ylmethyl)-U/-indole-6 -carboxamide (18.9 mg, 54.4 pmol, 39% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 344.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 11.38 (s, 1H), 8.77 (t, J= 5.8 Hz, 1H), 8.55 (br s, 3H), 8.24 (d, J = 7.9 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.62 - 7.47 (m, 4H), 7.43 (s, 1H), 7.35 (s, 1H), 6.47 (s, 1H), 4.93 (d, J= 5.8 Hz, 2H), 4.17 (q, J= 5.7 Hz, 2H), 2.41 (s, 3H).

Example 43: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e

(Compound 147)

Step 1

43A-1 43A-2

Compound 147

Step 1: l-(Naphthalen-l-yl)cyclopropanamine (43A-2)

A mixture of 1 -naphthonitrile (30.0 g, 196 mmol, 1.0 eq) in anhydrous Et20 (1000 mL) was degassed and purged with N2 three times. The mixture was stirred with a mechanical stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (61.2 g, 215 mmol, 63.4 mL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 144 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (55.6 g, 392 mmol, 48.3 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (500 mL) and MTBE (500 mL), and extracted with MTBE (500 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (500 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(Naphthalen-l-yl)cyclopropanamine (15.0 g, 81.9 mmol, 21% yield) was obtained as a yellow oil. M + H ⁺ = 184.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.47 - 8.45 (br d, J = 8.31 Hz, 1H), 7.91 (br d, J= 8.19 Hz, 1H), 7.78 (br d, J= 8.19 Hz, 1H), 7.67 - 7.57 (m, 1H), 7.56 - 7.50 (m, 2H), 7.46 - 7.38 (m, 1H), 1.25 - 1.18 (m, 2H), 1.09 - 1.00 (m, 2H). Step 2: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-nitrobenzamid e (43A-3)

To a solution of l-(naphthalen-l-yl)cyclopropanamine (70.0 mg, 382 pmol, 1.0 eq) and 2- methyl-5-nitrobenzoic acid (76.1 mg, 420 pmol, 1.1 eq) in DCM (2.0 mL) were added TEA (116 mg, 1.15 mmol, 160 pL, 3.0 eq), EDCI (87.9 mg, 458 pmol, 1.2 eq) and HOBt (61.9 mg, 458 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.7). 2-Methyl-7V-(l- (naphthalen-l-yl)cyclopropyl)-5-nitrobenzamide (50.0 mg, 144 pmol, 38% yield) was obtained as a white solid. M + H ⁺ = 347.2 (LCMS).

Step 3: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (Compound 14 7)

To a solution of 2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)-5 -nitrobenzamide (30.0 mg, 86.7 pmol, 1.0 eq) in a mixture of MeOH (2.0 mL) and H2O (0.5 mL) were added iron powder (24.2 mg, 433 pmol, 5.0 eq) and NH4CI (23.2 mg, 433 pmol, 5.0 eq). The resulting mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Amino-2-methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (10.1 mg, 28.4 pmol, 33% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 317.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.33 (s, 1H), 8.56 (d, J= 8.3 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.82 (d, J = 8.3 Hz, 1H), 7.60 - 7.42 (m, 3H), 7.30 - 7.26 (m, 2H), 7.03 (d, J= 2.0 Hz, 1H), 2.20 - 1.92 (m, 3H), 1.55 - 1.39 (m, 2H), 1.38 - 1.25 (m, 2H). Example 44: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)cyclobutyl)benzamide (Compound 219)

Compound 219

Step 1: l-(Naphthalen-l-yl)cyclobutanol (44A-2)

A test tube with magnesium (572 mg, 23.5 mmol, 1.65 eq) was flame dried under vacuum. After cooling to 25 °C under argon, I2 (36.2 mg, 143 pmol, 0.01 eq) and THF (21 mL) were added, followed by a solution of 1 -bromonaphthalene (4.43 g, 21.4 mmol, 10.7 mL, 1.5 eq) in THF (10 mL) in portions at 25 °C. The reaction mixture was then stirred at 70 °C for 1.5 h. The mixture was cooled to 0 °C and cyclobutanone (1.00 g, 14.3 mmol, 1.10 mL, 1.0 eq) was added dropwise. The resulting mixture was stirred for 16 h at 25 °C. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(Naphthalen-l-yl)cyclobutanol (2.40 g, 12.1 mmol, 8% yield) was obtained as a white solid. flT NMR (400 MHz, CDCh) 8 8.36 - 8.25 (m, 1H), 7.93 - 7.86 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.57 - 7.48 (m, 3H), 7.47 - 7.41 (m, 1H), 2.88 (ddd, J= 5.9, 8.8, 12.3 Hz, 2H), 2.64 (ddd, J = 6.7, 9.3, 12.3 Hz, 2H), 2.32 - 2.22 (m, 1H), 2.17 (dddd, J = 3.4, 5.6, 9.2, 11.2 Hz, 1H), 1.79 - 1.64 (m, 1H).

Step 2: 1-(1-Azidocyclobutyl)naphthalene (44A-3)

To a solution of 1 -(naphthal en-l-yl)cy cl obutanol (500 mg, 2.52 mmol, 1.0 eq) and azidotrimethylsilane (349 mg, 3.03 mmol, 1.2 eq) in DCM (13 mL) was added FeCh (8.18 mg, 50.4 pmol, 0.02 eq) at 0 °C under a N2 atmosphere. Then the reaction mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was quenched by H2O (30 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product l-(l-azidocyclobutyl)naphthalene (560 mg) as a yellow gum, which was used in the next step without any further purification.

Step 3: l-(Naphthalen-l-yl)cyclobutanamine (44A-4)

To a solution of l-(l-azidocyclobutyl)naphthalene (100 mg, 448 pmol, 1.0 eq) in THF (4.0 mL) was added LiAlHj (17.9 mg, 470 pmol, 1.0 eq) at 0 °C under a N2 atmosphere. Then the reaction mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by the addition of saturated aqueous NH4CI (10 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product 1 -(naphthal en-l-yl)cy cl obutanamine as a yellow gum, which was used in the next step without any further purification. M + H ⁺ = 198.1 (LCMS).

Step 4: 2-Methyl- \-( l-(naphthalen-l-yl)cyclobutyl)-5-nitrobenzamide (44A-5)

To a solution of 2-methyl-5-nitrobenzoic acid (70.7 mg, 390 pmol, 1.1 eq) and 1 -(naphthal en- l-yl)cy cl obutanamine (70.0 mg, 355 pmol, 1.0 eq) in DMF (4 mL) was added DIEA (138 mg, 1.06 mmol, 185 pL, 3.0 eq). After stirring 5 min, HATU (148 mg, 390 pmol, 1.1 eq) was added. The resulting mixture was stirred at 25 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL), and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.4). 2-Methyl-7V-(l- (naphthalen-l-yl)cyclobutyl)-5-nitrobenzamide (100 mg, 277 pmol, 78% yield) was obtained as a white solid. Step 5: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)cyclobutyl)benzamide (Compound 219)

To a stirred solution of 2-methyl-7V-(l-(naphthalen-l-yl)cyclobutyl)-5-nitrobenzamide (100 mg, 277 pmol, 1.0 eq) in a mixture of MeOH (10 mL) and H2O (2.5 mL) was added iron powder (77.5 mg, 1.39 mmol, 5.0 eq), followed by NH4CI (74.2 mg, 1.39 mmol, 5.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The suspension was filtered through a pad of Celite and the filtrate were poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 10 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-Amino-2-methyl-7V-(l-(naphthalen-l- yl)cyclobutyl)benzamide (35.9 mg, 107 pmol, 39% yield) was obtained as a white solid. M + H ⁺ = 331.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.03 - 7.96 (m, 1H), 7.95 - 7.89 (m, 1H), 7.80 (d, J= 7.4 Hz, 2H), 7.56 - 7.42 (m, 3H), 6.90 (d, J = 8.0 Hz, 1H), 6.62 - 6.50 (m, 2H), 6.27 (br s, 1H), 3.67 - 3.38 (m, 2H), 3.25 (ddd, J= 6.1, 9.3, 12.6 Hz, 2H), 3.03 - 2.88 (m, 2H), 2.37 - 2.26 (m, 1H), 2.19 (s, 3H), 1.95 - 1.82 (m, 1H).

Example 45: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 177)

45A-1

Compound 177 Step 1: tert-Butyl 3-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enyl) amino)azetidine-l-carboxylate (45A-1)

To a solution of l-(l-naphthyl)cyclopropanamine (39.5 mg, 215 pmol, 1.1 eq) and 5-((l-(tert- butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (60.0 mg, 196 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (59.5 mg, 588 pmol, 81.8 pL, 3.0 eq), EDCI (113 mg, 588 pmol, 3.0 eq) and HOBt (79.4 mg, 588 pmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3 -((4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl) carbamoyl)phenyl)amino) azetidine- 1 -carboxylate (100 mg), which was used in the next step without any further purification. M + H ⁺ = 472.3 (LCMS).

Step 2: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(naphthalen-l-yl)cyclo propyl)benzamide (Compound 177)

To a solution of tert-butyl 3 -((4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl)phenyl) amino)azetidine-l -carboxylate (100 mg, 212 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (21.7 mg, 58.4 pmol, 28% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 372.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.02 - 8.88 (m, 3H), 8.68 - 8.62 (m, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.62 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 6.88 (d, J= 8.3 Hz, 1H), 6.41 (dd, J= 2.5, 8.1 Hz, 1H), 6.20 (d, = 2.4 Hz, 1H), 4.29 - 4.20 (m, 1H), 4.31 - 4.20 (m, 2H), 4.19 - 4.10 (m, 2H), 1.99 - 1.83 (m, 3H), 1.39 - 1.28 (m, 2H), 1.19 - 1.07 (m, 2H). Example 46: 5-(Cyanomethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) benzamide (Compound 313)

Compound 313

Step 1: 5-(Hydroxymethyl)-2-methylbenzoic acid (46A-2)

To a solution of (3-bromo-4-methylphenyl)methanol (1.00 g, 4.97 mmol, 1.0 eq) in THF (10 mL) was added w-BuLi (2.5 M in hexane, 4.97 mL, 2.5 eq) at -78 °C. The mixture was stirred at the same temperature for 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH4CI (10 mL) and acidified to pH 6 using HCI (1 M, aqueous). The product was extracted with EtOAc (5.0 mL x 3). The organic layer was washed with brine (5.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by trituration from EtOAc/petroleum ether = 1/5, then filtered. 5-(Hydroxymethyl)-2- methylbenzoic acid (280 mg, 1.68 mmol, 29% yield) was obtained as a white solid. 'H NMR (400 MHz, DMSO ) 8 13.67 - 12.06 (m, 1H), 7.98 (d, J= 0.6 Hz, 1H), 8.04 - 7.93 (m, 1H), 7.55 (dd, J= 1.4, 7.8 Hz, 1H), 7.42 (d, J= 7.8 Hz, 1H), 4.68 (s, 2H), 2.68 (s, 3H).

Step 2: 5-(Hydroxymethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (46A-3) To a solution of 5-(hydroxymethyl)-2-methylbenzoic acid (280 mg, 1.68 mmol, 1.0 eq), 1-(1- naphthyl)cyclopropanamine (309 mg, 1.68 mmol, 1.0 eq) in DMF (10 mL) were added TEA (511 mg, 5.05 mmol, 704 pL, 3.0 eq), EDCI (323 mg, 1.68 mmol, 1.0 eq) and HOBt (228 mg, 1.68 mmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H2O (5.0 mL) and dried under vacuum to give the crude product 5-(hydroxymethyl)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (570 mg) as a white solid. 'H NMR (400 MHz, DMSO ) 8 9.12 (s, 1H), 8.66 (d, J= 8.2 Hz, 1H), 7.96 - 7.91 (m, 1H), 7.83 (d, J = 7.7 Hz, 2H), 7.60 - 7.43 (m, 3H), 7.17 (br d, J= 7.7 Hz, 1H), 7.07 (d, J= 7.8 Hz, 1H), 7.01 (s, 1H), 5.14 (s, 1H), 4.39 (d, J= 5.5 Hz, 2H), 2.01 (s, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Step 3: 5-(Chloromethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )benzamide (46A- 4)

To a solution of 5-(hydroxymethyl)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (400 mg, 1.21 mmol, 1.0 eq) in DCM (20 mL) was added TEA (122 mg, 1.21 mmol, 168 pL, 1.0 eq), followed by MsCl (138 mg, 1.21 mmol, 93.0 pL, 1.0 eq). The mixture was stirred at 0 °C for 3 h and then at 20 °C for 9 h. LCMS indicated that the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/10. 5-(Chloromethyl)-2-methyl-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (300 mg, 858 pmol, 71% yield) was obtained as a white solid. M + H ⁺ = 350.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.48 (d, J= 8.4 Hz, 1H), 7.93 (dd, J= 7.6, 16.7 Hz, 2H), 7.82 (d, J= 8.3 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.55 - 7.45 (m, 2H), 7.25 (s, 1H), 7.15 (d, J= 1.3 Hz, 1H), 7.10 (d, J= 7.9 Hz, 1H), 6.50 (br s, 1H), 4.47 (s, 2H), 2.17 (s, 3H), 1.55 - 1.55 (m, 1H), 1.63 - 1.55 (m, 1H), 1.45 - 1.38 (m, 2H).

Step 4: 5-(Cyanomethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) benzamide (Comp ound 313)

To a solution of 5-(chloromethyl)-2-methyl-A-(l -(naphthal en-l-yl)cyclopropyl)benzamide (300 mg, 858 pmol, 1.0 eq) in THF (9.0 mL) were added NaHCOs (1 M aqueous, 15.0 mL), KI (285 mg, 1.72 mmol, 2.0 eq), NaCN (510 mg, 10.4 mmol, 12.0 eq) and H2O (9.0 mL).The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to warm to room temperature and concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 80% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(Cyanomethyl)-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (31.9 mg, 89.0 pmol, 10% yield, FA salt) was obtained as a white solid. M + H ⁺ = 341.1 (LCMS); flT NMR (400 MHz, DMSO ) 8 9.18 (s, 1H), 8.63 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.83 (dd, J= 4.0, 7.6 Hz, 2H), 7.60 - 7.42 (m, 3H), 7.25 - 7.19 (m, 1H), 7.18 - 7.13 (m, 1H), 7.03 (d, J= 1.3 Hz, 1H), 3.93 (s, 2H), 1.99 (s, 3H), 1.35 (s, 2H), 1.18 (br s, 2H).

Example 47 : 5-(2-Aminoethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )benzamide (Compound 378)

Compound 313 Compound 378

Step 1: 5-(2-Aminoethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )benzamide (Com pound 378)

To a solution of 5 -(cyanomethyl)-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (70.0 mg, 206 pmol, 1.0 eq) in THF (10 mL) were added Raney -Ni (17.6 mg, 206 pmol, 1.0 eq) and NH3.H2O (26.7 mg, 206 pmol, 29.3 pL, 27% purity, 1.0 eq) under a N2 atmosphere. The mixture reaction was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The combined organic layers were filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-Aminoethyl)-2-methyl-A-(l- (naphthalen-l-yl)cyclopropyl)benzamide (17.6 mg, 44.4 pmol, 22% yield, FA salt) was obtained as as a white solid. M + H ⁺ = 345.0 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.14 (s, 1H), 8.66 (br d, J= 8.2 Hz, 1H), 8.42 (br s, 1H), 7.93 (d, J= 8.1 Hz, 1H), 7.83 (dd, J= 2.9, 7.6 Hz, 2H), 7.61 - 7.44 (m, 3H), 7.13 - 7.03 (m, 2H), 6.92 (s, 1H), 2.82 (br d, J= 6.4 Hz, 2H), 2.68 (br d, J= 7.1 Hz, 2H), 2.00 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 48: 6-Methyl-/V ¹ -(l-(naphthalen-l-yl)cyclopropyl)isophthalamide (Compound 257)

Compound 257

Step 1: 5-Cyano-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (48A-2)

To a solution of l-(naphthalen-l-yl)cyclopropanamine (114 mg, 621 pmol, 1.0 eq) and 5- cyano-2-m ethylbenzoic acid (100 mg, 621 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (188 mg, 1.86 mmol, 283 pL, 3.0 eq), EDCI (297 mg, 1.55 mmol, 2.5 eq) and HOBt (210 mg, 1.55 mmol, 2.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. 5-Cyano-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (150 mg, 460 pmol, 74% yield) was obtained as a yellow oil. M + H ⁺ = 327.2 (LCMS).

Step 2: 6-Methyl-/VL(l-(naphthalen-l-yl)cyclopropyl)isophthalamide (Compound 257)

A mixture of 5-cyano-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (200 mg, 434 pmol, 1.0 eq) in H2SO4 (3.0 mL) was stirred at 70 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 35% - 55% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 6- Methyl-A ¹ -(l-(naphthalen-l-yl)cyclopropyl) isophthalamide (16.0 mg, 43.2 pmol, 14% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 345.0 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 9.19 (s, 1H), 8.64 (s, 1H), 7.98 - 7.88 (m, 2H), 7.84 (d, J= 7.9 Hz, 2H), 7.74 (br d, J = 7.9 Hz, 1H), 7.64 - 7.43 (m, 4H), 7.27 (br s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 2.06 (s, 3H), 1.38 (s, 2H), 1.19 (br s, 2H).

Example 49: 5-(2-Amino-2-oxoethyl)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 312)

Step 1

Compound 313 Compound 312

Step 1: 5-(2-Amino-2-oxoethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclo propyl)benzamide (Compound 312)

To a solution of 5 -(cyanomethyl)-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 294 pmol, 1.0 eq) in a mixture of DMSO (1.0 mL) and EtOH (3.0 mL) were added H2O2 (99.9 mg, 881 pmol, 84.7 pL, 30% purity, 3.0 eq) and NaOH (2 M aqueous, 441 pL, 3.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NaSCL (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by trituration from EtOAc/petroleum ether = 1/5, then filtered. 5- (2-Amino-2-oxoethyl)-2-methyl-N-(l -(naphthal en-l-yl)cyclopropyl)benzamide (35.2 mg, 89.7 pmol, 31% yield) was obtained as a white solid. M + H ⁺ = 359.0 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.11 (s, 1H), 8.64 (br d, J= 8.4 Hz, 1H), 7.93 (br d, J= 7.9 Hz, 1H), 7.83 (br d, J= 7.7 Hz, 2H), 7.60 - 7.44 (m, 3H), 7.38 (br s, 1H), 7.13 (br d, J= 7.6 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.95 (s, 1H), 6.81 (br s, 1H), 3.25 (s, 2H), 1.96 (s, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H). Example 50: 5-(2,5-Dihydro-lH-pyrrol-3-yl)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 398)

Compound 398

Step 1: 5-Bromo-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (50A-1)

To a solution of l-(naphthalen-l-yl)cyclopropanamine (155 mg, 846 pmol, 1.0 eq) and 5- bromo-2-methylbenzoic acid (200 mg, 930 pmol, 1.1 eq) in DMF (2.0 mL) were added TEA (257 mg, 2.54 mmol, 353 pL, 3.0 eq), EDCI (243 mg, 1.27 mmol, 1.5 eq) and HOBt (171 mg, 1.27 mmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.7). 5-Bromo-2-methyl- 7V-(1 -(naphthal en-l-yl)cy cl opropyl) benzamide (260 mg, 684 pmol, 81% yield) was obtained as a white solid. M + H ⁺ = 380.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.25 (s, 1H), 8.63 (d, J= 8.2 Hz, 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.82 (dd, J= 7.8, 11.1 Hz, 2H), 7.62 - 7.50 (m, 2H), 7.48 - 7.39 (m, 2H), 7.21 (d, J= 1.8 Hz, 1H), 7.10 (d, J= 8.2 Hz, 1H), 1.97 (s, 3H), 1.37 (br s, 2H), 1.17 (br s, 2H).

Step 2: tert- Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe nyl)-

2. -d iliy dr o- 1 //-py r role- 1 -car boxy late (50A-2)

To a stirred solution of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (60.0 mg, 158 pmol, 1.0 eq) and tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-

2.5-dihydro- l //-pyrrol e- l -carboxylate (55.9 mg, 189 pmol, 1.2 eq) in a mixture of dioxane (1.0 mL) and H2O (0.3 mL) were added Pd(dppf)C12 (11.5 mg, 15.8 pmol, 0.1 eq), K2CO3 (65.4 mg, 473 pmol, 3.0 eq) in one portion. The mixture was degassed and purged with N2 three times and then was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.4). tert-Butyl 3 -(4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl) phenyl)-2,5-dihydro-l//-pyrrole-l-carboxylate (70.0 mg, 149 pmol, 95% yield) was obtained as a white solid. M + H ⁺ = 469.2 (LCMS).

Step 3: 5-(2.5-l)ihydro-l//-pyrrol-3-yl)-2-methyl- \-( l-(naphthalen-l-yl)cyclopropyl) benzamide (Compound 398)

To a stirred solution of tert-butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)-2,5-dihydro-l//-pyrrole-l-carboxylate (70.0 mg, 149 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5 -(2, 5 -Dihydro- 1 //-pyrrol-3-yl )-2-methyl-/' -( l -(naphthal en- 1 - yl)cyclopropyl)benzamide (25.3 mg, 68.7 pmol, 46% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 369.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.45 (br s, 2H), 9.16 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.86 - 7.79 (m, 2H), 7.62 - 7.55 (m, 1H), 7.54 (br d, J= 1.4 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.21 - 7.12 (m, 2H), 6.34 (t, J= 1.8 Hz, 1H), 4.25 (br d, J= 1.8 Hz, 2H), 4.10 (br s, 2H), 2.03 (s, 3H), 1.42 - 1.34 (m, 2H), 1.24 - 1.15 (m, 2H). Example 51: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(l,2,3,6-tetr ahydropyridin- 4-yl)benzamide (Compound 399)

Compound 399

Step 1: tert-Butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe nyl)-

5.6-dihydr opyr idine- 1 (2ET)-carboxylate (51 A- 1)

To a stirred solution of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (60.0 mg, 158 pmol, 1.0 eq) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-

5.6-dihydropyridine-l(2rt)-carboxylate (58.5 mg, 189 pmol, 1.2 eq) in a mixture of dioxane (1.0 mL) and FLO (0.3 mL) was added Pd(dppf)C12 (11.5 mg, 15.8 pmol, 0.1 eq), K2CO3 (65.4 mg, 473 pmol, 3.0 eq) in one portion. The mixture was degassed and purged with N2 three times and then was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.4). tert-Butyl 4-(4-methyl-3 -((1 -(naphthal en-1- yl)cyclopropyl)carbamoyl)phenyl)-5,6-dihydropyridine-l(2rt)- carboxylate (70.0 mg, 145 pmol, 92% yield) was obtained as a white solid. M + H ⁺ = 483.2 (LCMS).

Step 2: 2-Methyl- \-( l-(naphthalen-l -yl)cyclopropyl)-5-( 1,2,3, 6-tetrahydropyridin-4- yl)benzamide (Compound 399)

To a stirred solution of tert-butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)-5,6-dihydropyridine-l(2rt)-carboxylate (70.0 mg, 145 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCI/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-5-(l, 2,3,6- tetrahydropyridin-4-yl)benzamide (50.0 mg, 131 pmol, 90% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 383.1 (LCMS); fld NMR (400 MHz, DMSO-t/e) 8 9.17 (s, 1H), 9.11 (br s, 2H), 8.66 (d, J= 8.3 Hz, 1H), 7.94 (d, J= 7.9 Hz, 1H), 7.83 (t, J= 7.1 Hz, 2H), 7.61 - 7.55 (m, 1H), 7.55 - 7.49 (m, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.36 (dd, J= 1.8, 8.1 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.10 (br s, 1H), 3.70 (br s, 2H), 3.27 (br s, 2H), 2.58 (br s, 2H), 2.03 (s, 3H), 1.42

- 1.33 (m, 2H), 1.24 - 1.14 (m, 2H).

Example 52: (L)-M ethyl 4-(2-(3-(2-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenyl)propanoyl)hydrazinyl)-4-oxob ut-2-enoate (Compound 373)

Step 1: 2-(3-Methoxy-3-oxopropyl)benzoic acid (52A-2)

To a solution of 2-(2-carboxyethyl)benzoic acid (2.00 g, 10.0 mmol, 1.0 eq) in MeOH (30 mL) was added H2SO4 (1.00 g, 10.0 mmol, 500 pL, 1.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The reaction mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 2-(3-Methoxy-3-oxo-propyl)benzoic acid (1.50 g, 7.00 mmol, 70% yield) was obtained as a white solid. M + H ⁺ = 209.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 7.93 (d, 1H), 7.44 - 7.50 (m, 1H), 7.28 - 7.35 (m, 2H), 3.65 (s, 3H), 3.28 - 3.34 (m, 2H), 2.66 (t, 2H).

Step 2: Methyl 3-(2-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phenyl)propa noate (52A-3)

To a solution of 2-(3-methoxy-3-oxo-propyl)benzoic acid (300 mg, 1.44 mmol, 1.0 eq) and 1- (l-naphthyl)cyclopropanamine (264 mg, 1.44 mmol, 1.0 eq) in DCM (10 mL) were added TEA (437 mg, 4.32 mmol, 601 pL, 3.0 eq), HOBt (292 mg, 2.16 mmol, 1.5 eq) and EDCI (414 Mg, 2.16 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). Methyl 3 -(2-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenyl)propanoate (109 mg, 300 pmol, 20% yield) was obtained a white solid. M + H ⁺ = 374.2 (LCMS).

Step 3: 2-(3-Hydrazinyl-3-oxopropyl)-/V-(l-(naphthalen-l-yl)cyclopro pyl)benzamide (52A-4)

To a mixture of methyl 3-(2-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phenyl)propa noate (90.0 mg, 200 pmol, 1.0 eq) in EtOH (3.0 mL) was added NH2NH2.H2O (120 mg, 2.00 mmol, 100 pL, 10 eq) at 25 °C. The reaction mixture was stirred at 80 °C for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, concentrated under vacumm to give the crude product 2-(3-hydrazino-3- oxo-propyl)-A-[l-(l-naphthyl)cyclopropyl]benzamide (90.0 mg), which was used in the next step without any further purification. M + H ⁺ = 374.2 (LCMS).

Step 4: (E)-Methyl 4-(2-(3-(2-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phenyl ) propanoyl)hydrazinyl)-4-oxobut-2-enoate (Compound 373)

To a mixture of (£)-4-methoxy-4-oxo-but-2-enoic acid (200 mg, 1.54 mmol, 1.0 eq) and DMF (11.2 mg, 154 pmol, 11.8 pL, 0.1 eq) in DCM (1.0 mL) was added (COC1)2 (390 mg, 3.07 mmol, 269 pL, 2.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was concentrated under vacuum to give a residue which was diluted with DCM (500 pL). The solution was added to a mixture of 2-(3-hydrazino-3-oxo-propyl)-7V-[l-(l- naphthyl)cyclopropyl]benzamide (90.0 mg, 241 pmol, 1.0 eq) and DIEA (156 mg, 1.20 mmol, 210 pL, 5.0 eq) in DCM (1.0 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 15 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (E)-Methyl 4-(2-(3-(2-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenyl) propanoyl)hydrazinyl)-4-oxobut-2-enoate (11.9 mg, 23.8 pmol, 11% yield) was obtained as a white solid. M + H ⁺ = 486.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.22 (s, 1H), 8.66 (br d, J= 8.4 Hz, 1H), 7.93 (br d, J= 7.8 Hz, 1H), 7.82 (br dd, J= 2.4, 7.6 Hz, 2H), 7.62 - 7.42 (m, 3H), 7.32 - 7.18 (m, 2H), 7.17 - 6.96 (m, 3H), 6.69 (d, J = 15.6 Hz, 1H), 3.75 (s, 3H), 2.78 (br t, J= 7.8 Hz, 2H), 2.38 (br t, J= 7.8 Hz, 2H), 1.39 (br s, 2H), 1.17 (br s, 2H).

Example 53: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 215)

Compound 215

Step 1: tert-Butyl (2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl) phenoxy) ethyl)carbamate (53A-1)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (124 mg, 677 pmol, 1.0 eq) and 5-(2- ((/ert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (200 mg, 677 pmol, 1.0 eq) in DCM (10 mL) were added TEA (206 mg, 2.03 mmol, 283 pL, 3.0 eq), EDCI (325 mg, 1.69 mmol, 2.5 eq) and HOBt (229 mg, 1.69 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. /c/7-Butyl (2-(4-methyl-3-((l- (naphthalen-l-yl)cyclopropyl) carbamoyl)phenoxy)ethyl) carbamate (300 mg, 651 pmol, 96% yield) was obtained as a yellow gum. M + H ⁺ = 461.2 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.47 (br d, J= 8.3 Hz, 1H), 7.93 (br dd, J= 7.6, 17.4 Hz, 2H), 7.81 (br d, J= 8.2 Hz, 1H), 7.62

- 7.55 (m, 1H), 7.54 - 7.45 (m, 2H), 7.00 (br d, J= 8.6 Hz, 1H), 6.78 - 6.72 (m, 1H), 6.69 (br s, 1H), 6.50 (br s, 1H), 3.95 - 3.83 (m, 2H), 3.46 (br d, J= 4.8 Hz, 2H), 1.50 - 1.36 (m, 13H).

Step 2: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (Compound 215)

To a stirred solution of ZerLbutyl (2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)ethyl) carbamate (200 mg, 434 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-(2-aminoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl ) benzamide (140 mg, 334 pmol, 77% yield, HC1 salt) as a white solid. M + H ⁺ = 361.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.14 (s, 1H), 8.66 (d, J = 8.3 Hz, 1H), 8.13 (br s, 3H), 7.93 (d, J = 7.5 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.62 - 7.42 (m, 3H), 7.07 (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 2.6, 8.4 Hz, 1H), 6.67 (d, J= 2.8 Hz, 1H), 4.09 (t, J= 5.1 Hz, 2H), 3.17 - 3.08 (m, 2H), 1.97 (s, 3H), 1.39

- 1.33 (m, 2H), 1.21 - 1.13 (m, 2H). Example 54: 5-(2-Aminoethoxy)-\.2-dimethyl-\-( l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 211)

Compound 211

Step 1: te/7- Butyl (2-(4-methyl-3-(methyl(l-(naphthalen-l-yl)cyclopropyl)carbam oyl) phenoxy)ethyl)carbamate (54A-1)

To a solution of tert-butyl (2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph en oxy)ethyl)carbamate (50.0 mg, 109 pmol, 1.0 eq) in THF (3.0 mL) was added sodium hydride (8.68 mg, 217 pmol, 60% purity, 2.0 eq) and the mixture was stirred at 0 °C for 30 min. Mel (7.70 mg, 54.3 pmol, 3.38 pL, 0.5 eq) was added at 0 °C and was stirred at 20 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 50% - 80% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). te/7-Butyl (2-(4-methyl-3-(methyl(l-(naphthalen-l-yl)cyclopropyl)carbam oyl)phenoxy)ethyl)carbamate (50.0 mg, 105 pmol, 97% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 475.1.

Step 2: 5-(2-Aminoethoxy)-\.2-dimethyl-\-( l-(naphthalen-l-yl)cyclopropyl)benzamide (Compound 211)

To a solution of tert-butyl (2-(4-methyl-3-(methyl(l-(naphthalen-l-yl)cyclopropyl)carbam oyl) phenoxy)ethyl)carbamate (50.0 mg, 105 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HClZEtOAc (4 M, 2.91 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give 5-(2-aminoethoxy)-7V,2-dimethyl-7V-(l- (naphthalen- l-yl)cy cl opropyl )benzamide (38.0 mg, 84.2 pmol, 76% yield, HC1 salt) as a white solid. M + H ⁺ = 375.1; 'H NMR (400 MHz, DMSO-tL) 8 9.20 - 9.07 (m, 1H), 8.08 (br s, 2H), 8.14 - 8.01 (m, 1H), 7.99 - 7.85 (m, 3H), 7.64 - 7.47 (m, 3H), 7.13 - 7.07 (m, 1H), 6.90 - 6.82 (m, 1H), 6.62 - 6.54 (m, 1H), 4.15 - 4.06 (m, 2H), 3.16 - 3.09 (m, 2H), 2.78 - 2.71 (m, 3H), 1.86 - 1.81 (m, 5H), 1.37 (br s, 2H).

Example 55: 5-(3-Aminopropoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 316)

Compound 316

Step 1: 5-Hydroxy-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (55A-2)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (4.82 g, 26.3 mmol, 0.8 eq) and 5- hydroxy-2-methylbenzoic acid (5.00 g, 32.9 mmol, 1.0 eq) in DMF (100 mL) were added TEA (3.33 g, 32.7 mmol, 4.57 mL, 1.0 eq), EDCI (6.61 g, 34.5 mmol, 1.1 eq) and HOBt (888 mg, 6.57 mmol, 0.2 eq). The mixture was stirred at 25 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (100 mL) and extracted with EtOAc (20 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was triturated from a mixture of EtOAc (10 mL) and petroleum ether (30 mL) and stirred at room temperature for 10 min. 5-Hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl) benzamide (5.00 g, 15.8 mmol, 48% yield) was obtained as a white solid. M + H ⁺ = 318.1 (LCMS). Step 2: tert-Butyl (3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) propyl)carbamate (55A-3)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 315 pmol, 1.0 eq) and tert-butyl (3-hydroxypropyl)carbamate (55.2 mg, 315 pmol, 54.1 pL, 1.0 eq) in anhydrous toluene (5.0 mL) was degassed and purged with N2 three times. To the mixture was added CMBP (114 mg, 473 pmol, 1.5 eq) dropwise at 20 °C. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.5). tert- Butyl (3 -(4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenoxy)propyl) carbamate (70.0 mg, 148 pmol, 47% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 475.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.07 (s, 1H), 8.66 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.60 - 7.43 (m, 3H), 7.02 (d, J= 8.4 Hz, 1H), 6.88 - 6.78 (m, 2H), 6.60 (d, J= 2.6 Hz, 1H), 3.86 (t, J= 6.3 Hz, 2H), 3.02 (q, J= 6.5 Hz, 2H), 1.95 (s, 3H), 1.76 (q, J= 6.5 Hz, 2H), 1.35 (s, 11H), 1.19 - 1.16 (m, 2H).

Step 3: 5-(3-Aminopropoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cycloprop yl)benzamide (Compound 316)

To a stirred solution of tert-butyl (3 -(4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl) phenoxy )propyl)carbamate (70.0 mg, 148 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(3-Aminopropoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cycloprop yl) benzamide (53.7 mg, 131 pmol, 87% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 375.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.09 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.98 - 7.85 (m, 4H), 7.85 - 7.80 (m, 2H), 7.60 - 7.49 (m, 2H), 7.46 (dd, J= 7.3, 8.1 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 6.84 (dd, J = 2.8, 8.4 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 3.96 (t, J= 6.2 Hz, 2H), 2.94 - 2.83 (m, 2H), 1.99 - 1.91 (m, 5H), 1.38 - 1.32 (m, 2H), 1.21 - 1.12 (m, 2H). Example 56: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-( l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 233)

Compound 233

Step 1: Methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoate (56A-1)

To a solution of methyl 5 -hydroxy-2-m ethylbenzoate (1.00 g, 6.02 mmol, 1.0 eq) and tert-butyl (2 -hydroxy ethyl)(methyl)carbamate (1.58 g, 9.03 mmol, 1.5 eq) in toluene (30 mL) were added TMAD (3.11 g, 18.1 mmol, 3.0 eq) and PPI13 (4.74 g, 18.1 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times, and then stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoate (600 mg, 1.86 mmol, 31% yield) was obtained as a yellow oil. M - 56+ H ⁺ = 268.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.43 (br s, 1H), 7.14 (d, J= 8.4 Hz, 1H), 6.95 (dd, J= 2.4, 8.3 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.89 (s, 3H), 3.60 (br s, 2H), 2.98 (s, 3H), 2.52 (s, 3H), 1.46 (s, 9H).

Step 2: 5-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (56A-2)

To a solution of methyl 5-(2-((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoate (550 mg, 1.70 mmol, 1.0 eq) in a mixture of MeOH (16 mL) and THF (8.0 mL) was added NaOH (2 M aqueous, 3.40 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and the mixture was washed with MTBE (15 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-(2-((terLbutoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenz oic acid (470 mg), which was used in the next step without any further purification. M - 56+ H ⁺ = 254.1 (LCMS); ^X H NMR (400 MHz, CDCh) 8 7.58 (br d, J= 1.9 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.01 (dd, J= 2.8, 8.4 Hz, 1H), 4.12 (br s, 2H), 3.62 (br s, 2H), 3.00 (s, 3H), 2.58 (s, 3H), 1.47 (s, 9H).

Step 3: /+/7‘- Butyl methyl(2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbam oyl) phenoxy)ethyl)carbamate (56A-3)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (90.6 mg, 495 pmol, 0.9 eq), 5-(2-((tert- butoxycarbonyl)(methyl)amino)ethoxy)-2-methylbenzoic acid (170 mg, 550 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (111 mg, 1.10 mmol, 153 pL, 2.0 eq), EDCI (126 mg, 659 pmol, 1.2 eq) and HOBt (89.1 mg, 659 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl methyl(2-(4-methyl-3-((l- (naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)ethyl)carbamate (90.0 mg, 190 pmol, 35% yield) was obtained as a yellow oil. Step 4: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(naphthalen-l-yl)cy clopropyl)benzam ide (Compound 233)

To a solution of tert-butyl methyl(2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbam oyl) phenoxy)ethyl)carbamate (90.0 mg, 190 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (71.0 mg, 173 pmol, 91% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 375.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.16 (s, 1H), 9.02 (br s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.62 - 7.39 (m, 3H), 7.07 (d, J = 8.4 Hz, 1H), 6.89 (dd, J= 2.6, 8.4 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 4.16 (t, J = 4.9 Hz, 2H), 3.29 - 3.17 (m, 2H), 2.56 (t, J= 5.3 Hz, 3H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 57: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-((5)-2,2,2-tri fluoro-l-

(naphthalen-l-yl)ethyl)benzamide (Compound 386)

Step 3 Step 4

57A-2 57A-3

Step 5 57A-4 Compound 386

Step 1: tert- Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-l- carboxylate (57 A- 1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq) and tertbutyl 2-(hydroxymethyl)azetidine-l -carboxylate (592 mg, 3.16 mmol, 1.1 eq) in toluene (15 mL) were added TMAD (1.55 g, 9.03 mmol, 3.0 eq) and PPhi (2.37 g, 9.03 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl 2-((3 -(methoxy carbonyl)-4- methylphenoxy) methyl) azetidine- 1 -carboxylate (900 mg, 2.68 mmol, 89% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 280.0 (LCMS); ^X H NMR (400 MHz, CDCh) 8 7.50 - 7.47 (m, 1H), 7.17 - 7.12 (m, 1H), 7.03 - 6.97 (m, 1H), 4.56 - 4.45 (m, 1H), 4.34 - 4.24 (m, 1H), 4.13 (br d, J= 4.0 Hz, 1H), 4.18 - 4.07 (m, 1H), 3.95 (br s, 4H), 2.55 - 2.51 (m, 3H), 2.42 - 2.20 (m, 2H), 1.47 - 1.40 (m, 9H).

Step 2: Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (57A-2)

To a solution of tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine-1- carboxylate (800 mg, 2.39 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (3.26 g, 28.6 mmol, 2.12 mL, 12 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product methyl 5-(azetidin-2- ylmethoxy)-2-methylbenzoate (800 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification as a yellow oil. M + H ⁺ = 236.1 (LCMS). Step 3: Methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (57A-3)

To a solution of (methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (400 mg, 1.03 mmol, 1.0 eq, TFA salt) in MeOH (8.0 mL) was added TEA (80.0 pL), followed by the addition of formaldehyde (335 mg, 4.12 mmol, 307 pL, 37% purity in water, 4.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (518 mg, 8.25 mmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product methyl 2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzoate (400 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 250.1 (LCMS).

Step 4: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (57A-4)

A solution of methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (300 mg, 1.20 mmol, 1.0 eq) in HC1 (2 M aqueous 9.00 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H2O (10 mL) and washed with MTBE (20 mL x 2). The aqueous was acidified to pH 6 with NaOH (2 M aqueous). The product was extracted with DCM (10 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuum to give the crude product 2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzoic acid (220 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 236.1 (LCMS).

Step 5: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-N-((S)-2,2,2-tri fluoro-l- (naphthalen-l-yl)ethyl)benzamide (Compound 386)

To a solution of (5)-2,2,2-trifluoro-l-(naphthalen-l-yl)ethanamine (47.9 mg, 213 pmol, 1.0 eq) in acetonitrile (2.0 mL) was added 2-methyl-5-((l-methylazetidin-2-yl)methoxy) benzoic acid (50.0 mg, 213 pmol, 1.0 eq), followed by TCFH (71.6 mg, 255 pmol, 1.2 eq) and 1- methylimidazole (61.1 mg, 744 pmol, 59.3 pL, 3.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5 mL) and extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 * 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 5% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). CS’)- /c/V-Butyl 2-((3-(methoxycarbonyl)-4-methyl phenoxy )methyl)azeti dine- 1 -carboxylate (46.1 mg, 93.6 pmol, 44% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 443.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.36 - 9.75 (m, 1H), 8.31 - 8.24 (m, 1H), 8.07 - 7.99 (m, 2H), 7.96 - 7.88 (m, 1H), 7.73 - 7.55 (m, 3H), 7.24 - 7.18 (m, 1H), 7.06 - 6.98 (m, 1H), 6.91

- 6.79 (m, 2H), 4.70 - 4.57 (m, 1H), 4.32 - 4.24 (m, 2H), 4.09 - 3.98 (m, 1H), 3.92 - 3.81 (m, 1H), 2.88 - 2.81 (m, 3H), 2.44 - 2.30 (m, 2H), 2.23 - 2.14 (m, 3H).

Example 58: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 214)

Compound 215 Compound 214

Step 1 : 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l-yl) cyclopropyl)benza mide (Compound 214)

To a solution of 5-(2-aminoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (130 mg, 361 pmol, 1.0 eq) in MeOH (3.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (58.5 mg, 721 pmol, 53.7 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (45.3 mg, 721 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-(2-(dimethylamino)ethoxy)-2-methyl-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (61.0 mg, 157 pmol, 43% yield, HC1 salt) as a white solid. M + H ⁺ = 389.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 10.43 (br s, 1H), 9.14 (s, 1H), 8.66 (d, J=

8.3 Hz, 1H), 7.93 (d, J= 7.5 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.61 - 7.43 (m, 3H), 7.07 (d, J =

8.4 Hz, 1H), 6.90 (dd, J= 2.8, 8.4 Hz, 1H), 6.69 (d, J= 2.7 Hz, 1H), 4.26 (t, J= 5.1 Hz, 2H), 3.45 - 3.41 (m, 2H), 2.78 (d, J = 4.6 Hz, 6H), 1.96 (s, 3H), 1.39 - 1.33 (m, 2H), 1.20 - 1.15 (m, 2H).

Example 59: 5-(2-(Ethyl:imino)ethoxy)-2-methyl- \-(l-(n:iphthalen-l- yl)cyclopropyl)benzamide (Compound 351)

Compound 351

Step 1: 5-(2-Bromoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (59A-1)

To a solution of 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (1.00 g, 3.15 mmol, 1.0 eq) and 1,2-dibromoethane (5.92 g, 31.5 mmol, 2.38 mL, 10 eq) in acetone (30 mL) were added potassium carbonate (1.00 g, 7.25 mmol, 2.3 eq) and 18-crown-6 (41.6 mg, 158 pmol, 0.05 eq). The mixture was stirred at 60 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 100/1. 5-(2-Bromoethoxy)-2-methyl-7V-(l- (naphthalen-l-yl)cyclopropyl)benzamide (800 mg, 1.89 mmol, 60% yield) was obtained as a colorless oil. M + H ⁺ = 424.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.09 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.61 - 7.42 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.86 (dd, J = 2.8, 8.4 Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H), 4.26 - 4.20 (m, 2H), 3.77 - 3.72 (m, 2H), 1.96 (s, 3H), 1.39 - 1.34 (m, 2H), 1.19 (s, 2H). Step 2: 5-(2-(Ethylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyc lopropyl) benzamide (Compound 351)

To a solution of 5-(2-bromoethoxy)-2-methyl-7V-(l -(naphthal en-l-yl)cyclopropyl)benzamide (70.0 mg, 165 pmol, 1.0 eq) in acetonitrile (3.0 mL) was added ethanamine (8.18 mg, 181 pmol, 11.9 pL, 1.1 eq), followed by KI (5.48 mg, 33.0 pmol, 0.2 eq) and K2CO3 (45.6 mg, 330 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Ethylamino)ethoxy)- 2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl) benzamide (33.0 mg, 77.7 pmol, 47% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 389.1 (LCMS); NMR (400 MHz, DMSO- d ₆ ) 6 9.14 - 9.11 (m, 1H), 8.67 - 8.61 (m, 1H), 7.96 - 7.90 (m, 1H), 7.85 - 7.79 (m, 2H), 7.61

- 7.43 (m, 3H), 7.10 - 7.04 (m, 1H), 6.93 - 6.85 (m, 1H), 6.68 - 6.64 (m, 1H), 4.18 - 4.10 (m, 2H), 3.29 - 3.21 (m, 2H), 3.02 - 2.92 (m, 2H), 1.99 - 1.93 (m, 3H), 1.38 - 1.32 (m, 2H), 1.22

- 1.14 (m, 5H).

Example 60: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(2-((2,2,2- trifluoroethyl)amino)ethoxy)benzamide (Compound 247) Step 2 Step 3

60A-2

Compound 247

Step 1: Methyl 5-(2-aminoethoxy)-2-methylbenzoate (60A-1)

To a solution of methyl 5-(2-((terLbutoxycarbonyl)amino)ethoxy)-2-methylbenzoate (500 mg, 1.62 mmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give the crude product methyl 5-(2-aminoethoxy)- 2-methylbenzoate (400 mg, HC1 salt), which was used in the next step without any further purification. M + H ⁺ = 210.1 (LCMS).

Step 2: Methyl 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoate (60A-2)

To a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (333 mg, 1.43 mmol, 1.0 eq) and methyl 5-(2-aminoethoxy)-2-methylbenzoate (300 mg, 1.43 mmol, 1.0 eq) in THF (6.0 mL) was added TEA (435 mg, 4.30 mmol, 599 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (6.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 2/1. Methyl 2- methyl-5-(2-((2,2,2-trifluoroethyl) amino)ethoxy)benzoate (300 mg, 954 pmol, 67% yield) was obtained as a yellow oil. M + H ⁺ = 292.0 (LCMS).

Step 3: 2-Methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoic acid (60A-3)

To a solution of methyl 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoate (300 mg, 1.03 mmol, 1.0 eq) in a mixture of MeOH (8.0 mL) and THF (4.0 mL) was added NaOH (2 M aqueous, 2.16 mL). The mixture was stirred at 20 °C for 16 h. LCMS indicated that 14% of the starting material remained and the 80% of desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and washed with MTBE (3.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoic acid (280 mg), which was used in the next step without any further purification. M + H ⁺ = 278.0 (LCMS).

Step 4: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(2-((2,2,2-tr ifluoroethyl)amino)et hoxy)benzamide (Compound 247)

To a solution of 2-methyl-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)benzoic acid (80.0 mg, 289 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (52.9 mg, 289 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (58.4 mg, 577 pmol, 80.3 pL, 2.0 eq), EDCI (66.4 mg, 346 pmol, 1.2 eq) and HOBt (46.8 mg, 346 pmol, 1.2 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 40% - 70% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2 -Methyl-A-(1 -(naphthal en-1- yl)cyclopropyl)-5-(2-((2,2,2-trifluoroethyl)amino)ethoxy)ben zamide (52.4 mg, 115 pmol, 40% yield, HC1 salt) was obtained as a yellow oil. M + H ⁺ = 443.1 (LCMS); 'H NMR (400 MHz, CDCL) 8 8.46 (d, J= 8.3 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.81 (d, J= 8.4 Hz, 1H), 7.63 - 7.43 (m, 3H), 7.01 (d, J= 8.4 Hz, 1H), 6.77 (dd, J= 2.6, 8.4 Hz, 1H), 6.69 (d, J= 2.6 Hz, 1H), 6.68 - 6.66 (m, 1H), 3.95 (t, J = 5.1 Hz, 2H), 3.23 (d, J= 9.4 Hz, 2H), 3.05 (t, J= 4.9 Hz, 2H), 2.11 (s, 3H), 1.43 - 1.37 (m, 2H), 1.27 (s, 2H). Example 61: 5-(2-(Isopropylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 362)

Step 1

59A-1 Compound 362

Step 1: 5-(2-(Isopropylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l-yl )cyclopropyl) benzamide (Compound 362)

To a solution of propan-2-amine (10.7 mg, 181 pmol, 15.6 pL, 1.1 eq) in ACN (5.0 mL) were added 5-(2 -bromoethoxy )-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (70.0 mg, 165 pmol, 1.0 eq), KI (2.74 mg, 16.5 pmol, 0.1 eq) and K2CO3 (45.6 mg, 330 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Isopropylamino)ethoxy)-2-methyl-A- (l-(naphthalen-l-yl)cyclopropyl)benzamide (21.9 mg, 49.6 pmol, 30% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 403.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.18 - 9.08 (m, 1H), 8.74 - 8.69 (m, 1H), 8.68 - 8.63 (m, 1H), 7.97 - 7.91 (m, 1H), 7.86 - 7.80 (m, 2H), 7.61 - 7.43 (m, 3H), 7.12 - 7.05 (m, 1H), 6.93 - 6.86 (m, 1H), 6.70 - 6.65 (m, 1H), 4.19 - 4.13 (m, 2H), 3.26 (br s, 3H), 1.97 (s, 3H), 1.40 - 1.33 (m, 2H), 1.23 (d, J = 6.5 Hz, 6H), 1.20 - 1.16 (m, 2H). Example 62: 5-(2-((Cyclopropylmethyl)amino)ethoxy)-2-methyl-/V-(l-(napht halen-l- yl)cyclopropyl)benzamide (Compound 361)

Step 1

59A-1 Compound 361

Step 1: 5-(2-((Cyclopropylmethyl)amino)ethoxy)-2-methyl-/V-(l-(napht halen-l-yl)cyclo propyl)benzamide (Compound 361)

To a solution of cyclopropylmethanamine (12.9 mg, 181 pmol, 1.1 eq) in ACN (5.0 mL) were added 5-(2 -bromoethoxy )-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (70.0 mg, 165 pmol, 1.0 eq), KI (2.74 mg, 16.5 pmol, 0.1 eq) and K2CO3 (45.6 mg, 330 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-((Cyclopropylmethyl)amino)ethoxy)- 2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (18.9 mg, 41.6 pmol, 25% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 415.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.13 (s, 1H), 9.01 - 8.80 (m, 2H), 8.72 - 8.61 (m, 1H), 7.98 - 7.91 (m, 1H), 7.82 (br d, J = 5.9 Hz, 2H), 7.62 - 7.42 (m, 3H), 7.13 - 7.03 (m, 1H), 6.95 - 6.86 (m, 1H), 6.72 - 6.63 (m, 1H), 4.23 - 4.12 (m, 2H), 3.29 (br d, J= 4.9 Hz, 2H), 2.93 - 2.79 (m, 2H), 1.97 (s, 3H), 1.45 - 1.30 (m, 2H), 1.24 - 1.14 (m, 2H), 1.11 - 0.99 (m, 1H), 0.63 - 0.50 (m, 2H), 0.35 (br s, 2H). Example 63: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(2-

(phenylamino)ethoxy)benzamide (Compound 315)

55A-2 Compound 315

Step 1: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(2 - (phenylamino) ethoxy) benzamide (Compound 315)

A mixture of 5-hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 315 pmol, 1.0 eq) and 2-(phenylamino)ethanol (43.2 mg, 315 pmol, 1.0 eq) in anhydrous toluene (5.0 mL) was degassed and purged with N2 three times. To the mixture was added CMBP (114 mg, 473 pmol, 1.5 eq) dropwise at 20 °C. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-A-(l -(naphthal en-l-yl) cyclopropyl)-5- (2-(phenylamino)ethoxy) benzamide (55.9 mg, 113 pmol, 95% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 437.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 89.09 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.85 - 7.78 (m, 2H), 7.58 - 7.42 (m, 3H), 7.13 (t, J= 7.8 Hz, 2H), 7.03 (d, J= 8.5 Hz, 1H), 6.85 (dd, J= 2.6, 8.4 Hz, 1H), 6.77 - 6.60 (m, 4H), 4.02 (t, J= 5.5 Hz, 2H), 3.41 (br s, 2H), 1.96 (s, 3H), 1.39 - 1.32 (m, 2H), 1.20 - 1.13 (m, 2H).

Example 64: 5-(2-(Benzylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 360)

59A-1 Compound 360 Step 1: 5-(2-(Benzylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl) benzamide (Compound 360)

To a solution of 5-(2-bromoethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (50.0 mg, 118 pmol, 1.0 eq) and phenylmethanamine (13.9 mg, 130 pmol, 14.1 mL, 1.1 eq) in acetonitrile (5.0 mL) were added potassium iodide (1.96 mg, 11.8 pmol, 0.1 eq) and potassium carbonate (32.6 mg, 236 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Benzylamino)ethoxy)-2-methyl-A-(l -(naphthal en- 1 - yl)cyclopropyl)benzamide (64.6 mg, 132 pmol, 28% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 451.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.26 (br s, 2H), 9.12 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.4 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.61 - 7.38 (m, 8H), 7.07 (d, J= 8.4 Hz, 1H), 6.88 (dd, J = 2.7, 8.4 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 4.26 - 4.10 (m, 4H), 3.25 (br s, 2H), 1.97 (s, 3H), 1.40 - 1.31 (m, 2H), 1.20 - 1.15 (m, 2H).

Example 65: 5-(2-((2-Hydroxyethyl)amino)ethoxy)-2-methyl-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 359)

59A-1 Compound 359

Step 1: 5-(2-((2-Hydroxyethyl)amino)ethoxy)-2-methyl-/V-(l-(naphthal en-l-yl)cyclo propyl)benzamide (Compound 359)

To a solution of 5-(2-bromoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (70.0 mg, 165 pmol, 1.0 eq) and 2-aminoethanol (11.1 mg, 181 pmol, 11.0 mL, 1.1 eq) in acetonitrile (5.0 mL) were added potassium iodide (2.74 mg, 16.5 pmol, 0.1 eq) and potassium carbonate (45.6 mg, 330 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-((2-Hydroxyethyl)amino)ethoxy)-2-methyl-A-(l -(naphthal en- 1 - yl)cyclopropyl)benzamide (16.1 mg, 36.5 pmol, 22% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 405.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.12 (s, 1H), 8.72 (br d, J= 2.9 Hz, 2H), 8.65 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.83 (t, J= 6.5 Hz, 2H), 7.61 - 7.43 (m, 3H), 7.08 (d, J= 8.5 Hz, 1H), 6.88 (dd, J= 2.6, 8.4 Hz, 1H), 6.67 (d, J= 2.8 Hz, 1H), 5.31 - 5.13 (m, 1H), 4.17 (t, J = 5.1 Hz, 2H), 3.65 (t, = 5.3 Hz, 2H), 3.35 - 3.25 (m, 2H), 3.09 - 2.99 (m, 2H), 1.97 (s, 3H), 1.40 - 1.31 (m, 2H), 1.21 - 1.16 (m, 2H).

Example 66: 5-(2-((2-Methoxyethyl)amino)ethoxy)-2-methyl-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 358)

Compound 358

Step 1: 5-(2-((2-Methoxyethyl)amino)ethoxy)-2-methyl-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 358)

To a solution of 5-(2-bromoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (50.0 mg, 118 pmol, 1.0 eq) and 2-methoxyethanamine (9.74 mg, 130 pmol, 11.3 mL, 1.1 eq) in acetonitrile (5.0 mL) were added potassium iodide (1.96 mg, 11.8 pmol, 0.1 eq) and potassium carbonate (32.6 mg, 236 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5 -(2-((2 -Methoxy ethyl)amino) ethoxy)-2-methyl-A-(l -(naphthal en- 1 - yl)cyclopropyl) benzamide (19.0 mg, 41.6 pmol, 18% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 419.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.12 (s, 1H), 8.79 (br d, J= 1.4 Hz, 2H), 8.65 (d, J= 8.1 Hz, 1H), 7.94 (d, J= 7.5 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.61 - 7.43 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.88 (dd, J= 2.7, 8.3 Hz, 1H), 6.66 (d, J= 2.6 Hz, 1H), 4.16 (br t, J= 5.1 Hz, 2H), 3.58 (t, J= 5.1 Hz, 2H), 3.28 (s, 5H), 3.16 (quin, J = 5.3 Hz, 2H), 1.97 (s, 3H), 1.35 (s, 2H), 1.21 - 1.15 (m, 2H).

Example 67: 5-(2-(3-Fluoroazetidin-l-yl)ethoxy)-2-methyl-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 300)

Compound 300

Step 1: 2-(3-Fluoroazetidin-l-yl)ethanol (67A-2)

To a solution of 3 -fluoroazetidine (300 mg, 2.69 mmol, 1.0 eq, HC1 salt) in acetonitrile (6.0 mL) was added K2CO3 (1.12 g, 8.07 mmol, 3.0 eq). The mixture was stirred at 20 °C for 30 min, then 2-bromoethanol (336 mg, 2.69 mmol, 191 pL, 1.0 eq) was added. The mixture was stirred at 80 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.5). 2-(3-Fluoroazetidin-l-yl)ethanol (80.0 mg, 672 pmol, 25% yield) was obtained as a yellow oil. 'H NMR (400 MHz, CDCh) 6 3.89 - 3.83 (m, 1H), 3.75 (dd, J = 1.7, 5.2 Hz, 1H), 3.72 - 3.67 (m, 4H), 3.66 - 3.59 (m, 2H), 2.84 - 2.73 (m, 2H).

Step 2: 5-(2-(3-Fluoroazetidin-l-yl)ethoxy)-2-methyl-/V-(l-(naphthal en-l-yl)cyclopropyl) benzamide (Compound 300)

To a solution of 2-(3-fluoroazetidin-l-yl)ethanol (18.8 mg, 158 pmol, 1.0 eq) and 5-hydroxy- 2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (50.0 mg, 158 pmol, 1.0 eq) in toluene (2.0 mL) was added CMBP (38.0 mg, 158 pmol, 1.0 eq). The resulting mixture was degassed and purged with N2 three times and then the mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (2.0 mL) and extracted with EtOAc (1.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(3-Fluoroazetidin-l-yl)ethoxy)-2-methyl-A- (l-(naphthalen-l-yl)cyclopropyl)benzamide (8.20 mg, 19.6 pmol, 12% yield, FA salt) was obtained as a white solid. M + H ⁺ = 419.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.08 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.81 (dd, J= 7.9, 10.0 Hz, 2H), 7.60 - 7.41 (m, 3H), 7.02 (d, J= 8.4 Hz, 1H), 6.80 (dd, J= 2.7, 8.3 Hz, 1H), 6.58 (d, J= 2.6 Hz, 1H), 5.27 - 4.97 (m, 1H), 3.84 (t, J= 5.4 Hz, 2H), 3.62 - 3.49 (m, 2H), 3.20 - 3.05 (m, 2H), 2.73 (t, = 5.4 Hz, 2H), 1.95 (s, 3H), 1.35 (s, 2H), 1.19 - 1.12 (m, 2H).

Example 68: 2-AIel Iiyl-\-( 1 -( naphl Iialen- 1 -yl)cyclopropyl )-5-(2-( piperidin- 1 - yl)ethoxy)benzamide (Compound 254)

Step 1 55A-2 Compound 254 Step 1 : 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(2-(piperidin -l-yl)ethoxy) benzamide (Compound 254)

A mixture of 5-hydroxy-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)benzami de (70.0 mg, 221 pmol, 1.0 eq), 2-(piperidin-l-yl)ethanol (28.5 mg, 221 pmol, 29.3 pL, 1.0 eq) and CMBP (79.9 mg, 331 pmol, 1.5 eq) in toluene (3.5 mL) was degassed and purged with N2 three times. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-5- (2-(piperidin-l-yl)ethoxy)benzamide (60.1 mg, 140 pmol, 64% yield) was obtained as a yellow solid. M + H ⁺ = 429.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.09 (s, 1H), 8.66 (d, J = 8.1 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.61 - 7.42 (m, 3H), 7.02 (d, J = 8.6 Hz, 1H), 6.83 (dd, J= 2.7, 8.4 Hz, 1H), 6.61 (d, J= 2.7 Hz, 1H), 3.96 (t, J= 5.9 Hz, 2H), 2.65 - 2.57 (m, 3H), 2.39 (br s, 3H), 1.95 (s, 3H), 1.47 (quin, J= 5.5 Hz, 4H), 1.40 - 1.29 (m, 4H), 1.22 - 1.11 (m, 2H).

Example 69: 5-(2-(4,4-Difluoropiperidin-l-yl)ethoxy)-2-methyl-/V-(l-(nap hthalen-l- yl)cyclopropyl)benzamide (Compound 284)

Compound 284 Step 1: 2-(4,4-Difluoropiperidin-l-yl)ethanol (69A-2)

To a solution of 4,4-difluoropiperidine (500 mg, 4.13 mmol, 1.0 eq) in ACN (20 mL) were added K2CO3 (1.71 g, 12.4 mmol, 3.0 eq) and 2-bromoethanol (2.58 g, 20.6 mmol, 1.47 mL, 5.0 eq). The mixture was stirred at 90 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (7.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-(4,4-Difluoropiperidin-l-yl)ethanol (330 mg, 2.00 mmol, 48% yield) was obtained as a yellow oil. 'H NMR (400 MHz, CDCh) 8 3.62 (t, J =5.4 Hz, 2H), 2.68 - 2.54 (m, 6H), 2.16-1.85(m, 4H).

Step 2: 5-(2-(4,4-Difluoropiperidin-l-yl)ethoxy)-2-methyl-/V-(l-(nap hthalen-l-yl)cyclopr opyl)benzamide (Compound 284)

To a solution of 2-(4,4-difluoropiperidin-l-yl)ethanol (52.0 mg, 315 pmol, 1.0 eq), 5-hydroxy- 2-methyl -A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide ( 100 mg, 315 pmol, 1.0 eq) in toluene (2.5 mL) was added CMBP (76.1 mg, 315 pmol, 1.0 eq). The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(4,4-Difluoropiperidin-l-yl)ethoxy)-2-methyl- 7V-(1 -(naphthal en-l-yl)cy cl opropyl) benzamide (67.8 mg, 143 pmol, 45% yield, FA salt) was obtained as a white solid. M + H ⁺ = 465.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.08 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.96 - 7.91 (m, 1H), 7.87 - 7.78 (m, 2H), 7.61 - 7.41 (m, 3H), 7.03 (d, J= 8.5 Hz, 1H), 6.83 (dd, J = 2.7, 8.3 Hz, 1H), 6.62 (d, J= 2.8 Hz, 1H), 3.98 (t, J = 5.7 Hz, 2H), 2.72 (t, J= 5.7 Hz, 2H), 2.57 (br t, J = 5.4 Hz, 4H), 1.96 (s, 7H), 1.36 (br d, J = 1.6 Hz, 2H), 1.23 - 1.12 (m, 2H). Example 70: 2-Methyl-5-(2-morpholinoethoxy)-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 209)

Step 3 70A-2 Compound 209

Step 1: Methyl 2-methyl-5-(2-morpholinoethoxy)benzoate (70A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq) and 4-(2- chloroethyl)morpholine (804 mg, 3.61 mmol, 1.2 eq) in acetone (20 mL) was added K2CO3 (1.66 g, 12.0 mmol, 4.0 eq). The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 2- methyl-5-(2 -morpholinoethoxy )benzoate (300 mg, 1.07 mmol, 36% yield) was obtained as a colorless oil. M + H ⁺ = 280.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.46 (d, J= 2.8 Hz, 1H), 7.14 (d, J= 8.4 Hz, 1H), 6.97 (dd, J= 2.8, 8.4 Hz, 1H), 4.12 (t, J= 5.7 Hz, 2H), 3.89 (s, 3H), 3.77 - 3.71 (m, 4H), 2.80 (t, J= 5.7 Hz, 2H), 2.61 - 2.55 (m, 4H), 2.51 (s, 3H).

Step 2: 2-Methyl-5-(2-morpholinoethoxy)benzoic acid (70A-2)

To a solution of methyl 2-methyl-5-(2 -morpholinoethoxy )benzoate (200 mg, 716 pmol, 1.0 eq) in a mixture of MeOH (4.0 mL), H2O (2.0 mL) and THF (8.0 mL) was added LiOH.H2O (60.1 mg, 1.43 mmol, 2.0 eq). The mixture was stirred at 25 °C for 1 h, then the mixture was stirred at 70 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with MTBE (5.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with dimethyltetrahydrofuran (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-methyl-5-(2-morpholinoethoxy)benzoic acid (80.0 mg), which was used in the next step without any further purification. 'H NMR (400 MHz, DMSO-tL) 6 7.33 (d, J = 2.6 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 2.6, 8.4 Hz, 1H), 4.09 (br t, J= 5.6 Hz, 2H), 3.60 - 3.56 (m, 4H), 2.71 (br s, 2H), 2.54 - 2.51 (m, 4H), 2.42 (s, 3H).

Step 3: 2-Methyl-5-(2-morpholinoethoxy)-/V-(l-(naphthalen-l-yl)cyclo propyl)benzamide (Compound 209)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (50.0 mg, 273 pmol, 1.0 eq) and 2- methyl-5-(2-morpholinoethoxy)benzoic acid (72.4 mg, 273 pmol, 1.0 eq) in DCM (10 mL) were added TEA (82.8 mg, 819 pmol, 114 pL, 3.0 eq), EDCI (105 mg, 546 pmol, 3.0 eq) and HOBt (73.7 mg, 546 pmol, 2.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-Methyl-5-(2- morphol i noethoxy )-/f-( l -(naphthal en -l-yl)cyclopropyl)benzamide (45.4 mg, 102 pmol, 38% yield) was obtained as a white solid. M + H ⁺ = 431.1 (LCMS); ¹ H NMR (400 MHz, CDCL) 8 8.45 (d, J= 8.4 Hz, 1H), 7.92 (dd, J= 7.8, 15.8 Hz, 2H), 7.81 (d, J= 8.3 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.45 (m, 2H), 7.00 (d, J= 8.4 Hz, 1H), 6.78 (dd, J= 2.7, 8.4 Hz, 1H), 6.70 (d, J= 2.7 Hz, 1H), 3.99 (t, J= 5.6 Hz, 2H), 3.76 - 3.67 (m, 4H), 2.72 (t, J= 5.6 Hz, 2H), 2.56 - 2.49 (m, 4H), 2.11 (s, 3H), 1.57 (br s, 2H), 1.42 - 1.37 (m, 2H).

Example 71: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 324)

Step 1 55A-2 71A-1

Step 2

Compound 324

Step 1: te/7- Butyl (l-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) propan-2-yl)carbamate (71A-1)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 315 pmol, 1.0 eq), tert-butyl (l-hydroxypropan-2-yl)carbamate (55.2 mg, 315 pmol, 1.0 eq) and CMBP (114 mg, 473 pmol, 1.5 eq) in toluene (5.0 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was used without further purification. tert-Butyl ( l-(4-methyl-3-((l -(naphthal ene-1- yl)cyclopropyl)carbamoyl)phenoxy) propan-2 -yl)carbamate (90.0 mg, 190 pmol, 60% yield) was obtained as a white solid.

Step 2: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cycloprop yl)benzamide (Compound 324)

To a stirred solution of tert-butyl (l-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy )propan-2-yl)carbamate (80.0 mg, 169 pmol, 1.0 eq) in EtOAc (8.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- (2 -Aminopropoxy)-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl) benzamide (50.9 mg, 124 pmol, 73% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 375.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 5 9.18 - 9.06 (m, 1H), 8.69 - 8.61 (m, 1H), 7.94 (br d, J= 7.9 Hz, 4H), 7.83 (t, J= 7.4 Hz, 2H), 7.60 - 7.44 (m, 3H), 7.11 - 7.05 (m, 1H), 6.92 - 6.86 (m, 1H), 6.69 - 6.63 (m, 1H), 4.08 - 3.97 (m, 1H), 3.89 - 3.80 (m, 1H), 3.60 - 3.49 (m, 1H), 1.97 (s, 3H), 1.35 (br s, 2H), 1.27 - 1.16 (m, 5H).

Example 72: 5-(2-Amino-3,3-dimethylbutoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 343)

Step 1: / f/- Butyl (l-hydroxy-3,3-dimethylbutan-2-yl)carbamate (72A-2)

To a mixture of 2-(/ert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (500 mg, 2.16 mmol, 1.0 eq) and NMM (219 mg, 2.16 mmol, 238 pL, 1.0 eq) in THF (4.0 mL) was added isobutyl carbonochloridate (295 mg, 2.16 mmol, 284 pL, 1.0 eq) at -10 °C, the reaction mixture was stirred at -10 °C for 30 min. TLC indicated that the starting material was completely consumed. Then the reaction mixture was filtered. To the filtrate was added NaBE (123 mg, 3.24 mmol, 1.5 eq) in portions at -10 °C. The resulting reaction mixture was stirred at the same temperature for 30 min. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.2). Zc/V-Butyl (l-hydroxy-3,3-dimethylbutan-2-yl)carbamate (220 mg, 1.01 mmol, 47% yield) was obtained as a white solid.

Step 2: tert-Butyl(3,3-dimethyl-l-(4-methyl-3-((l-(naphthalen-l-yl)c yclopropyl) carbamoyl)phenoxy)butan-2-yl)carbamate (72A-3) A mixture of 5-hydroxy-2-methyl-7V-[l-(l-naphthyl)cyclopropyl]benzamide (150 mg, 472 pmol, 1.0 eq), tert-butyl A-[l-(hydroxymethyl)-2,2-dimethyl-propyl]carbamate (205 mg, 945 pmol, 2.0 eq) and CMBP (171 mg, 709 pmol, 1.5 eq) in toluene (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.3). ter/-Butyl(3,3-dimethyl-l-(4-methyl-3-((l-(naphthalene-l-yl) cyclopropyl)carbamoyl). phenoxy )butan-2-yl)carbamate (45 mg, 87.1 pmol, 18% yield) was obtained as a white solid. M + H ⁺ = 517.3 (LCMS)

Step 3: 5-(2-Amino-3,3-dimethylbutoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl) benzamide (Compound 343)

To a mixture of tert-butyl A-[2,2-dimethyl-l-[[4-methyl-3-[[l-(l-naphthyl)cyclopropyl] carbamoyl]phenoxy]methyl]propyl]carbamate (45.0 mg, 87.1 pmol, 1.0 eq) in EtOAc (500 pL) was added HCl/EtOAc (4 M, 1.0 mL). The reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-Amino-3,3-dimethyl-butoxy)-2-methyl-A-[l-(l- naphthyl)cyclopropyl]benzamide (18.0 mg, 45.0 pmol, 47% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 9.11 (s, 1H), 8.66 (d, J= 8.0 Hz, 1H), 8.02 - 7.76 (m, 6H), 7.64 - 7.40 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.93 (dd, J= 2.8, 8.4 Hz, 1H), 6.71 (d, J= 2.8 Hz, 1H), 4.16 (dd, J= 3.2, 10.4 Hz, 1H), 3.91 (br t, J = 9.6 Hz, 1H), 3.26 - 3.09 (m, 1H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H), 1.00 (s, 9H).

Example 73: 5-(2-Amino-3-methoxypropoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 400) 73A-1 73A-2 73A-3

Compound 400

Step 1: 2-((tert-Butoxycarbonyl)amino)-3-methoxypropanoic acid (73A-2)

To a mixture of 2-amino-3-m ethoxy-propanoic acid (500 mg, 4.20 mmol, 1.0 eq) and NaOH (336 mg, 8.39 mmol, 2.0 eq) in a mixture of THF (4.0 mL) and H2O (2.0 mL) was added tert- butoxycarbonyl tert-butyl carbonate (1.01 g, 4.62 mmol, 1.1 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.3). 2-((tert-Butoxycarbonyl)amino)-3-methoxy-propanoic acid (320 mg, 1.46 mmol, 35% yield) was obtained as white oil. 'H NMR (400 MHz, CDCh) 8 9.38 - 9.92 (m, 1H), 5.76 (br s, 1H), 4.19 (br s, 1H), 3.62 - 3.76 (m, 1H), 3.50 (br s, 1H), 3.26 (s, 3H), 1.35 (s, 9H).

Step 2: tert-Butyl (l-hydroxy-3-methoxypropan-2-yl)carbamate (73A-3)

To a mixture of 2-(tert-butoxycarbonylamino)-3-methoxy -propanoic acid (220 mg, 1.00 mmol, 1.0 eq) and NMM (101 mg, 1.00 mmol, 1.0 eq) in THF (2.0 mL) was added isobutyl carb onochlori date (137 mg, 1.00 mmol, 1.0 eq) at -10°C. The reaction mixture was stirred at - 10 °C for 30 min. TLC indicated that the starting material was completely consumed. The reaction mixture was filtered. To the filtrate was added NaBH4 (57.0 mg, 1.51 mmol, 1.5 eq) at -10°C, the reaction mixture was stirred at -10 °C for 30 min. TLC indicated that the intermediate was completely consumed. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.1). tert-Butyl (1 -hydroxy-3 -methoxypropan-2- yl)carbamate (100 mg, 487 pmol, 49% yield) was obtained as a colorless oil.

Step 3: te/7- Butyl (l-methoxy-3-(4-methyl-3-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl) phenoxy)propan-2-yl)carbamate (73A-4)

A mixture of 5-hydroxy-2-methyl-A-[l-(l-naphthyl)cyclopropyl]benzamide (150 mg, 473 pmol, 1.0 eq), tert-butyl A-[l-(hydroxymethyl)-2-methoxy-ethyl]carbamate (97.0 mg, 473 pmol, 1.0 eq) and CMBP (114 mg, 473 pmol, 1.0 eq) in toluene (4.0 mL) was degassed and purged with N2 three times. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.7). te/7- Butyl(l-methoxy-3-(4-methyl-3-((l-(naphthalen-l-yl)cycloprop yl)carbamoyl)phenoxy) propan-2-yl)carbamate (140 mg, 277 pmol, 59% yield) was obtained as a white solid. M + H ⁺ = 505.2 (LCMS).

Step 4: 5-(2-Amino-3-methoxypropoxy)-2-methyl-/V-(l-(naphthalen-l-yl )cyclopropyl) benzamide (Compound 400)

To a solution of tert-butyl (l-methoxy-3-(4-methyl-3-((l -(naphthal en-l-yl)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (140 mg, 277 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-amino-3-methoxy-propoxy)-2-methyl-A-[l-(l- naphthyl)cyclopropyl] benz amide (92.7 mg, 210 pmol, 74% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 405.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.19 (s, 1H), 8.58 (d, J= 8.4 Hz, 1H), 7.94 - 7.76 (m, 3H), 7.60 - 7.38 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.90 (dd, J= 2.8, 8.4 Hz, 1H), 6.69 (d, J= 2.8 Hz, 1H), 4.15 - 3.99 (m, 2H), 3.74 - 3.57 (m, 3H), 3.41 (s, 3H), 2.00 (s, 3H), 1.51 - 1.40 (m, 2H), 1.34 - 1.28 (m, 2H). Example 74: 5-(2-Amino-2-phenylethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 367)

Compound 367 Step 1: te/7- Butyl (2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy)- l-phenylethyl)carbamate (74A-1)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (200 mg, 630 pmol, 1.0 eq) and tert-butyl (2-hydroxy-l-phenylethyl)carbamate (141 mg, 630 pmol, 1.0 eq) in toluene (10 mL) was degassed and purged with N2 three times. To the mixture were added TMAD (326 mg, 1.89 mmol, 3.0 eq), PPI13 (496 mg, 1.89 mmol, 3.0 eq), and the mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. te/7-Butyl (2-(4-methyl-3-((l- (naphthalen-l-yl)cyclopropyl)carbamoyl)phenoxy)-l -phenylethyl) carbamate (150 mg, 280 pmol, 44% yield) was obtained as a yellow oil. M + H ⁺ = 537.4 (LCMS). Step 2: 5-(2-Amino-2-phenylethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)c yclopropyl)benza mide (Compound 367)

To a solution of tert-butyl (2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)- 1 -phenylethyl) carbamate (150 mg, 280 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- (2-Amino-2-phenylethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyc lopropyl)benzamide (73.2 mg, 155 pmol, 55% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 437.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.11 (s, 1H), 8.63 (br s, 4H), 7.98 - 7.90 (m, 1H), 7.82 (t, J = 8.3 Hz, 2H), 7.59 - 7.41 (m, 8H), 7.06 (d, J = 8.6 Hz, 1H), 6.90 (dd, J= 2.4, 8.3 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 4.74 - 4.65 (m, 1H), 4.26 - 4.12 (m, 2H), 1.96 (s, 3H), 1.34 (br s, 2H), 1.17 (br s, 2H).

Example 75: 5-(2-Amino-3-phenylpropoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 322)

Compound 322 Step 1: tert-Butyl (l-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy)- 3-phenylpropan-2-yl)carbamate (75A-1)

A mixture of 5-hydroxy-2-methyl-7V-[l-(l-naphthyl)cyclopropyl]benzamide (80.0 mg, 252 pmol, 1.0 eq), tert-butyl 7V-(l-benzyl-2-hydroxy-ethyl)carbamate (63.3 mg, 252 pmol, 1.0 eq) and CMBP (91.2 mg, 378 pmol, 1.5 eq) in toluene (4.0 mL) was degassed and purged with N2 atmosphere, and then the mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, Rf = 0.4). tert-Butyl (1- (4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)pheno xy)-3-phenylpropan-2- yl)carbamate (80.0 mg, 145 pmol, 58% yield) was obtained as a white solid. M + H ⁺ = 551.2 (LCMS).

Step 2: 5-(2-Amino-3-phenylpropoxy)-2-methyl-/V-(l-(naphthalen-l-yl) cyclopropyl) benzamide (Compound 322)

To a mixture of tert-butyl 7V-[l-benzyl-2-[4-methyl-3-[[l-(l-naphthyl)cyclopropyl]carba moyl] phenoxy]ethyl]carbamate (70.0 mg, 127 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-Amino-3-phenyl-propoxy)-2-methyl-7V-[l-(l-naphthyl)cycl opropyl]benzamide (25.0 mg, 51.7 pmol, 41% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 451.1 (LCMS); ^T H NMR (400 MHz, DMSO ) 8 9.11 (s, 1H), 8.64 (br d, J= 8.4 Hz, 1H), 8.25 (br s, 3H), 7.94 (br d, J= 7.8 Hz, 1H), 7.83 (br t, J= 7.8 Hz, 2H), 7.60 - 7.40 (m, 3H), 7.36 - 7.17 (m, 5H), 7.05 (br d, J= 8.4 Hz, 1H), 6.88 - 6.78 (m, 1H), 6.63 (br s, 1H), 4.00 - 3.61 (m, 3H), 3.14 - 2.88 (m, 2H), 1.95 (s, 3H), 1.43 - 1.04 (m, 4H). Example 76: 5-(2-Amino-2-methylpropoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 352)

Compound 352

Step 1: tert- Butyl (2-methyl-l-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)car bamoyl) phenoxy)propan-2-yl)carbamate (76A-1)

To a solution of 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (100 mg, 315 pmol, 1.0 eq) in DMF (5.0 mL) was added sodium hydride (18.9 mg, 473 pmol, 60% purity, 1.5 eq) under a N2 atmosphere, the mixture was stirred at 0 °C for 30 min, then tertbutyl 4,4-dimethyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (119 mg, 473 pmol, 1.5 eq) was added. The resulting mixture was stirred at 70 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.7). tert- Butyl (2-methyl- 1 -(4-methyl-3 -((1 -(naphthal en- 1 -yl)cyclopropyl)carbamoyl)phenoxy) propan-2-yl)carbamate (140 mg, 287 pmol, 91% yield) was obtained as a yellow solid. ^T H NMR (400 MHz, CDCh) 8 8.48 (d, J= 8.6 Hz, 1H), 7.95 (d, J= 7.0 Hz, 1H), 7.90 (d, J= 8.1 Hz, 1H), 7.81 (d, J= 8.3 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.54 - 7.45 (m, 2H), 6.99 (d, J = 8.5 Hz, 1H), 6.79 (dd, J= 2.6, 8.3 Hz, 1H), 6.71 (d, J= 2.5 Hz, 1H), 6.48 (br s, 1H), 3.84 (s, 2H), 2.10 (s, 3H), 1.46 - 1.38 (m, 13H), 1.35 (s, 6H).

Step 2: 5-(2-Amino-2-methylpropoxy)-2-methyl-/V-(l-(naphthalen-l-yl) cyclopropyl) benzamide (Compound 352) To a solution of tert-butyl (2 -m ethyl- l-(4-methyl-3-((l -(naphthal en-l-yl)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (80.0 mg, 164 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCI/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-(2-amino-2-methylpropoxy)-2-methyl-7V-(l-(naphthalen-l-yl) cyclopropyl)benzamide (38.6 mg, 90.7 pmol, 55% yield) as a brown solid. M + H ⁺ = 389.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.13 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 8.18 (br d, J= 1.9 Hz, 3H), 7.93 (d, J= 8.0 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.64 - 7.39 (m, 3H), 7.07 (d, J = 8.5 Hz, 1H), 6.89 (dd, J = 2.6, 8.3 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 3.87 (s, 2H), 1.96 (s, 3H), 1.36 (s, 2H), 1.29 (s, 6H), 1.22 - 1.12 (m, 2H).

Example 77: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 256)

Compound 256

Step 1: te/7- Butyl (l-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)cyclopropyl)carbamate (77A-1)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (200 mg, 586 pmol, 1.0 eq) and tert-butyl (l-(hydroxymethyl)cyclopropyl)carbamate (165 mg, 879 pmol, 1.5 eq) in toluene (2.0 mL) was degassed and purged with N2 three times. To the mixture was added CMBP (212 mg, 879 pmol, 1.5 eq) in portions at 25 °C. The resulting mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.5). Zc/V-Butyl (l-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy )methyl)cyclopropyl)carbamate (150 mg, 308 pmol, 53% yield) was obtained as a yellow oil. M + H ⁺ = 487.2 (LCMS).

Step 2: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (Co mpound 256)

To a stirred solution of /c/V-butyl (l-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl) carbamoyl)phenoxy)methyl)cyclopropyl)carbamate (150 mg, 308 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-Aminoethoxy)-2-methyl-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (69.2 mg, 179 pmol, 68% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 387.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.71 (br s, 3H), 8.59 (br d, J= 8.3 Hz, 1H), 7.95 (d, J= 7.1 Hz, 1H), 7.85 (d, J= 8.1 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.37 (br s, 1H), 6.82 - 6.72 (m, 2H), 6.68 (br d, J= 7.2 Hz, 1H), 3.80 (s, 2H), 1.99 (s, 3H), 1.53 (br s, 2H), 1.34 (br s, 2H), 1.19 (s, 2H), 0.68 (br s, 2H).

Example 78: 5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 274)

55A-2 78A-1

Compound 274

Step 1: te/7- Butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) methyl)azetidine-l-carboxylate (78A-1)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (300 mg, 945 pmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)azetidine-l -carboxylate (177 mg, 945 pmol, 1.0 eq) in toluene (15 mL) was added CMBP (342 mg, 1.42 mmol, 1.5 eq). The mixture was degassed and purged with N2 three times and then the mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. te/7-Butyl 2-((4-methyl-3 -((1 -(naphthal en-1- yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine- 1 -carboxylate (300 mg, 617 pmol, 65% yield) was obtained as a colorless oil. M + H ⁺ = 387.1 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.50 (d, J = 8.4 Hz, 1H), 7.96 (d, J= 7.1 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.80 (d, J= 8.1 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.54 - 7.45 (m, 2H), 7.00 (d, J= 8.4 Hz, 1H), 6.82 (dd, J= 2.6, 8.3 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 6.64 (s, 1H), 4.43 (br dd, J= 2.9, 5.1 Hz, 1H), 4.22 - 4.15 (m, 1H), 4.04 - 3.96 (m, 1H), 3.87 (t, J= 7.6 Hz, 2H), 2.12 (s, 3H), 2.06 (s, 2H), 1.57 (s, 2H), 1.40 (br s, 2H), 1.36 (s, 9H).

Step 2: 5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyc lopropyl)benzamid e (Compound 274)

To a solution of tert-butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy) methyl)azetidine-l -carboxylate (100 mg, 206 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.00 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(Azetidin-2-ylmethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cycl opropyl) benzamide (30.1 mg, 71.2 pmol, 35% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 387.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.37 (s, 1H), 9.15 (m, 2H), 8.67 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.62 - 7.42 (m, 3H), 7.08 (d, J = 8.6 Hz, 1H), 6.90 (dd, J = 2.7, 8.4 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 4.63 (br d, J= 6.0 Hz, 1H), 4.29 (dd, J= 7.5, 11.2 Hz, 1H), 4.13 (dd, J = 3.2, 11.1 Hz, 1H), 3.95 - 3.76 (m, 2H), 2.47 - 2.26 (m, 2H), 1.97 (s, 3H), 1.36 (s, 2H), 1.23 - 1.13 (m, 2H).

Example 79: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(naphtha len-l- yl)cyclopropyl)benzamide (Compound 310)

Step 1: (S)-/c/7-Butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph en oxy)methyl)azetidine- 1-carboxylate (79 A- 1)

To a mixture of 5 -hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 315 pmol, 1.0 eq) and fS')-/c/7-butyl 2-(hydroxymethyl)azetidine- 1-carboxylate (59.0 mg, 315 pmol, 1.0 eq) in toluene (5.0 mL) was added CMBP (114 mg, 473 pmol, 1.5 eq). The resulting mixture was degassed and purged with N2 three times and then was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.6). fS')- /c/V-Butyl 2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenoxy)methyl) azetidine- 1-carboxylate (130 mg, 267 pmol, 85% yield) was obtained as a yellow solid. M + H ⁺ = 487.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.50 (d, J= 8.2 Hz, 1H), 7.96 (d, J= 7.1 Hz, 1H), 7.90 (d, J= 8.1 Hz, 1H), 7.81 (d, J= 8.3 Hz, 1H), 7.64 - 7.43 (m, 3H), 7.05 - 6.95 (m, 1H), 6.88 - 6.73 (m, 2H), 6.64 (br s, 1H), 4.48 - 4.38 (m, 1H), 4.22 - 4.15 (m, 1H), 4.03 - 3.96 (m, 1H), 3.87 (br t, J= 7.2 Hz, 2H), 2.38 - 2.17 (m, 2H), 2.12 (s, 3H), 1.57 - 1.53 (m, 2H), 1.46 - 1.31 (m, 11H).

Step 2: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(naphthalen-l-yl )cyclopropyl) benzamide (79A-2)

To a solution of CS')-/c77-butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-l -carboxylate (130 mg, 267 pmol, 1.0 eq) in DCM (10 mL) was added TFA (2.5 mL). The resulting mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give crude product fS')-5-(azetidin-2- ylmethoxy)-2-methyl-7V-(l -(naphthal en-l-yl)cyclopropyl)benzamide (100 mg, 199 pmol, 78% yield, TFA salt) as a yellow gum, which was used in the next step without any further purification. M + H ⁺ = 387.2 (LCMS).

Step 3: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(napht halen-l-yl)cyclo propyl)benzamide (Compound 310)

To a stirred solution of (8)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (100 mg, 259 pmol, 1.0 eq, TFA salt) in MeOH (5.0 mL) were added TEA (26.2 mg, 259 pmol, 36.0 pL, 1.0 eq) and formaldehyde (42.0 mg, 517 pmol, 38.5 pL, 37% purity in aqueous, 2.0 eq). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6, and then NaBHiCN (32.5 mg, 517 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (5)-2-methyl-5-((l-methylazetidin-2- yl)methoxy)-7V-(l -(naphthal en-l-yl)cy cl opropyl) benzamide (44.3 mg, 110 pmol, 43% yield) as a white solid. M + H ⁺ = 401.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 89.07 (s, 1H), 8.66 (br d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.82 (t, J= 7.6 Hz, 2H), 7.61 - 7.41 (m, 3H), 7.02 (d, J= 8.5 Hz, 1H), 6.82 (dd, J= 2.5, 8.3 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 3.85 (d, J = 5.4 Hz, 2H), 3.27 - 3.15 (m, 2H), 2.79 - 2.67 (m, 1H), 2.21 (s, 3H), 2.04 - 1.90 (m, 4H), 1.89 - 1.77 (m, 1H), 1.36 (br s, 2H), 1.17 (br s, 2H).

Example 80: (l?)-2-Methyl-5-(( 1 -met hylazelidin-2-yI)nielIioxy )-\-( 1 -( naplitlialen- 1 -yl ) cyclopropyl)benzamide (Compound 309)

80A-2 yl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-l-carboxylate (80A-1) A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 315 pmol, 1.0 eq) and (/?)-/c/7-butyl 2-(hydroxymethyl)azetidine-l -carboxylate (59.0 mg, 315 pmol, 3.97 pL, 1.0 eq) in anhydrous toluene (5.0 mL) was degassed and purged with N2 three times. To the mixture was added CMBP (114 mg, 473 pmol, 1.5 eq) at 20 °C. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (/?)-/c77-Butyl 2-((4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine- 1 -carboxylate (280 mg, 575 pmol, 91% yield) was obtained as a white solid. M + H ⁺ = 487.3 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 9.08 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.5 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.60 - 7.42 (m, 3H), 7.03 (d, J= 8.4 Hz, 1H), 6.86 (dd, J= 2.6, 8.4 Hz, 1H), 6.65 (d, J= 2.6 Hz, 1H), 4.43 - 4.33 (m, 1H), 4.13 (dd, = 4.9, 10.3 Hz, 1H), 3.98 (dd, J = 2.9, 10.3 Hz, 1H), 3.72 (br d, J = 6.6 Hz, 2H), 2.31 - 2.21 (m, 1H), 2.12 - 2.01 (m, 1H), 1.95 (s, 3H), 1.38 - 1.35 (m, 2H), 1.35 - 1.26 (m, 9H), 1.17 (s, 2H).

Step 2: (7?)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(naphthalen-l-y l)cyclopropyl) benzamide (80A-2)

To a stirred solution of (/ )-/c77-butyl 2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (280 mg, 575 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (5.6 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product (/ )-5-(azetidin-2- ylmethoxy)-2-methyl-7V-(l -(naphthal en-l-yl)cyclopropyl)benzamide (280 mg, crude, TFA salt) as a white solid. M + H ⁺ = 387.1 (LCMS).

Step 3: (7?)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(naph thalen-l-yl) cyclopropyl)benzamide (Compound 309)

To a solution of (7?)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(naphthalen-l-y l)cyclopropyl) benzamide (140 mg, 280 pmol, 1.0 eq, TFA salt) in MeOH (6.0 mL) was added TEA (39.0 pL), followed by the addition of formaldehyde (45.4 mg, 559 pmol, 41.7 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (35.2 mg, 559 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (7?)-2-Methyl-5-((l-methylazetidin- 2-yl)methoxy)-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamide (30.3 mg, 75.7 pmol, 27% yield) was obtained as a colorless oil. M + H ⁺ = 401.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 5 9.06 (s, 1H), 8.66 (d, J= 8.3 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.85 - 7.78 (m, 2H), 7.59 - 7.42 (m, 3H), 7.01 (d, J= 8.5 Hz, 1H), 6.82 (dd, J= 2.8, 8.4 Hz, 1H), 6.59 (d, J= 2.8 Hz, 1H), 3.85 (d, J= 5.5 Hz, 2H), 3.27 - 3.16 (m, 2H), 2.75 - 2.68 (m, 1H), 2.20 (s, 3H), 1.98 - 1.90 (m, 4H), 1.89 - 1.78 (m, 1H), 1.38 - 1.33 (m, 2H), 1.19 - 1.13 (m, 2H).

Example 81: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(3-(naphthale n-l- yl)oxetan-3-yl)benzamide (Compound 387)

Compound 387

81A-4

Step 1: tert- Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-l- carboxylate (81A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq) and tertbutyl 2-(hydroxymethyl)azetidine-l -carboxylate (592 mg, 3.16 mmol, 1.1 eq) in toluene (15 mL) were added TMAD (1.55 g, 9.03 mmol, 3.0 eq) and PPhi (2.37 g, 9.03 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-l- carboxylate (900 mg, 2.68 mmol, 89% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 280.0 (LCMS); ^X H NMR (400 MHz, CDCh) 8 7.50 - 7.47 (m, 1H), 7.17 - 7.12 (m, 1H), 7.03 - 6.97 (m, 1H), 4.56 - 4.45 (m, 1H), 4.34 - 4.24 (m, 1H), 4.13 (br d, J = 4.0 Hz, 1H), 4.18 - 4.07 (m, 1H), 3.95 (br s, 4H), 2.55 - 2.51 (m, 3H), 2.42 - 2.20 (m, 2H), 1.47 - 1.40 (m, 9H).

Step 2: Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (81A-2)

To a solution of tert-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine-1- carboxylate (800 mg, 2.39 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (3.26 g, 28.6 mmol, 2.12 mL, 12 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product methyl 5-(azetidin-2- ylmethoxy)-2-methylbenzoate (800 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification as a yellow oil. M + H ⁺ = 236.1 (LCMS).

Step 3: Methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (81A-3)

To a solution of (methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (400 mg, 1.03 mmol, 1.0 eq, TFA salt) in MeOH (8.0 mL) was added TEA (80.0 pL), followed by formaldehyde (335 mg, 4.12 mmol, 307 pL, 37% purity in water, 4.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (518 mg, 8.25 mmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product methyl 2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzoate (400 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 250.1 (LCMS).

Step 4: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (81A-4)

A solution of methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (300 mg, 1.20 mmol, 1.0 eq) in HC1 (2 M aqueous, 9.00 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H2O (10 mL) and washed with MTBE (20 mL x 2). The aqueous was acidified to pH 6 with NaOH (2 M aqueous). The product was extracted with DCM (10 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuum to give the crude product 2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzoic acid (220 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 236.1 (LCMS).

Step 5: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(3-(naphthale n-l-yl)oxetan-3- yl)benzamide (Compound 387)

To a solution of 2-methyl-5-[(l-methylazetidin-2-yl)methoxy]benzoic acid (50.0 mg, 212 pmol, 1.0 eq) in DMF (2.0 mL) was added 3-(l-naphthyl)oxetan-3-amine (42.3 mg, 213 pmol, 1.0 eq), followed by HATU (88.9 mg, 234 pmol, 1.1 eq) and DIEA (82.4 mg, 638 pmol, 111 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 40 mm, 10 pm); flow rate: 60 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(3- (naphthalen-l-yl) oxetan-3-yl)benzamide (23.6 mg, 56.3 pmol, 27% yield) was obtained as a yellow solid. M + H ⁺ = 417.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.69 (s, 1H), 8.01 - 7.95 (m, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.78 (br d, J= 6.8 Hz, 2H), 7.57 - 7.47 (m, 3H), 7.04 (d, J= 8.4 Hz, 1H), 6.86 (dd, J = 2.8, 8.4 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 5.30 - 5.18 (m, 4H), 3.86 (d, J= 5.4 Hz, 2H), 3.28 - 3.17 (m, 2H), 2.75 - 2.68 (m, 1H), 2.21 (s, 3H), 1.94 (s, 4H), 1.89 - 1.79 (m, 1H).

Example 82: ( )-2-Methyl-5-(2-(methylamino)ethoxy)-/V-(2,2,2-trifluoro-l-( naphthalen- l-yl)ethyl)benzamide (Compound 349)

56A-2 ^82A ' ¹

Compound 349

Step 1: (S)-/cr/-Butyl methyl(2-(4-methyl-3-((2,2,2-trifluoro-l-(naphthalen-l- yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (82A-1)

To a solution of 5-(2-((/er/-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (100 mg, 323 pmol, 1.0 eq), (8)-2,2,2-trifluoro-l -(naphthal en-l-yl)ethanamine (72.8 mg, 323 pmol, 1.0 eq) in ACN (5.0 mL) were added TCFH (109 mg, 388 pmol, 1.2 eq) and 1- methylimidazole (92.9 mg, 1.13 mmol, 90.2 pL, 3.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. CS')-/c/7-Butyl methyl(2-(4-methyl-3 -((2,2,2-trifluoro- 1 -(naphthal en- 1 -yl)ethyl)carbamoyl)phenoxy)ethyl) carbamate (90.0 mg, 174 pmol, 54% yield) was obtained as a colorless oil.

Step 2: (5)-2-Methyl-5-(2-(methylamino)ethoxy)-/V-(2,2,2-trifluoro-l -(naphthalen-l-yl)et hyl)benzamide (Compound 349)

To a solution of CS')-/c/7-butyl methyl(2-(4-methyl-3 -((2,2,2-trifluoro- 1 -(naphthal en-1- yl)ethyl)carbamoyl)phenoxy)ethyl)carbamate (90.0 mg, 174 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCI/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). fS')-2-Methyl-5-(2-(methylamino)ethoxy)-/'/-(2, 2, 2-trifluoro- l -(naphthal en- l - yl)ethyl)benzamide (43.6 mg, 96.2 pmol, 55% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.0 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.82 (d, J= 9.3 Hz, 1H), 8.98 (br s, 2H), 8.28 (d, J= 8.5 Hz, 1H), 8.03 (d, J= 8.3 Hz, 2H), 7.93 (d, J= 7.3 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.65 - 7.58 (m, 2H), 7.21 (d, J= 8.6 Hz, 1H), 7.01 (dd, J = 2.7, 8.4 Hz, 1H), 6.90 - 6.79 (m, 2H), 4.22 (t, J= 5.0 Hz, 2H), 3.28 (t, J= 4.9 Hz, 2H), 2.59 (s, 3H), 2.20 (s, 3H). Example 83: 5-((l-Ethylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(naphthalen -l- yl)cyclopropyl)benzamide (Compound 314)

Compound 274 Compound 314

Step 1: 5-((l-Ethylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(naphthalen -l-yl)cyclopropyl)b enzamide (Compound 314)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cycl opropyl) benzamide (100 mg, 259 pmol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of acetaldehyde (57.0 mg, 517 pmol, 72.6 pL, 40% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (32.5 mg, 517 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((l-Ethylazetidin-2-yl)methoxy)-2-methyl-A-(l- (naphthalen-l-yl)cyclopropyl)benzamide (23.7 mg, 51.5 pmol, 35% yield, FA salt) was obtained as a white solid. M + H ⁺ = 415.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 9.10 (s, 1H), 8.63 (d, J= 8.3 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J= 7.7 Hz, 1H), 7.81 (dd, J= 7.8, 10.1 Hz, 2H), 7.60 - 7.40 (m, 3H), 7.02 (d, J= 8.4 Hz, 1H), 6.82 (dd, J= 2.8, 8.4 Hz, 1H), 6.59 (d, J= 2.7 Hz, 1H), 3.98 - 3.85 (m, 2H), 3.61 - 3.55 (m, 1H), 3.39 (dt, J= 2.4, 8.0 Hz, 1H), 2.92 (br d, J= 8.1 Hz, 1H), 2.72 - 2.66 (m, 1H), 2.46 - 2.39 (m, 1H), 2.09 - 1.99 (m, 1H), 1.94 (s, 4H), 1.34 (br s, 2H), 1.16 (br s, 2H), 0.87 (t, J= 7.2 Hz, 3H). Example 84: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-((l-(2,2,2- trifluoroethyl)azetidin-2-yl)methoxy)benzamide (Compound 396)

Compound 274 Compound 396

Step 1 : 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-((l-(2,2,2-tr ifluoroethyl)azetidin- 2-yl)methoxy)benzamide (Compound 396)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyc lopropyl) benzamide (100 mg, 259 pmol, 1.0 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (60.0 mg, 259 pmol, 1.0 eq) in DMF (10 mL) was added TEA (157 mg, 1.55 mmol, 216 pL, 6.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified preparative HPLC (Phenomenex C18 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 45% - 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2 -Methyl-A-(1 -(naphthal en-1- yl)cyclopropyl)-5-((l-(2,2,2-trifluoroethyl)azetidin-2-yl)me thoxy)benzamide (14.2 mg, 29.9 pmol, 12% yield) was obtained as a white solid. M + H ⁺ = 469.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.09 (s, 1H), 8.65 (d, J= 8.1 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.82 (t, J = 8.3 Hz, 2H), 7.63 - 7.40 (m, 3H), 7.02 (d, J= 8.6 Hz, 1H), 6.83 (dd, J= 2.7, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.89 (d, J= 5.4 Hz, 2H), 3.73 - 3.62 (m, 1H), 3.44 - 3.35 (m, 2H), 3.22 - 3.04 (m, 2H), 2.10 - 1.96 (m, 2H), 1.94 (s, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Example 85: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-((l-phenylaze tidin-2- yl)methoxy)benzamide (Compound 331)

Compound 274 Compound 331

Step 1 : 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-((l-phenylaze tidin-2-yl)methoxy) benzamide (Compound 331)

To a mixture of 5-(azeti din-2 -ylmethoxy)-2-methyl-7V-(l -(naphthal en-1- yl)cyclopropyl)benzamide (150 mg, 300 pmol, 1.0 eq, TFA salt), phenylboronic acid (43.9 mg, 360 pmol, 1.2 eq) in DCE (10 mL) were added Cu(OAc)2 (60.0 mg, 330 pmol, 1.1 eq), TEA (121 mg, 1.20 mmol, 167 pL, 4.0 eq), and 4 A molecular sieve (70.0 mg, 1.20 mmol, 4.0 eq). The mixture was degassed and purged with O2 three times and then it was stirred at 80 °C for 16 h under an O2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (200 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 65% - 98% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2 -methyl-A-(l -(naphthal en-1- yl)cyclopropyl)-5-((l-phenylazetidin-2-yl)methoxy)benzamide (140 mg, 334 pmol, 77% yield) as a white solid. M + H ⁺ = 463.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.09 (s, 1H), 8.14 (s, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.82 (t, J= 7.4 Hz, 2H), 7.60 - 7.42 (m, 3H), 7.13 (t, J = 7.9 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.89 (dd, J= 2.6, 8.3 Hz, 1H), 6.73 - 6.64 (m, 2H), 6.60 (d, J= 7.9 Hz, 2H), 4.26 (br t, J= 6.2 Hz, 1H), 4.12 (d, J= 5.0 Hz, 2H), 3.93 - 3.86 (m, 1H), 3.55 (q, J= 7.8 Hz, 1H), 2.40 - 2.30 (m, 1H), 2.29 - 2.18 (m, 1H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.17 (br s, 2H). Example 86: 5-((l-Benzylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(naphthale n-l- yl)cyclopropyl)benzamide (Compound 330)

Compound 274 Compound 330

Step 1 : 5-((l-Benzylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(naphthale n-l-yl)cyclopropyl) benzamide (Compound 330)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyc lopropyl) benzamide (100 mg, 200 pmol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of benzaldehyde (21.2 mg, 200 pmol, 158 pL, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (134 mg, 2.13 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-((l-Benzylazetidin-2-yl)methoxy)-2-methyl-A-(l- (naphthalen-l-yl)cyclopropyl)benzamide (33.0 mg, 69.2 pmol, 35% yield) was obtained as a white solid. M + H ⁺ = 477.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.06 (s, 1H), 8.66 (br d, J= 8.4 Hz, 1H), 7.92 (br d, J= 7.8 Hz, 1H), 7.82 (br t, J= 6.4 Hz, 2H), 7.59 - 7.43 (m, 3H), 7.25 - 7.18 (m, 4H), 7.18 - 7.11 (m, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.76 (dd, J = 2.5, 8.3 Hz, 1H), 6.54 (d, J= 2.5 Hz, 1H), 3.87 - 3.71 (m, 3H), 3.54 - 3.40 (m, 2H), 3.17 (br t, J= 6.2 Hz, 1H), 2.79 (q, J = 7.9 Hz, 1H), 2.01 (br d, J= 8.4 Hz, 1H), 1.95 (s, 3H), 1.92 - 1.83 (m, 1H), 1.35 (br s, 2H), 1.17 (br s, 2H). Example 87: 5-((l-Isopropylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(naphth alen-l- yl)cyclopropyl)benzamide (Compound 323)

Step 1

Compound 274 Compound 323

Step 1 : 5-((l-Isopropylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(naphth alen-l- yl)cyclopropyl)benzamide (Compound 323)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cycl opropyl) benzamide (100 mg, 99.9 pmol, 50% purity, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of acetone (11.6 mg, 200 pmol, 14.7 pL, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (12.6 mg, 200 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((l-Isopropylazetidin-2-yl)methoxy)-2-methyl-A-(l-(naphtha len-l- yl)cyclopropyl)benzamide (18.5 mg, 43.1 pmol, 43% yield) was obtained as a white solid. M + H ⁺ = 429.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.54 (d, J = 8.4 Hz, 1H), 7.96 (dd, J = 0.9, 7.0 Hz, 1H), 7.89 (d, J= 8.1 Hz, 1H), 7.80 (d, J= 8.3 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.54 - 7.44 (m, 2H), 7.02 - 6.97 (m, 1H), 6.95 - 6.84 (m, 1H), 6.73 (s, 2H), 4.47 - 4.28 (m, 1H), 4.17 - 3.74 (m, 3H), 3.45 - 3.29 (m, 1H), 3.04 - 2.88 (m, 1H), 2.31 (br d, J= 2.1 Hz, 2H), 2.12 (s, 3H), 1.62 - 1.53 (m, 2H), 1.45 - 1.35 (m, 2H), 1.29 - 1.13 (m, 6H). Example 88: 5-((l-(Cyclopropylmethyl)azetidin-2-yl)methoxy)-2-methyl-/V- (l- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 332)

Compound 274 Compound 332

Step 1: 5-((l-(Cyclopropylmethyl)azetidin-2-yl)methoxy)-2-methyl-/V- (l-(naphthalen-l-y l)cyclopropyl)benzamide (Compound 332)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cycl opropyl) benzamide (100 mg, 200 pmol, 1.0 eq) in MeOH (3.0 mL) was added TEA (10.0 pL), followed by the addition of cyclopropanecarbaldehyde (28.0 mg, 400 pmol, 30.0 pL, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, and then NaBHiCN (25.1 mg, 400 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((l-(Cyclopropylmethyl)azetidin-2-yl)methoxy)-2-methyl-A-( l- (naphthalene-l-yl)cyclopropyl)benzamide (13.3 mg, 30.2 pmol, 15% yield, FA salt) was obtained as a white solid. M + H ⁺ = 441.1 (LCMS); 'H NMR (400 MHz, DMSO ) 89.79 (m, 1H), 9.10 (s, 1H), 8.64 (d, J= 8.4 Hz, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.83 (t, J= 7.9 Hz, 2H), 7.61 - 7.40 (m, 3H), 7.08 (d, J = 8.3 Hz, 1H), 6.90 (dd, J = 2.6, 8.4 Hz, 1H), 6.68 (d, J= 2.6 Hz, 1H), 4.70 (br s, 1H), 4.33 - 4.15 (m, 2H), 4.06 - 3.89 (m, 2H), 3.23 - 3.12 (m, 1H), 3.02 - 2.87 (m, 1H), 2.43 - 2.25 (m, 2H), 1.97 (s, 3H), 1.35 (br s, 2H), 1.19 (br s, 2H), 0.95 (br s, 1H), 0.52 (td, J= 4.3, 8.6 Hz, 2H), 0.41 - 0.19 (m, 2H). Example 89: 5-((l-(2-Methoxyethyl)azetidin-2-yl)methoxy)-2-methyl-/V-(l- (naphthalen- l-yl)cyclopropyl)benzamide (Compound 348)

Compound 348

Step 1: 5-((l-(2-Methoxyethyl)azetidin-2-yl)methoxy)-2-methyl-/V-(l- (naphthalen-l-yl)cy clopropyl)benzamide (Compound 348)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyc lopropyl) benzamide (150 mg, 388 pmol, 1.0 eq) in ACN (6.0 mL) was added K2CO3 (161 mg, 1.16 mmol, 3.0 eq). The mixture was stirred at 20 °C for 30 min, then 1 -bromo-2-m ethoxy ethane (80.9 mg, 582 pmol, 54.7 pL, 1.5 eq) was added. The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5 -((1 -(2 -Methoxy ethyl)azeti din-2 -yl)methoxy)-2-methyl-A-(l -(naphthal en-1- yl)cyclopropyl)benzamide (27.4 mg, 54.8 pmol, 14%yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 445.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 8 10.53 (br d, J= 3.8 Hz, 1H), 9.15 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.82 (t, J= 7.2 Hz, 2H), 7.60 - 7.43 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.89 (dd, J= 2.5, 8.4 Hz, 1H), 6.68 (d, J= 2.4 Hz, 1H), 4.78 - 4.63 (m, 1H), 4.38 (dd, J= 8.3, 11.1 Hz, 1H), 4.16 (dd, J= 3.2, 11.2 Hz, 1H), 3.96 - 3.89 (m, 2H), 3.62 - 3.55 (m, 1H), 3.54 - 3.46 (m, 1H), 3.43 - 3.32 (m, 2H), 3.18 (s, 3H), 2.42 - 2.22 (m, 2H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H). Example 90: 5-((l-(2-Hydroxyethyl)azetidin-2-yl)methoxy)-2-methyl-/V-(l- (naphthalen- l-yl)cyclopropyl)benzamide (Compound 341)

Compound 274 Compound 341

Step 1: 5-((l-(2-Hydroxyethyl)azetidin-2-yl)methoxy)-2-methyl-/V-(l- (naphthalen-l-yl)cy clopropyl)benzamide (Compound 341)

To a solution of 5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyc lopropyl) benzamide (200 mg, 517 pmol, 1.0 eq) and 2-bromoethanol (64.7 mg, 517 pmol, 36.7 pL, 1.0 eq) in ACN (5.0 mL) was added K2CO3 (215 mg, 1.55 mmol, 3.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-((l-(2-Hydroxyethyl)azetidin-2-yl)methoxy)-2-methyl-A-(l- (naphthalen-l-yl)cyclopropyl) benzamide (32.9 mg, 68.5 pmol, 13% yield, FA salt) was obtained as a white solid. M + H ⁺ = 431.1 (LCMS); ¹ H NMR (400 MHz, DMSO ) 8 9.08 (s, 1H), 8.67 (d, J= 8.4 Hz, 1H), 8.20 (s, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.62 - 7.42 (m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 6.83 (dd, J= 2.7, 8.3 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.95 - 3.84 (m, 2H), 3.44 (br d, J= 3.4 Hz, 1H), 3.39 - 3.29 (m, 3H), 2.88 (br d, J= 8.1 Hz, 1H), 2.69 (td, J = 6.1, 11.9 Hz, 1H), 2.45 (br dd, J= 6.1, 11.8 Hz, 1H), 2.06 - 1.85 (m, 5H), 1.37 (s, 2H), 1.22 - 1.11 (m, 2H). Example 91: 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-/V-(l-(naphthale n-l- yl)cyclopropyl)benzamide (Compound 394)

Compound 394

Step 1: te/7- Butyl 2-methyl-2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)car bamoyl) phenoxy)methyl)azetidine-l-carboxylate (91A-1)

To a solution of 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (300 mg, 945 pmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)-2-methylazetidine-l -carboxylate (190 mg, 945 pmol, 1.0 eq) in toluene (18 mL) were added TMAD (488 mg, 2.84 mmol, 3.0 eq), PPhi (744 mg, 2.84 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl 2-methyl-2-((4-methyl-3-((l- (naphthalen- 1 -yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine- 1 -carboxylate (370 mg, 246 pmol, 26% yield) was obtained as a yellow solid. M + H ⁺ = 501.3 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.53 (br s, 1H), 8.00 - 7.93 (m, 1H), 7.90 (br d, J= 8.1 Hz, 1H), 7.79 (s, 1H), 7.62 - 7.54 (m, 1H), 7.54 - 7.44 (m, 2H), 7.05 - 6.94 (m, 1H), 6.85 - 6.62 (m, 3H), 4.13 - 4.02 (m, 1H), 3.90 - 3.67 (m, 3H), 2.44 - 2.31 (m, 1H), 2.19 - 2.08 (m, 3H), 1.99 - 1.89 (m, 1H), 1.58 (br d, J= 17.9 Hz, 3H), 1.52 - 1.40 (m, 4H), 1.36 - 1.22 (m, 9H). Step 2: 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-/V-(l-(naphthale n-l-yl)cyclopropyl) benzamide (Compound 394)

To a stirred solution of tert-butyl 2-methyl-2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (180 mg, 360 pmol, 1.0 eq) in DCM (9.0 mL) was added TFA (3.6 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5- ((2-methylazeti din-2 -yl)methoxy)-A-(l -(naphthal en- 1 -yl)cyclopropyl)benzamide (13.5 mg, 25.9 pmol, 7% yield, HC1 salt) was obtained as a brown solid. M + H ⁺ = 401.1 (LCMS); ^T H NMR (400 MHz, DMSO ) 8 9.10 (s, 1H), 9.02 - 8.85 (m, 1H), 8.82 - 8.58 (m, 2H), 7.97 - 7.90 (m, 1H), 7.87 - 7.80 (m, 2H), 7.61 - 7.42 (m, 3H), 7.14 - 7.05 (m, 1H), 6.96 - 6.89 (m, 1H), 6.75 - 6.69 (m, 1H), 4.21 - 4.13 (m, 1H), 4.01 - 3.94 (m, 1H), 3.88 - 3.73 (m, 2H), 2.46 (br d, J= 10.8 Hz, 1H), 2.26 (br s, 1H), 2.01 - 1.93 (m, 3H), 1.61 - 1.52 (m, 3H), 1.41 - 1.33 (m, 2H), 1.22 - 1.13 (m, 2H).

Example 92: 5-(2-Hydroxyethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 393)

Step 1

55A-2 Compound 393

Step 1 : 5-(2-Hydroxyethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopro pyl)benzamide (Compound 393)

To a solution of 5-hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (70.0 mg, 221 pmol, 1.0 eq) and l,3-dioxolan-2-one (38.9 mg, 441 pmol, 2.0 eq) in toluene (3.5 mL) was added K2CO3 (61.0 mg, 441 pmol, 2.0 eq), the mixture was degassed and purged with N2 three times and stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Welch Ultimate XB SIO2 (100 x 30 mm, 10 pm); flow rate: 40 mL/min; gradient: 5% - 95% B over 10 min; mobile phase A: heptane, mobile phase B: EtOH). 5 -(2 -Hydroxy ethoxy )-2-methyl-M( l -(naphthal en- l-yl)cyclopropyl)benzamide (30.9 mg, 81.9 pmol, 37% yield) was obtained as a brown solid. M + H ⁺ = 362.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.14 - 9.02 (m, 1H), 8.70 - 8.62 (m, 1H), 7.98 - 7.89 (m, 1H), 7.86 - 7.78 (m, 2H), 7.61 - 7.41 (m, 3H), 7.06 - 6.99 (m, 1H), 6.86 - 6.79 (m, 1H), 6.63 - 6.58 (m, 1H), 4.83 - 4.76 (m, 1H), 3.92 - 3.84 (m, 2H), 3.69 - 3.60 (m, 2H), 2.01 - 1.92 (m, 3H), 1.40 - 1.31 (m, 2H), 1.21 - 1.12 (m, 2H).

Example 93: 5-(2-Amino-2-oxoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 285)

55A-2 Compound 285

Step 1 : 5-(2-Amino-2-oxoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cycl opropyl) benzamide (Compound 285)

To a solution of 2-iodoacetamide (61.2 mg, 331 pmol, 1.5 eq) in acetone (10 mL) was added K2CO3 (91.5 mg, 662 pmol, 3.0 eq). The mixture was stirred at 20 °C for 30 min. 5-hydroxy- 2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (70.0 mg, 221 pmol, 1.0 eq) was added. The mixture was stirred at 90 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-Amino-2-oxoethoxy)-2- methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (37.2 mg, 99.4 pmol, 45% yield) was obtained as a white solid. M + H ⁺ = 375.0 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.09 (s, 1H), 8.65 (d, J= 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.82 (dd, J= 3.1, 7.6 Hz, 2H), 7.60 - 7.42 (m, 4H), 7.33 (br s, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.69 (d, = 2.6 Hz, 1H), 4.34 (s, 2H), 1.95 (s, 3H), 1.35 (s, 2H), 1.17 (s, 2H). Example 94: 5-(Azetidin-3-yloxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 171)

Compound 171

Step 1: tert-Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe noxy) azetidine-l-carboxylate (94A-1)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (59.7 mg, 326 pmol, 1.0 eq) and 5-((l- (tert-butoxycarbonyl)azetidin-3-yl)oxy)-2-methylbenzoic acid (100 mg, 326 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (98.8 mg, 978 pmol, 136 pL, 3.0 eq), EDCI (62.4 mg, 489 pmol, 1.5 eq) and HOBt (43.8 mg, 489 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (20 mL) and extracted with DCM (15 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ =0.4). ZerLButyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)azetidine -1 -carboxylate (90.0 mg, 190 pmol, 65% yield) was obtained as a brown solid. M + H ⁺ = 473.2 (LCMS).

Step 2: 5-(Azetidin-3-yloxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopr opyl)benzamide (Compound 171)

To a solution of /c/7-butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl) phenoxy) azetidine-l-carboxylate (80.0 mg, 169 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.00 mL, 319 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-yloxy)-2-methyl-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (40.0 mg, 82.2 pmol, 49% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 373.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.24 - 9.20 (m, 1H), 8.60 - 8.56 (m, 1H), 7.93 - 7.89 (m, 2H), 7.84 - 7.81 (m, 1H), 7.62 - 7.43 (m, 3H), 7.12 - 7.08 (m, 1H), 6.80 - 6.76 (m, 1H), 6.54 - 6.51 (m, 1H), 5.06 - 5.00 (m, 1H), 4.46 - 4.41 (m, 2H), 4.07 (br s, 2H), 2.00 (s, 3H), 1.47 - 1.43 (m, 2H), 1.33 - 1.31 (m, 2H).

Example 95: 5-(3-Aminocyclobutoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 265)

Compound 265

Step 1: te/7- Butyl (3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) cyclobutyl)carbamate (95A-1)

To a solution of 5-hydroxy-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)benzami de (200 mg, 630 pmol, 1.0 eq) and tert-butyl (3-hydroxycyclobutyl)carbamate (177 mg, 945 pmol, 1.5 eq) in toluene (3.0 mL) was added CMBP (228 mg, 945 pmol, 1.5 eq) at 25 °C. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tert-butyl (3-(4-methyl-3- ((1 -(naphthal en-l-yl)cy cl opropyl) carbamoyl)phenoxy)cyclobutyl) carbamate (300 mg), which was used in the next step without any further purification. M + H ⁺ = 431.1 (LCMS). Step 2: 5-(3-Aminocyclobutoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclo propyl)benzamide (Compound 265)

To a mixture of tert-butyl (3 -(4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl) carbamoyl) phenoxy)cyclobutyl) carbamate (300 mg, 617 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 25 ° C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(3-Aminocyclobutoxy)-2-methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (96.3 mg, 249 pmol, 40% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 387.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 8 9.13 (d, J = 4.4 Hz, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.35 (br d, J = 10.9 Hz, 3H), 7.93 (d, J = 8.2 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.63 - 7.56 (m, 1H), 7.56 - 7.50 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.08 - 6.98 (m, 1H), 6.77 - 6.67 (m, 1H), 6.48 (d, J = 2.6 Hz, 1H), 4.97 - 4.40 (m, 1H), 3.77 - 3.31 (m, 1H), 2.77 - 2.65 (m, 1H), 2.60 - 2.52 (m, 1H), 2.38 - 2.28 (m, 1H), 2.20 - 2.09 (m, 1H), 1.96 (d, J = 3.7 Hz, 3H), 1.35 (br s, 2H), 1.17 (br s, 2H).

Example 96: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(pyrrolidin-2 - ylmethoxy)benzamide (Compound 263)

Compound 263 Step 1: te/7- Butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) methyl)pyrrolidine-l-carboxylate (96A-1)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (150 mg, 473 pmol, 1.0 eq), tert-butyl 2-(hydroxymethyl)pyrrolidine-l -carboxylate (95.1 mg, 473 pmol, 1.0 eq) and CMBP (171 mg, 709 pmol, 1.5 eq) in toluene (8.0 mL) was degassed and purged with N2 three times. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert- Butyl 2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenoxy)methyl) pyrrolidine- 1 -carboxylate (200 mg, 400 pmol, 85% yield) was obtained as a yellow oil. M + H ⁺ = 429.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.53 - 8.46 (m, 1H), 7.98 - 7.93 (m, 1H), 7.92 - 7.87 (m, 1H), 7.83 - 7.77 (m, 1H), 7.60 - 7.45 (m, 3H), 7.02 - 6.96 (m, 1H), 6.67 (br s, 3H), 4.09 - 4.00 (m, 1H), 3.82 - 3.65 (m, 1H), 3.46 - 3.28 (m, 2H), 2.12 (s, 3H), 2.01 - 1.82 (m, 4H), 1.60 (s, 7H), 1.49 - 1.43 (m, 6H).

Step 2: 2-Methyl- \-( l-(naphthalen-l-yl)cyclopropyl)-5-(pyrrolidin-2-ylmethoxy)be nz amide (Compound 263)

To a stirred solution of tert-butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)pyrrolidine-l -carboxylate (100 mg, 200 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 10 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 65% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2 -Methyl-7V-(1 -(naphthal en-l-yl)cy cl opropyl)-5-(pyrrolidin-2- ylmethoxy)benzamide (51.3 mg, 117 pmol, 59% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 401.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.53 - 9.36 (m, 1H), 9.12 (s, 1H), 8.88 (br dd, J= 1.7, 3.6 Hz, 1H), 8.66 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.61 - 7.44 (m, 3H), 7.07 (d, J= 8.4 Hz, 1H), 6.88 (dd, J= 2.6, 8.4 Hz, 1H), 6.67 (d, = 2.6 Hz, 1H), 4.18 - 4.11 (m, 1H), 4.08 - 4.00 (m, 1H), 3.82 (br d, J= 2.9 Hz, lH), 3.16 (br s, 2H), 2.14 - 2.01 (m, 1H), 1.97 (s, 3H), 1.95 - 1.81 (m, 2H), 1.73 - 1.63 (m, 1H), 1.36 (s, 2H), 1.21 - 1.15 (m, 2H).

Example 97: 2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(naphtha len-l- yl)cyclopropyl)benzamide (Compound 283)

Step 1

Compound 263 Compound 283

Step 1 : 2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(naphtha len-l- yl)cyclopropyl)benzamide (Compound 283)

To a solution of 2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-5-(pyrrolidin-2- ylmethoxy)benzamide (160 mg, 200 pmol, 1.0 eq) in MeOH (4 mL) was added TEA (200 pL), followed by the addition of formaldehyde (32.4 mg, 400 pmol, 29.8 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (25.1 mg, 400 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-A-(l- (naphthalen-l-yl)cyclopropyl) benzamide (35.9 mg, 86.6 pmol, 43% yield) as a yellow gum. M + H ⁺ = 415.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.07 (s, 1H), 8.65 (s, 1H), 7.96 - 7.90 (m, 1H), 7.85 - 7.79 (m, 2H), 7.59 - 7.42 (m, 3H), 7.04 - 6.99 (m, 1H), 6.82 (dd, J= 2.8, 8.4 Hz, 1H), 6.60 (d, J= 2.6 Hz, 1H), 3.91 - 3.68 (m, 2H), 2.92 (td, J= 4.3, 9.1 Hz, 1H), 2.53 - 2.52 (m, 1H), 2.30 (s, 3H), 2.15 (d, J= 8.5 Hz, 1H), 2.07 - 1.73 (m, 4H), 1.72 - 1.59 (m, 2H), 1.57 - 1.45 (m, 1H), 1.40 - 1.32 (m, 2H), 1.22 - 1.10 (m, 2H). Example 98: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-3- yloxy)benzamide (Compound 268)

Compound 268

Step 1: tert-Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe noxy) piperidine-l-carboxylate (98A-1)

To a solution of 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (200 mg, 630 pmol, 1.0 eq) and tert-butyl 3-hydroxypiperidine-l-carboxylate (190 mg, 945 pmol, 1.5 eq) in toluene (3.0 mL) was added CMBP (228 mg, 945 pmol, 1.5 eq) at 25 °C. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-(4-methyl-3-((l- (naphthalen-l-yl)cyclopropyl) carbamoyl)phenoxy) piperidine-l-carboxylate (125 mg), which was used in the next step without any further purification. M + H ⁺ = 445.2 (LCMS).

Step 2: 2-Methyl- \-( l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-3-yloxy)benzami de (Compound 268)

To a mixture of tert-butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl) phenoxy) piperidine-l-carboxylate (125 mg, 250 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HClZEtOAc (4 M, 4.0 mL). The mixture was stirred at 25 ° C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-3-y loxy)benzamide (42.4 mg, 106 pmol, 42% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 401.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 5 9.32 - 9.20 (m, 1H), 9.14 (s, 1H), 8.65 (br d, J = 8.3 Hz, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.61 - 7.49 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.62 (br s, 1H), 3.28 - 3.16 (m, 1H), 3.15 - 3.04 (m, 1H), 3.00 (br s, 2H), 1.95 (s, 3H), 1.87 - 1.77 (m, 2H), 1.77 - 1.69 (m, 1H), 1.62 (br t, J = 10.4 Hz, 1H), 1.36 (s, 2H), 1.23 - 1.12 (m, 2H).

Example 99: 2-Methyl-5-((l-methylpiperidin-3-yl)oxy)-/V-(l-(naphthalen-l - yl)cyclopropyl)benzamide (Compound 289)

Compound 268 Compound 289

Step 1: 2-Methyl-5-((l-methylpiperidin-3-yl)oxy)-/V-(l-(naphthalen-l -yl)cyclopropyl)ben zamide (Compound 289)

To a solution of 2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-3- yloxy) benzamide (15.0 mg, 37.5 pmol, 1.0 eq) inMeOH (1.0 mL) was added TEA (300 pL), followed by the addition of formaldehyde (2.25 mg, 74.9 pmol, 2.06 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (4.71 mg, 74.9 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were washed with brine (3.0 mL x 3), dried over Na2SO4, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-Methyl-5-((l- methylpiperi din-3 -yl)oxy)-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (4.70 mg, 11.3 pmol, 30% yield) was obtained as a white solid. M + H ⁺ = 415.2 (LCMS); ¹ HNMR (400 MHz, DMSO- d _e ) 8 9.07 (s, 1H), 8.65 (d, J = 8.3 Hz, 1H), 7.97 - 7.74 (m, 3H), 7.61 - 7.43 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.86 - 6.81 (m, 1H), 6.59 (d, J = 2.5 Hz, 1H), 4.27 - 4.20 (m, 1H), 2.75 (br d, J = 8.4 Hz, 1H), 2.14 (s, 3H), 2.03 - 1.60 (m, 8H), 1.56 - 1.42 (m, 1H), 1.35 (br s, 2H), 1.25 (br d, J = 11.0 Hz, 1H), 1.17 (br s, 2H).

Example 100: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-2- ylmethoxy)benzamide (Compound 339)

Compound 339

Step 1: te/7- Butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) methyl)piperidine-l-carboxylate (100A-1)

To a solution of 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (450 mg, 1.42 mmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)piperidine-l -carboxylate (915 mg, 4.26 mmol, 3.0 eq) in toluene (15 mL) were added TMAD (732 mg, 4.26 mmol, 3.0 eq) and PPhi (1.12 g, 4.26 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (12 mL) and extracted with EtOAc (9.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. tert-Butyl 2-((4-methyl-3-((l- (naphthalen- l-yl)cy cl opropyl)carbamoyl)phenoxy)m ethyl) piperidine- 1 -carboxylate (113 mg, 15% yield) was obtained as a white solid. M + H ⁺ = 515.3 (LCMS).

Step 2: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-2- ylmethoxy) benzamide (Compound 339)

To a solution of tert-butyl 2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)piperidine-l -carboxylate (113 mg, 220 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-2-y lmethoxy)benzamide (15.7 mg, 34.8 pmol, 16% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 415.1 (LCMS); ^T H NMR (400 MHz, DMSO ) 5 9.15 - 9.09 (m, 1H), 8.65 (d, J= 8.6 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.86 - 7.80 (m, 2H), 7.60 - 7.44 (m, 3H), 7.11 - 7.06 (m, 1H), 6.93 - 6.87 (m, 1H), 6.69 - 6.65 (m, 1H), 4.13 - 4.02 (m, 1H), 3.98 - 3.87 (m, 1H), 3.49 - 3.41 (m, 1H), 3.23 (br d, J = 14.1 Hz, 1H), 2.98 - 2.83 (m, 1H), 1.97 (s, 3H), 1.87 - 1.68 (m, 3H), 1.59 - 1.44 (m, 3H), 1.39 - 1.33 (m, 2H), 1.20 - 1.17 (m, 2H).

Example 101: 2-Methyl-5-((l-methylpiperidin-2-yl)methoxy)-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 288) and 2-methyl-5-((l-methylazepan-3-yl)oxy)- /V-(l-(naphthalen-l-yl)cyclopropyl)benzamide (Compound 293)

Compound 293 Step 1: 2-Methyl-5-((l-methylpiperidin-2-yl)methoxy)-/V-(l-(naphthal en-l-yl)cyclo propyl)benzamide (Compound 288) and 2-methyl-5-((l-methylazepan-3-yl)oxy)-/V-(l- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 293)

To a solution of 5-hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (70.0 mg, 221 pmol, 1.0 eq) and (1-methylpiperi din-2 -yl)m ethanol (28.5 mg, 221 pmol, 29.0 pL, 1.0 eq) in toluene (3.5 mL) was added CMBP (80.0 mg, 331 pmol, 1.5 eq). The mixture was degassed and purged with N2 three times and stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-Methyl-5-((l-methylpiperidin-2-yl)methoxy)-A-(l- (naphthalen-l-yl)cyclopropyl)benzamide (12.3 mg, 28.7 pmol, 13% yield) was obtained as a yellow solid. M + H ⁺ = 429.3 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.09 (s, 1H), 8.68 - 8.63 (m, 1H), 7.96 - 7.90 (m, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.42 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 6.83 (dd, J= 2.7, 8.3 Hz, 1H), 6.62 - 6.57 (m, 1H), 3.93 (br d, J= 4.5 Hz, 1H), 3.78 (br d, J= 4.9 Hz, 1H), 2.76 - 2.68 (m, 1H), 2.19 - 2.08 (m, 4H), 1.95 (s, 4H), 1.66 (br d, J = 10.0 Hz, 2H), 1.57 - 1.47 (m, 1H), 1.45 - 1.10 (m, 7H). 2-Methyl-5-((l-methylazepan-3- yl)oxy)-A-(l -(naphthal en-l-yl)cyclopropyl) benzamide (17.6 mg, 41.1 pmol, 19% yield) was obtained as a white solid. M + H ⁺ = 429.3 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.09 (s, 1H), 8.74 - 8.58 (m, 1H), 7.93 (d, = 7.8 Hz, 1H), 7.81 (dd, J= 7.8, 11.7 Hz, 2H), 7.61 - 7.41 (m, 3H), 7.11 - 6.95 (m, 1H), 6.79 (dd, J= 2.8, 8.4 Hz, 1H), 6.54 (d, J = 2.6 Hz, 1H), 4.49 - 4.27 (m, 1H), 2.79 - 2.63 (m, 2H), 2.61 - 2.56 (m, 1H), 2.47 - 2.35 (m, 1H), 2.26 - 2.17 (m, 3H), 2.02 - 1.93 (m, 3H), 1.92 - 1.83 (m, 1H), 1.69 - 1.52 (m, 4H), 1.48 - 1.40 (m, 1H), 1.38 - 1.30 (m, 2H), 1.20 - 1.09 (m, 2H). Example 102: 2-Methyl-5-(morpholin-3-ylmethoxy)-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 286) Step 2

Compound 286

Step 1: tert- Butyl 3-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enoxy) methyl)morpholine-4-carboxylate (102A-1)

To a solution of 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (100 mg, 315 pmol, 1.0 eq) and tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (68.5 mg, 315 pmol, 1.0 eq) in toluene (5.0 mL) was added CMBP (114 mg, 473 pmol, 1.5 eq). The mixture was degassed and purged with N2 three times and stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.6). tert-Butyl 3-((4-methyl- 3 -((1 -(naphthal en-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)morpholine-4-carboxylate (40.0 mg, 77.4 pmol, 25% yield) was obtained as a yellow oil. M + H ⁺ = 517.2 (LCMS).

Step 2: 2-Methyl-5-(morpholin-3-ylmethoxy)-/V-(l-(naphthalen-l-yl)cy clopropyl)benza mide (Compound 286)

To a solution of tert-butyl 3-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenoxy)methyl)morpholine-4-carboxylate (40.0 mg, 77.4 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCI/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-(morpholin-3-ylmethoxy)-A-(l-(naphthalen-l-yl)cyc lopropyl)benzamide (22.9 mg, 49.9 pmol, 65% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.56 - 9.41 (m, 1H), 9.40 - 9.24 (m, 1H), 9.13 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.83 (dd, J= 4.1, 7.6 Hz, 2H), 7.64 - 7.42 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.90 (dd, J = 2.6, 8.4 Hz, 1H), 6.68 (d, J= 2.6 Hz, 1H), 4.18 - 3.87 (m, 4H), 3.75 - 3.56 (m, 3H), 3.26 - 3.07 (m, 2H), 1.96 (s, 3H), 1.40 - 1.34 (m, 2H), 1.21 - 1.15 (m, 2H).

Example 103: 2-Methyl-5-((4-methylmorpholin-3-yl)methoxy)-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 302)

Step 1

Compound 286 Compound 302

Step 1: 2-Methyl-5-((4-methylmorpholin-3-yl)methoxy)-/V-(l-(naphthal en-l-yl)cyclo propyl)benzamide (Compound 302)

To a solution of 2-methyl-5-(morpholin-3-ylmethoxy)-7V-(l-(naphthalen-l-yl)cy clopropyl) benzamide (40.0 mg, 96.0 pmol, 1.0 eq) in MeOH (3.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (15.6 mg, 192 pmol, 14.3 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (12.1 mg, 192 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-5-((4-methylmorpholin-3-yl)methoxy)-A-(l-(naphthale n-l-yl)cyclo propyl)benzamide (22.9 mg, 52.1 pmol, 54% yield, FA salt) was obtained as a white solid. M + H ⁺ = 431.1 (LCMS); ^X H NMR (400 MHz, DMSO4) 69.09 (s, 1H), 8.65 (d, J = 8.3 Hz, 1H), 7.93 (d, J= 7.3 Hz, 1H), 7.82 (t, J= 8.4 Hz, 2H), 7.61 - 7.43 (m, 3H), 7.03 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.7 Hz, 1H), 4.00 (dd, J= 4.2, 10.3 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.71 - 3.63 (m, 1H), 3.48 (dt, J= 2.4, 10.7 Hz, 1H), 3.28 (dd, J= 9.5, 10.9 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.37 - 2.30 (m, 1H), 2.26 - 2.13 (m, 4H), 1.95 (s, 3H), 1.35 (s, 2H), 1.21 - 1.12 (m, 2H).

Example 105: 5-((Hexahydro-LH-pyrrolizin-7a-yl)methoxy)-2-methyl-/V-(l-(n aphthalen- l-yl)cyclopropyl)benzamide (Compound 376)

55A-2 Compound 376

Step 1: 5-((Hexahydro-LH-pyrrolizin-7a-yl)methoxy)-2-methyl-/V-( 1 -(naphthalen-1- yl)cyclopropyl)benzamide (Compound 376)

A mixture of 5-hydroxy-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)benzami de (70.0 mg, 221 pmol, 1.0 eq), (hexahydro- U/-pyrrolizin-7a-yl)m ethanol (62.3 mg, 441 pmol, 2.0 eq) TMAD (114 mg, 662 pmol, 3.0 eq) and PPI13 (174 mg, 662 pmol, 3.0 eq) in toluene (5.0 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 5-((hexahydro-U/-pyrrolizin-7a-yl)methoxy)-2-methyl- 7V-(1 -(naphthal en-l-yl)cyclo propyl)benzamide (17.1 mg, 38.6 pmol, 18% yield) as a yellow solid. M + H ⁺ = 441.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.06 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.88 - 7.75 (m, 2H), 7.61 - 7.40 (m, 3H), 6.98 - 6.95 (m, 1H), 7.00 (d, J= 8.4 Hz, 1H), 6.81 (dd, J = 2.7, 8.3 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 3.51 (s, 2H), 2.95 - 2.83 (m, 2H), 2.56 - 2.51 (m, 2H), 1.95 (s, 3H), 1.87 - 1.63 (m, 6H), 1.60 - 1.46 (m, 2H), 1.41 - 1.31 (m, 2H), 1.23 - 1.11 (m, 2H).

Example 106: 5-(2-(Dimethylamino)ethoxy)-2-methoxy-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 303)

Compound 303

Step 1: 5-Hydroxy-2-methoxy-/V-(l-(naphthalen-l-yl)cyclopropyl)benza mide (106A-2)

To a solution of 5-hydroxy-2-methoxybenzoic acid (100 mg, 595 pmol, 1.0 eq) and 1- (naphthalen-l-yl)cyclopropanamine (109 mg, 595 pmol, 1.0 eq) in DMF (3.0 mL) was added TEA (60.2 mg, 595 pmol, 82.8 pL, 1.0 eq), followed by EDCI (120 mg, 625 pmol, 1.1 eq) and HOBt (16.1 mg, 119 pmol, 0.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.5). 5-Hydroxy-2-methoxy-7V-(l-(naphthalen-l-yl)cyclopropyl)benza mide (120 mg) was obtained as a yellow oil. M + H ⁺ = 334.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methoxy-/V-(l-(naphthalen-l-yl )cyclopropyl) benzamide (Compound 303)

To a solution of 5-hydroxy-2-methoxy-7V-(l-(naphthalen-l-yl)cyclopropyl)benza mide (120 mg, 360 pmol, 1.0 eq) and 2-(dimethylamino)ethanol (35.3 mg, 396 pmol, 39.7 pL, 1.1 eq) in toluene (4.0 mL) was added CMBP (95.6 mg, 396 pmol, 1.1 eq). The mixture was degassed and purged with N2 three times, and then was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methoxy-7V-(l-(naphthalen-l- yl)cyclopropyl) benzamide (81.0 mg, 181 pmol, 50% yield) was obtained as a brown solid. M + H ⁺ = 405.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 8 8.98 - 8.92 (m, 1H), 8.63 - 8.55 (m, 1H), 7.97 - 7.90 (m, 1H), 7.86 - 7.76 (m, 2H), 7.67 - 7.59 (m, 1H), 7.57 - 7.38 (m, 2H), 7.09 - 7.03 (m, 1H), 6.99 - 6.91 (m, 2H), 3.97 - 3.89 (m, 2H), 3.74 - 3.65 (m, 3H), 2.56 - 2.54 (m, 2H), 2.24 - 2.10 (m, 6H), 1.42 - 1.35 (m, 2H), 1.24 - 1.15 (m, 2H).

Example 107: 2-Bromo-5-(2-(dimethylamino)ethoxy)-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 269)

Step 3 107A-3 Compound 269

Step 1: Methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (107A-2)

To a solution of 2-chloro-7V,7V-dimethylethanamine (1.25 g, 8.66 mmol, 1.0 eq, HCI salt) in DMF (10 mL) was added K2CO3 (5.98 g, 43.3 mmol, 5.0 eq). The mixture was stirred at 25 °C for 30 min, then 18-crown-6 (3.62 g, 13.7 mmol, 1.6 eq), KI (2.41 g, 14.5 mmol, 1.7 eq) and methyl 2-bromo-5-hydroxybenzoate (2.00 g, 8.66 mmol, 1.0 eq) were added. The mixture was stirred at 70 °C for 5 h. TLC indicated that that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried overNa2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 2-bromo-5-(2-(dimethylamino) ethoxy )benzoate (570 mg, 1.32 mmol, 22% yield) was obtained as a white solid. M + H ⁺ = 302.0 (LCMS).

Step 2: 2-Bromo-5-(2-(dimethylamino)ethoxy)benzoic acid (107A-3)

A mixture of methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (570 mg, 1.89 mmol, 1.0 eq) in HC1 (2 M aqueous, 15 mL) was stirred at 100 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and treated with NaOH (2 M aqueous) to adjust the pH to 6. The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with DCM/MeOH (V/V = 10/1, 15 mL) then filtered. The filter cake was washed with DCM/MeOH (15 mL x 2) to ensure that all product was washed from the solids. The combined organic layers were concentrated under vacuum to give the crude product 2-bromo-5-(2-(dimethylamino)ethoxy)benzoic acid (500 mg), which was used in the next step without any further purification. M + H ⁺ = 288.1 (LCMS).

Step 3: 2-Bromo-5-(2-(dimethylamino)ethoxy)-/V-(l-(naphthalen-l-yl)c yclopropyl) benzamide (Compound 269)

To a solution of 2-bromo-5-(2-(dimethylamino)ethoxy) benzoic acid (100 mg, 292 pmol, 1.2 eq) in DCM (1.0 mL) were added l-(naphthalen-l-yl)cyclopropanamine (44.5 mg, 243 pmol, 1.0 eq), EDCI (69.9 mg, 364 pmol, 1.5 eq), HOBt (49.2 mg, 364 pmol, 1.5 eq) and TEA (73.8 mg, 729 pmol, 101 pL, 3.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- Bromo-5-(2-(dimethylamino)ethoxy)-A-(l-(naphthalen-l-yl)cycl opropyl) benzamide (17.2 mg, 37.9 pmol, 16% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 453.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 10.45 - 10.29 (m, 1H), 9.31 (s, 1H), 8.62 (d, J= 8.2 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.58 - 7.44 (m, 4H), 6.98 - 6.93 (m, 1H), 6.74 (d, J= 3.1 Hz, 1H), 4.28 (t, J= 4.8 Hz, 2H), 3.45 - 3.39 (m, 2H), 2.76 (d, J= 4.8 Hz, 6H), 1.40 (s, 2H), 1.21 - 1.14 (m, 2H). Example 108: 5-(2-(Dimethylamino)ethoxy)-2-ethynyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 337)

Step 1 : 5-(2-(Dimethylamino)ethoxy)-/V-(l-(naphthalen-l-yl)cycloprop yl)-2- ((trimethylsilyl)ethynyl)benzamide (108A-1)

To a solution of 2-bromo-5-(2-(dimethylamino)ethoxy)-7V-(l-(naphthalen-l-yl)c yclopropyl) benzamide (200 mg, 408 pmol, 1.0 eq, HC1 salt) in a mixture of toluene (16 mL) and H2O (4.0 mL) were added ethynyltrimethylsilane (80.2 mg, 816 pmol, 113 pL, 2.0 eq), Pd(PPh3)2Ch (28.7 mg, 40.8 pmol, 0.1 eq), Cui (7.78 mg, 40.8 pmol, 0.1 eq) and TEA (207 mg, 2.04 mmol, 284 pL, 5.0 eq) under a N2 atmosphere. The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated that 48% of the starting material remained and 32% of desired product was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 70% - 98% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-7V-(l-(naphthalen-l- yl)cyclopropyl)-2-((trimethylsilyl)ethynyl) benzamide (50.0 mg, 106 pmol, 26% yield) was obtained as a white solid. M + H ⁺ = 471.2 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-ethynyl-/V-(l-(naphthalen-l-yl )cyclopropyl) benzamide (Compound 337)

To a solution of 5 -(2-(dimethylamino)ethoxy)-7V-(l -(naphthal en-l-yl)cyclopropyl)-2-((tri methylsilyl)ethynyl)benzamide (40.0 mg, 84.9 pmol, 1.0 eq) in MeOH (2.0 mL) was added CS2CO3 (138 mg, 425 pmol, 5.0 eq). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2- ethynyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (9.70 mg, 20.6 pmol, 24% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 399.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 10.39 (br s, 1H), 9.19 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.60 - 7.41 (m, 4H), 7.01 (dd, J= 2.6, 8.6 Hz, 1H), 6.81 (d, J= 2.6 Hz, 1H), 4.32 (t, J= 4.9 Hz, 2H), 3.89 (s, 1H), 3.43 (br d, J= 4.6 Hz, 2H), 2.77 (d, J= 4.5 Hz, 6H), 1.44 - 1.39 (m, 2H), 1.21 - 1.15 (m, 2H).

Example 109: 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)-/V-(l-(naphthalen- l- yl)cyclopropyl)benzamide (Compound 353)

Step 1: Methyl 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoate (109A-1)

To a solution of methyl 2-bromo-5-(2-(dimethylamino)ethoxy)benzoate (200 mg, 662 pmol, 1.0 eq) and cyclopropylboronic acid (171 mg, 1.99 mmol, 3.0 eq) in a mixture of toluene (10 mL) and H2O (1.0 mL) were added K3PO4 (422 mg, 1.99 mmol, 3.0 eq), PCy3 (9.28 mg, 33.1 pmol, 10.7 pL, 0.05 eq) and Pd(OAc)2 (7.43 mg, 33.1 pmol, 0.05 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.4). Methyl 2-cyclopropyl-5-(2-(dimethylamino) ethoxy )benzoate (100 mg, 380 pmol, 57% yield) was obtained as a yellow oil. M + H ⁺ = 264.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.35 (s, 1H), 6.98 (s, 2H), 4.07 (br t, J= 4.9 Hz, 2H), 3.92 (s, 3H), 2.74 (br t, J= 4.9 Hz, 2H), 2.58 - 2.46 (m, 1H), 2.35 (s, 6H), 0.93 (br d, J= 8.4 Hz, 2H), 0.61 (br d, J= 5.5 Hz, 2H).

Step 2: 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoic acid (109A-2)

To a solution of methyl 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoate (90.0 mg, 342 pmol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (2.5 mL) was added NaOH (2 M in aqueous, 684 pL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and acidified to pH 6 using HC1 (I M aqueous). The resulting mixture was concentrated under vacuum to remove the water completely. Then the slurry was treated with DCM/MeOH (V/V = 10/1, 10 mL) and stirred for 10 min. The mixture was filtered, and the filter cake was washed with DCM/MeOH = 10/1 (5.0 mL x 2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give crude 2-cyclopropyl-5-(2- (dimethylamino)ethoxy)benzoic acid (85 mg) as a yellow gum. M + H ⁺ = 250.1 (LCMS).

Step 3: 2-Cyclopropyl-5-(2-(dimethylamino)ethoxy)-/V-(l-(naphthalen- l-yl)cyclopropyl) benzamide (Compound 353)

To a solution of 2-cyclopropyl-5-(2-(dimethylamino)ethoxy)benzoic acid (70.0 mg, 281 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (51.5 mg, 281 pmol, 1.0 eq) in DMF (5.0 mL) were added TEA (85.2 mg, 842 pmol, 117 pL, 3.0 eq), EDCI (64.6 mg, 337 pmol, 1.2 eq) and HOBt (45.5 mg, 337 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Cyclopropyl-5-(2- (dimethylamino) ethoxy)-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (27.6 mg, 60.5 pmol, 22% yield, HC1 salt) was obtained as a yellow solid. M + H+ = 415.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.21 - 9.75 (m, 1H), 9.14 (s, 1H), 8.65 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.60 - 7.38 (m, 3H), 6.90 - 6.78 (m, 2H), 6.63 (d, J= 2.1 Hz, 1H), 4.23 (br s, 2H), 3.43 (q, J = 4.7 Hz, 2H), 2.79 (d, J = 4.6 Hz, 6H), 1.78 - 1.61 (m, 1H), 1.37 (br s, 2H), 1.19 (br s, 2H), 0.39 - 0.20 (m, 4H).

Example 110: 3-(2-(Dimethylamino)ethoxy)-2-fluoro-6-methyl-/V-(l-(naphtha len-l- yl)cyclopropyl)benzamide (Compound 311)

110A-4 Compound 311

Step 1: 6-Bromo-2-fluoro-3-methoxy-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (110A-2)

To a solution of 6-bromo-2-fluoro-3-methoxybenzoic acid (200 mg, 803 pmol, 1.2 eq) and 1-

(naphthalen-l-yl)cyclopropanamine (123 mg, 669 pmol, 1.0 eq) in DMF (3.0 mL) were added

TEA (203 mg, 2.01 mmol, 279 pL, 3.0 eq), EDCI (154 mg, 803 pmol, 2.5 eq) and HOBt (109 mg, 803 pmol, 1.2 eq). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 6-Bromo-2-fluoro-3-methoxy-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (220 mg, 531 pmol, 79% yield) was obtained as a yellow oil. M + H ⁺ = 414.1 (LCMS).

Step 2: 2-Fluoro-3-methoxy-6-methyl-/V-(l-(naphthalen-l-yl)cycloprop yl)benzamide (110A-3)

To a solution of 6-bromo-2-fluoro-3 -methoxy -7V-(1 -(naphthal en-l-yl)cyclopropyl) benzamide (180 mg, 435 pmol, 1.0 eq) in DMF (3.0 mL) were added 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (131 mg, 521 pmol, 146 pL, 50% purity in THF, 1.2 eq), CS2CO3 (467 mg, 1.43 mmol, 3.3 eq), and Pd(dppf)C12.CH2C12 (355 mg, 435 pmol, 1.0 eq). The reaction mixture was degassed and purged with N2 three times and then stirred at 115 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 2-Fluoro-3-methoxy-6-methyl-7V-(l-(naphthalen-l-yl)cycloprop yl)benzamide (220 mg, 531 pmol, 79% yield) was obtained as a yellow oil. M + H ⁺ = 350.1 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.44 (d, J= 8.4 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.80 (d, J= 8.1 Hz, 1H), 7.62 - 7.41 (m, 6H), 3.80 (s, 3H), 1.95 (s, 3H), 1.61 (br d, J= 1.9 Hz, 2H), 1.42 - 1.36 (m, 2H).

Step 3: 2-I luoro-3-hydroxy-6-methyl- \-( l-(naphthalen-l-yl)cyclopropyl)benzamide (110A-4)

To a solution of 2-fluoro-3-methoxy-6-methyl-7V-(l-(naphthalen-l-yl)cycloprop yl)benzamide (90.0 mg, 258 pmol, 1.0 eq) in DCM (5.0 mL) was added a solution of BBr, (968 mg, 3.86 mmol, 372 pL, 15 eq) in DCM (1.0 mL) dropwise at -78 °C. The resulting mixture was stirred at the same temperature for 1 h, warmed to 20 °C and stirred for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 2-Fluoro-3-hydroxy-6-methyl-7V-(l- (naphthalen-l-yl)cyclopropyl)benzamide (40.0 mg, 119 pmol, 46% yield) was obtained as a yellow oil. M + H ⁺ = 336.1 (LCMS). Step 4: 3-(2-(Dimethylamino)ethoxy)-2-fluoro-6-methyl-/V-(l-(naphtha len-l-yl)cyclopro pyl)benzamide (Compound 311)

To a solution of 2-fluoro-3-hydroxy-6-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (30.0 mg, 890 pmol, 1.0 eq) in DMF (3.0 mL) was added K2CO3 (61.8 mg, 447 pmol, 5.0 eq). The mixture was stirred at 20 °C for 30 min. To the reaction mixture were added 2-chloro-A,A- dimethylethanamine (12.9 mg, 89.5 pmol, 1.0 eq, HC1 salt), 18-crown-6 (37.8 mg, 143 pmol, 1.6 eq) and KI (25.2 mg, 152 pmol, 1.7 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 3-(2-(Dimethylamino)ethoxy)-2-fluoro-6-methyl-A-(l -(naphthal en-1- yl)cyclopropyl)benzamide (4.10 mg, 8.67 pmol, 10% yield, FA salt) was obtained as a white solid. M + H ⁺ = 407.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.35 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 7.96 - 7.89 (m, 1H), 7.87 - 7.76 (m, 2H), 7.62 - 7.40 (m, 3H), 7.02 (t, J= 8.6 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 4.03 (t, J= 5.7 Hz, 2H), 2.57 (t, J= 5.7 Hz, 2H), 2.18 (s, 6H), 1.78 (s, 3H), 1.31 (br s, 2H), 1.21 - 1.14 (m, 2H).

Example 111: 5-Amino-4-iodo-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)b enzamide (Compound 216)

Compound 216 Step 1: 5-Amino-4-iodo-2-methylbenzoic acid (111A-1)

To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (200 mg, 687 pmol, 1.0 eq) in MeOH (10 mL) was added NaOH (2 M in aqueous, 1.03 mL, 3.0 eq). The mixture was stirred at 25 °C for 2 h and then was stirred another 2 h at 70 °C. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and acidified to pH 6 with HC1 (1 M aqueous), and a precipitate was formed. The mixture was filtered and the solid was washed with H2O (5.0 mL), dried under vacuum to give 5-amino-4-iodo-2-methylbenzoic acid (180 mg, 650 pmol, 95% yield) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 278.0 (LCMS).

Step 2: 5-Amino-4-iodo-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)b enzamide (Compound 216)

To a solution of 5-amino-4-iodo-2-methylbenzoic acid (130 mg, 469 pmol, 1.0 eq) and 1- (naphthalen-l-yl)cyclopropanamine (86.0 mg, 469 pmol, 1.0 eq) in DMF (7.0 mL) were added TEA (142 mg, 1.41 mmol, 196 pL, 3.0 eq), EDCI (180 mg, 938 pmol, 2.0 eq) and HOBt (127 mg, 938 pmol, 2.0 eq). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H2O (5.0 mL), dried under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-Amino-4-iodo-2-methyl-7V-(l-(naphthalen-l-yl) cyclopropyl)benzamide (28.4 mg, 64.2 pmol, 20% yield) was obtained as a white solid. M + H ⁺ = 442.9 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.44 (d, J = 8.4 Hz, 1H), 8.00 - 7.87 (m, 2H), 7.81 (d, J= 8.3 Hz, 1H), 7.65 - 7.44 (m, 3H), 7.39 (s, 1H), 6.49 (s, 1H), 6.44 (br s, 1H), 3.91 (br s, 2H), 2.03 (s, 3H), 1.56 - 1.52 (m, 2H), 1.42 - 1.34 (m, 2H).

Example 112: 4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthal en-l- yl)cyclopropyl)benzamide (Compound 369)

Step 4

112A-3 Compound 369

Step 1: Methyl 4-bromo-5-hydroxy-2-methylbenzoate (112A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (200 mg, 1.20 mmol, 1.0 eq) in DCM (2.0 mL) was added K2CO3 (175 mg, 1.26 mmol, 1.05 eq) at 25 °C. The mixture was degassed and purged with N2 three times. To this mixture was added a solution of Bn (192 mg, 1.20 mmol, 62.0 pL, 1.0 eq) in DCM (4.0 mL) at -15 °C dropwise. After the addition was completed, the mixture was stirred at 25 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.6). Methyl 4-bromo-5-hydroxy-2-methylbenzoate (160 mg, 54% yield) was obtained as a yellow solid.

Step 2: Methyl 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (112A-2)

To a solution of 2-chloro-7V,7V-dimethylethanamine (188 mg, 1.31 mmol, 4.0 eq) in DMF (5.0 mL) was added K2CO3 (902 mg, 6.53 mmol, 20 eq) and the reaction mixture was stirred at 20 °C for 30 min. Methyl 4-bromo-5-hydroxy-2-methylbenzoate (80.0 mg, 326 pmol, 1.0 eq), 18-crown-6 (545 mg, 2.06 mmol, 6.3 eq) and KI (364 mg, 2.19 mmol, 6.7 eq) were added in sequence. The resulting mixture was stirred at 70 °C for 11 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Water Xbridge BEH C18 (100 x 30 mm, 10 pin); flow rate: 25 mL/min; gradient: 30% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). Methyl 4-bromo-5-(2- (dimethylamino)ethoxy)-2-methylbenzoate (88.0 mg, 273 pmol, 84% yield) was obtained as a yellow solid. M + H ⁺ = 316.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.38 (s, 1H), 7.37 (s, 1H), 4.09 (s, 2H), 3.82 (s, 3H), 2.76 (s, 2H), 2.43 (s, 3H), 2.33 (s, 6H).

Step 3: 4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (112A-3)

To a solution of methyl 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (68.0 mg, 215 pmol, 1.0 eq) in a mixture of MeOH (2.7 mL) and THF (1.4 mL) was added NaOH (2 M aqueous, 1.4 mL, 12.7 eq). The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with MTBE (2.0 mL x 2). The aqueous layer was acidified to pH 6 using HC1 (1 M aqueous). The mixture was extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (60.0 mg, 199 pmol, 92% yield) as a yellow solid. M + H ⁺ = 302.0 (LCMS); 'H NMR (400 MHz, CDCh) 6 7.53 (s, 1H), 7.38 (s, 1H), 4.52 - 4.38 (m, 2H), 3.36 - 3.24 (m, 2H), 2.78 (s, 6H), 2.53 (s, 3H).

Step 4: 4-Bromo-5-(2-(dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthal en-l-yl)cyclo propyl)benzamide (Compound 369)

To a solution of 4-bromo-5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (50.0 mg, 165 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (24.3 mg, 132 pmol, 0.8 eq) in DMF (2.5 mL) were added TEA (33.5 mg, 331 pmol, 46.1 pL, 2.0 eq), EDCI (47.6 mg, 248 pmol, 1.5 eq) and HOBt (33.5 mg, 331 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 4-Bromo-5-(2-(dimethylamino)ethoxy)-2- methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (15.6 mg, 30.9 pmol, 19% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 467.0 (LCMS); 'H NMR (400 MHz, CDCh) 6 13.08 - 12.84 (m, 1H), 8.67 - 8.57 (m, 1H), 8.01 - 7.92 (m, 1H), 7.92 - 7.86 (m, 1H), 7.83 - 7.76 (m, 1H), 7.67 - 7.58 (m, 1H), 7.54 - 7.43 (m, 2H), 7.01 (s, 1H), 6.87 (br s, 1H), 4.51 (br d, J= 1.4 Hz, 2H), 3.59 - 3.24 (m, 2H), 2.95 (br s, 6H), 2.10 (s, 3H), 1.64 - 1.55 (m, 2H), 1.45

- 1.35 (m, 2H).

Example 113: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 366)

113A-3 Compound 366

Step 1: 2-((4-lodo-5-methylpyridin-2-yl)oxy)- \. V-dimethyleth:in:imine (113A-2)

To a solution of 2-(dimethylamino) ethanol (1.69 g, 19.0 mmol, 3.0 eq) in NMP (10 mL) was added NaH (759 mg, 19.0 mmol, 60% purity, 3.0 eq) at 0°C, the reaction mixture was stirred at 25 °C for 30 min. 2-Fluoro-4-iodo-5-methyl-pyridine (1.50 g, 6.33 mmol, 1.0 eq) was added to the solution, and the reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex C18 (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-((4-iodo-5-methylpyridin-2-yl)oxy)-7V,7V- dimethylethanamine (600 mg, 2.00 mmol, 31% yield) as a white oil. M + H ⁺ = 307.0 (LCMS).

Step 2: Methyl 2-(2-(dimethylamino) ethoxy)-5-methylisonicotinate (113A-3)

A mixture of 2-[(4-iodo-5-methyl-2-pyridyl)oxy]-7V,7V-dimethyl-ethanamine (400 mg, 1.31 mmol, 1.0 eq), Pd(OAc)2 (29.3 mg, 131 pmol, 0.1 eq), DPPF (72.4 mg, 131 pmol, 0.1 eq) and TEA (661 mg, 6.53 mmol, 909 pL, 5.0 eq) in MeOH (10 mL) was stirred at 80 °C for 16 h under a CO (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated under vacuum to give a residue which was purified by preparative TLC ((EtOAc/petroleum ether = 1/1, R/= 0.4). Methyl 2- [2-(dimethylamino)ethoxy]-5-methyl-pyridine-4-carboxylate (300 mg, 1.00 mmol, 96% yield) was obtained as a brown oil. M + H ⁺ = 239.1 (LCMS).

Step 3: 2-(2-(Dimethylamino)ethoxy)-5-methyl-/V-(l-(naphthalen-l-yl) cyclopropyl) isonicotinamide (Compound 366)

To a mixture of methyl 2-[2-(dimethylamino)ethoxy]-5-methyl-pyridine-4-carboxylate (100 mg, 400 pmol, 1.0 eq) and l-(l-naphthyl)cyclopropanamine (76.9 mg, 400 pmol, 1.0 eq) in toluene (2.0 mL) was added AlMei (2 M in toluene, 600 pL, 3.0 eq) at 0 °C. The reaction mixture was stired at 100 °C for 1 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (100 pL) and TFA (100 pL), then the reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-[2-(Dimethylamino)ethoxy]-5-methyl-A-[l-(l- naphthyl)cyclopropyl]pyridine-4-carboxamide (48.8 mg, 69.7 pmol, 23% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 390.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.52 (br d, J= 4.0 Hz, 1H), 9.35 (s, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.01 - 7.90 (m, 2H), 7.83 (dd, J = 7.6, 15.6 Hz, 2H), 7.62 - 7.40 (m, 3H), 6.52 (s, 1H), 4.55 - 4.35 (m, 2H), 3.44 (br s, 2H), 2.81 (br s, 6H), 1.93 (s, 3H), 1.39 - 1.15 (m, 4H).

Example 114: 2-(2-(Dimethylamino)ethoxy)-5-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)pyrimidine-4-carboxamide (Compound 350)

Compound 350

Step 1 : 2-Chloro-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)pyrimid ine-4-carboxa mide (114A-2)

To a solution of 2-chloro-5-methylpyrimidine-4-carboxylic acid (150 mg, 869 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (143 mg, 782 pmol, 0.8 eq) in DCM (5.0 mL) were added TEA (264 mg, 2.61 mmol, 363 pL, 3.0 eq), EDCI (200 mg, 1.04 mmol, 1.2 eq) and HOBt (141 mg, 1.04 mmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.8). 2-Chloro-5-methyl-7V-(l- (naphthalen-l-yl)cyclopropyl)pyrimidine-4-carboxamide (60.0 mg, 178 pmol, 20% yield) was obtained as a yellow oil. M + H ⁺ = 338.1 (LCMS).

Step 2: 2-(2-(Dimethylamino)ethoxy)-5-methyl-/V-(l-(naphthalen-l-yl) cyclopropyl)pyrim idine-4-carboxamide (Compound 350)

To a solution of 2-chloro-5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)pyrimid ine-4-carboxa mide (100 mg, 296 pmol, 1.0 eq) and 2-(dimethylamino)ethanol (26.4 mg, 210 pmol, 29.7 pL, 0.7 eq, HC1 salt) in DMF (5.0 mL) were added 18-crown-6 (124 mg, 468 pmol, 1.6 eq), K2CO3 (205 mg, 1.48 mmol, 5.0 eq) and KI (82.6 mg, 497 pmol, 1.7 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-(2-(Dimethylamino)ethoxy)-5-methyl-7V-(l -(naphthal en-1- yl)cyclopropyl) pyrimidine-4-carboxamide (29.1 mg, 74.0 pmol, 25% yield, FA salt) was obtained as a white solid. M + H ⁺ = 391.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.45 (s, 1H), 8.68 (d, J= 8.3 Hz, 1H), 8.47 (s, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.62 - 7.43 (m, 3H), 4.33 (t, J= 5.7 Hz, 2H), 2.54 (s, 2H), 2.16 - 2.11 (m, 9H), 1.41 (s, 2H), 1.21 (br s, 2H).

Example 115: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)nicotinamide (Compound 275)

Step 3

115A-3 Compound 275

Step 1: Ethyl 5-(2-(dimethylamino)ethoxy)-2-methylnicotinate (115A-2)

A mixture of ethyl 5 -hydroxy -2-methylnicotinate (300 mg, 1.66 mmol, 1.0 eq) and 2-bromo- 7V,7V-dimethylethanamine (262 mg, 1.82 mmol, 1.1 eq, HC1) in DMF (10 mL) was degassed and purged with N2 three times. To the mixture were added 18-crown-6 (691 mg, 2.62 mmol, 1.6 eq), KI (462 mg, 2.78 mmol, 1.7 eq) and K2CO3 (1.1 g, 8.28 mmol, 5.0 eq). The resulting mixture was stirred at 70 °C for 14 h under a N2 atmosphere. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 200/1 to 10/1. Ethyl 5-(2-(dimethylamino) ethoxy)-2- methylnicotinate (200 mg, 380 pmol, 48% yield) was obtained as a white solid. M + H ⁺ = 253.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.35 (d, J= 3.0 Hz, 1H), 7.74 (d, J= 3.0 Hz, 1H), 4.39 (q, J= 7.1 Hz, 2H), 4.22 - 4.12 (m, 2H), 2.76 (s, 3H), 2.42 (br s, 6H), 1.41 (t, J= 7.1 Hz, 3H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methylnicotinic acid (115A-3)

A solution of ethyl 5-(2-(dimethylamino)ethoxy)-2-methylnicotinate (160 mg, 634 pmol, 1.0 eq) in HC1 (2 M aqueous, 5.0 mL) was stirred at 100 °C for 14 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature and concentrated under vacuum to give the crude product 5-(2-(dimethylamino) ethoxy) -2-methylnicotinic acid (160 mg), which was used in the next step without any further purification. M + H ⁺ = 225.2 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-N-(l-(naphthalen-l-yl)c yclopropyl) nicotinamide (Compound 275)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylnicotinic acid (100 mg, 446 pmol, 1.0 eq) and l-(naphthalen-l-yl)cyclopropanamine (82.0 mg, 446 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (135 mg, 1.34 mmol, 186 pL, 3.0 eq), EDCI (128 mg, 669 pmol, 1.5 eq) and HOBt (90.0 mg, 669 pmol, 1.5 eq). The mixture was stirred at 20 °C for 18 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A- (l-(naphthalen-l-yl)cyclopropyl) nicotinamide (60.0 mg, 155 pmol, 35% yield, FA salt) was obtained as a white solid. M + H ⁺ = 390.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 9.13 (s, 1H), 8.53 (d, J= 8.4 Hz, 1H), 8.04 (d, J= 2.9 Hz, 1H), 7.83 (d, J= 7.9 Hz, 1H), 7.73 (t, J= 13 Hz, 2H), 7.51 - 7.32 (m, 3H), 6.97 (d, J= 3.0 Hz, 1H), 3.94 (t, J= 5.7 Hz, 2H), 2.43 - 2.37 (m, 3H), 2.08 (s, 6H), 2.02 (s, 3H), 1.33 - 1.24 (m, 2H), 1.13 - 1.05 (m, 2H).

Example 116: 5-Methyl-/V-(l-(naphthalen-l-yl)cydopropyl)-lH-indole-6-carb oxamide (Compound 199)

20A-4 Compound 199 Step 1: 5-Methyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-l//-indole-6-carboxamide (Compo und 199)

To a solution of 5-methyl-lH-indole-6-carboxylic acid (140 mg, 800 pmol, 1.0 eq) and 1- (naphthalen-l-yl)cyclopropanamine (146 mg, 799 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (243 mg, 2.40 mmol, 300 pL, 3.0 eq), EDCI (383 mg, 2.00 mmol, 2.5 eq) and HOBt (267 mg, 2.00 mmol, 2.5 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini C18 column (80 X 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5 -Methyl-A-(1 -(naphthal en-1- yl)cyclopropyl)-U/-indole-6-carboxamide (200 mg, 512 pmol, 64% yield. HC1 salt) was obtained as a white solid. M + H+ = 341.1 (LCMS); 1H NMR (400 MHz, DMSO ) 5 11.20 - 10.85 (m, 1H), 9.02 (s, 1H), 8.82 - 8.61 (m, 1H), 7.99 - 7.90 (m, 1H), 7.87 - 7.80 (m, 2H), 7.64 - 7.42 (m, 3H), 7.34 - 7.29 (m, 1H), 7.26 - 7.23 (m, 1H), 7.11 (s, 1H), 6.29 (br s, 1H), 2.22 - 2.10 (m, 3H), 1.44 - 1.31 (m, 2H), 1.23 - 1.10 (m, 2H).

Example 117: 2-(Methoxymethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-LH- indole-6-carboxamide (Compound 240)

Step 4 Compound 240

Step 1: Methyl 5-amino-4-(3-methoxyprop-l-yn-l-yl)-2-methylbenzoate (117A-1)

To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (500 mg, 1.72 mmol, 1.0 eq) in TEA (10 mL) were added 3 -methoxyprop- 1-yne (120 mg, 1.72 mmol, 1.0 eq), Pd(PPh3)2C12 (120 mg, 172 pmol, 0.1 eq) and Cui (16.4 mg, 85.9 pmol, 0.1 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. Methyl 5-amino-4-(3-methoxyprop-l-yn- l-yl)-2-m ethylbenzoate (400 mg, 1.54 mmol, 90% yield) was obtained as a yellow oil. M + H ⁺ = 234.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.36 - 7.34 (m, 1H), 7.23 (s, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 3.53 (s, 3H), 2.53 - 2.48 (m, 3H).

Step 2: Methyl 2-(methoxymethyl)-5-methyl-l//-indole-6-carboxylate (117A-2)

To a solution of methyl 5-amino-4-(3-methoxyprop-l-yn-l-yl)-2-methylbenzoate (350 mg, 1.50 mmol, 1.0 eq) in DCE (6.0 mL) was added Cu(OAc)2 (545 mg, 3.00 mmol, 2.0 eq). The mixture was degassed and purged with N2 three times and stirred at 130 °C for 2 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, filtered and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.6). Methyl 2-(methoxymethyl)-5-methyl-U/-indole-6-carboxylate (180 mg, 772 pmol, 51% yield) was obtained as a yellow oil. M + H ⁺ = 234.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.41 (br s, 1H), 8.03 (s, 1H), 7.41 (s, 1H), 6.37 (s, 1H), 4.63 (s, 2H), 3.91 (s, 3H), 3.41 (s, 3H), 2.68 (s, 3H).

Step 3: 2-(Methoxyniethyl)-5-niethyl- 1 //-indole-6-carboxylic acid (117A-3)

To a solution of methyl 2-(methoxymethyl)-5-methyl-U/-indole-6-carboxylate (90.0 mg, 386 prnol, 1.0 eq) in a mixture of MeOH (4.0 mL) and THF (2.0 mL) was added NaOH (2 M, 1.0 mL, 5.2 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with MTBE (2.0 mL x 3). The aqueous layer was basified to pH 4 using HC1 (1 M aqueous) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(methoxymethyl)-5-methyl-U/-indole-6-carboxylic acid (60.0 mg), which was used in the next step without any further purification. M + H ⁺ = 220.0 (LCMS).

Step 4: 2-(Methoxymethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-lH-indole-6-ca rboxamide (Compound 240)

To a solution of 2-(methoxymethyl)-5-methyl-U/-indole-6-carboxylic acid (60.0 mg, 274 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (50.2 mg, 274 pmol, 1.0 eq) in DCM

(5.0 mL) were added TEA (83.1 mg, 821 pmol, 114 pL, 3.0 eq), EDCI (78.7 mg, 411 pmol, 1.5 eq) and HOBt (55.5 mg, 411 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 40% - 70% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-(Methoxymethyl)-5-methyl-A-(l- (naphthalen-l-yl)cyclopropyl)-U/-indole-6-carboxamide (5.20 mg, 12.3 pmol, 5% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 385.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 11.23 - 10.99 (m, 1H), 9.02 (s, 1H), 8.70 (d, J= 8.9 Hz, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.83 (d, J= 7.7 Hz, 2H), 7.61 - 7.43 (m, 3H), 7.20 (s, 1H), 7.04 (s, 1H), 6.24 (s, 1H), 4.47 (s, 2H), 3.23 (s, 3H), 2.13 (s, 3H), 1.36 (s, 2H), 1.17 (br d, J= 1.1 Hz, 2H).

Example 118: terf-Butyl ((5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-lH- indol-2-yl)methyl)carbamate (Compound 180)

Step 1

Compound 180 Step 1: tert-Butyl ((5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-LH-indol-2- yl)methyl)carbamate (Compound 180)

To a solution of 2-(((/crt-butoxycarbonyl)amino)methyl)-5-methyl- l//-indole-6-carboxylic acid (210 mg, 690 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (139 mg, 759 pmol, 1.1 eq) in DCM (5.0 mL) was added TEA (209 mg, 2.07 mmol, 288 pL, 3.0 eq), followed by HOBt (140 mg, 1.04 mmol, 1.5 eq) and EDCI (198 mg, 1.04 mmol, 1.5 eq). The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (8.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl((5- methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-l//-ind ol-2-yl)methyl) carbamate (270 mg, 533 pmol, 77% yield) was obtained as a white solid. M + H ⁺ = 470.1 (LCMS);

NMR (400 MHz, CD ₃ OD) 8 8.68 - 8.60 (m, 1H), 7.93 - 7.86 (m, 2H), 7.83 - 7.77 (m, 1H), 7.60 - 7.55 (m, 1H), 7.52 - 7.47 (m, 1H), 7.46 - 7.41 (m, 1H), 7.21 - 7.15 (m, 1H), 7.11 - 7.03 (m, 1H), 6.17 - 6.10 (m, 1H), 4.35 - 4.25 (m, 2H), 2.17 - 2.12 (m, 3H), 1.47 - 1.42 (m, 11H), 1.32 - 1.21 (m, 2H).

Example 119: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) -lH- indole-6-carboxamide (Compound 170)

Compound 180 Compound 170

Step 1 : 2-( m inomet hyl )-5-met hyl-\-( 1 -(napht halen- 1 -yl )cyclopropyl )- 1 //-indole-6- carboxamide (Compound 170)

To a solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-lZ7 - indol-2-yl)methyl)carbamate (200 mg, 426 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 30 mm, 5 pm); flow rate: 60 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)-l JT-indole-6- carboxamide (130 mg, 352 pmol, 83% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 370.0 (LCMS); 'H NMR (400 MHz,CD ₃ OD) 8 8.67 - 8.56 (m, 1H), 7.94 - 7.87 (m, 2H), 7.84 - 7.78 (m, 1H), 7.61 - 7.41 (m, 3H), 7.29 - 7.25 (m, 1H), 7.14 - 7.10 (m, 1H), 6.47 - 6.44 (m, 1H), 4.24 - 4.19 (m, 2H), 2.17 - 2.13 (m, 3H), 1.50 - 1.43 (m, 2H), 1.35 - 1.27 (m, 2H).

Example 120: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-2-yl)cyclopropyl) -LH- indole-6-carboxamide (Compound 248)

Compound 248

Step 1: l-(Naphthalen-2-yl)cyclopropanamine (120A-2)

A mixture of 2-naphthonitrile (2.00 g, 13.1 mmol, 307 pL, 1.0 eq) in anhydrous Et20 (50 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (4.08 g, 14.4 mmol, 4.24 mL, 1.1 eq) slowly and then EtMgBr (3 M in Et20, 9.57 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (3.71 g, 26.1 mmol, 3.22 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(Naphthalen-2-yl)cyclopropanamine (400 mg, 2.03 mmol, 16% yield) was obtained as a yellow solid. M + H ⁺ = 184.1 (LCMS).

Step 2: tert-Butyl ((5-methyl-6-(( 1 -(napht halen-2-yl )cyclopropyl (carbamoyl )-l//-indol-2- yl)methyl)carbamate (120A-3)

To a solution of l-(naphthalen-2-yl)cyclopropanamine (150 mg, 819 pmol, 1.0 eq) and 2- (((/c/7-butoxycarbonyl)amino)methyl)-5-methyl- l7/-indole-6-carboxylic acid (299 mg, 982 pmol, 1.2 eq) in DCM (2.0 mL) were added EDCI (235 mg, 1.23 mmol, 1.5 eq), HOBt (166 mg, 1.23 mmol, 1.5 eq) and TEA (248 mg, 2.46 mmol, 342 pL, 3.0 eq). The mixture was stirred at 25 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. /c/V-Butyl ((5- methyl-6-((l-(naphthalen-2-yl)cyclopropyl)carbamoyl)-U/-indo l-2-yl)methyl)carbamate (150 mg, 256 pmol, 31% yield) was obtained as a yellow solid. M + H ⁺ = 470.3 (LCMS).

Step 3: 2-( ininoinethyl)-5-methyl- \-( l-(ii:iphth:ileii-2-yl)cyclopropyl)-l//-iiidole-6-carb oxamide (Compound 248)

To a mixture of /c77-butyl ((5-methyl-6-((l-(naphthalen-2-yl)cyclopropyl)carbamoyl)-UT- indol-2-yl)methyl)carbamate (100 mg, 213 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (2 M, 10 mL). The mixture was stirred at 25 ° C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- (Aminomethyl)-5-methyl-A-(l-(naphthalen-2-yl)cyclopropyl)-lJ /-indole-6-carboxamide (65.0 mg, 176 pmol, 83% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 370.3 (LCMS); 'H NMR (400 MHz, DMSO-J,) 8 11.37 (s, 1H), 9.03 (s, 1H), 8.53 (br s, 3H), 7.89 - 7.78 (m, 4H), 7.51 - 7.37 (m, 5H), 6.49 (s, 1H), 4.20 (s, 2H), 2.40 (s, 3H), 1.37 (br d, J = 10.5 Hz, 4H).

Example 121: 2-(Aminomethyl)-5-methyl-/V-(l-phenylcyclopropyl)-LH-indole- 6- carboxamide (Compound 246)

Step 2

Compound 246

Step 1: tert-Butyl ((5-methyl-6-(( 1 -phenylcyclopropyl)carbamoyl)-LH-indol-2-yl)methyl) carbamate (121A-1)

To a solution of 2-(((/ert-butoxycarbonyl)amino)methyl)-5-methyl-U/-indole-6- carboxylic acid (80.0 mg, 263 pmol, 1.0 eq) and 1-phenylcyclopropanamine (35.0 mg, 263 pmol, 1.0 eq) in DCM (5.0 mL) was added TEA (79.8 mg, 789 pmol, 110 pL, 3.0 eq), followed by EDCI (75.6 mg, 394 pmol, 1.5 eq) and HOBt (53.3 mg, 394 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (8.0 mL x 5). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.5). ZerLButyl ((5-methyl-6-((l -phenylcyclopropyl) carbamoyl)- IT/-indol-2-yl)methyl) carbamate (80.0 mg, 191 pmol, 73% yield) was obtained as a yellow oil. M + H ⁺ = 420.2 (LCMS). Step 2: 2-(Aminomethyl)-5-methyl-\-( 1 -phenylcyclopropyl)-l//-indole-6-c:irbox:unide

(Compound 246)

To a solution of tert-butyl ((5-methyl-6-((l-phenylcyclopropyl)carbamoyl)-l/Z-indol-2- yl)methyl) carbamate (80.0 mg, 191 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (6.16 g, 54.0 mmol, 4.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 ° C to give the residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(Aminomethyl)-5-methyl-A-(l-phenylcyclopropyl)-l/Z-indole- 6-carboxamide (9.20 mg, 21.2 pmol, 11% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 320.1

NMR (400 MHz, DMS0- ₆ ) 8 11.19 - 11.04 (m, 1H), 8.91 - 8.82 (m, 1H), 8.29 - 8.19 (m, 2H), 7.51 - 7.42 (m, 1H), 7.40 - 7.14 (m, 6H), 6.60 - 6.12 (m, 1H), 4.23 - 4.13 (m, 2H), 2.39 - 2.35 (m, 3H), 1.31 - 1.20 (m, 4H). Example 122: /V-(l-([l,l'-Biphenyl]-4-yl)cyclopropyl)-2-(aminomethyl)-5-m ethyl-LH- indole-6-carboxamide (Compound 244) Step 1 Step 2

122A-2

122A-3

Compound 244

Step 1: tert-Butyl (l-([l,l'-biphenyl]-4-yl)cyclopropyl)carbamate (122A-2)

A mixture of tert-butyl (1 -(4-bromophenyl)cyclopropyl)carbamate (1.00 g, 3.20 mmol, 1.0 eq), phenylboronic acid (781 mg, 6.40 mmol, 2.0 eq) and K2CO3 (2 M, 6.41 mL, 4.0 eq) in DMF (30 mL) was degassed and purged with N2 three times. To the mixture was added Pd(PPh3)4 (370 mg, 0.32 mmol, 0.1 eq). The resulting mixture was stirred at 90 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. tert-Butyl (l-([l,l'-biphenyl]-4-yl)cyclopropyl)carbamate (500 mg, 1.62 mmol, 50% yield) was obtained as a white solid. M - 56 + H ⁺ = 254.1 (LCMS).

Step 2: l-([l,l'-Biphenyl]-4-yl)cyclopropanamine (122A-3)

To a stirred solution of tert-butyl (l-([l,l'-biphenyl]-4-yl)cyclopropyl)carbamate (200 mg, 646 prnol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give l-([l,l'-biphenyl]-4-yl)cyclopropanamine (150 mg, 720 pmol, 88% yield, HC1 salt) as a white solid. M + H ⁺ = 210.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.98 (br s, 3H), 7.77 - 7.61 (m, 4H), 7.56 - 7.43 (m, 4H), 7.41 - 7.33 (m, 1H), 1.51 - 1.35 (m, 2H), 1.23 (s, 2H)

Step 3: tert-Butyl ((6-((l-([ l,l'-biphenyl]-4-yl)cyclopropyl)carbamoyl)-5-methyl-lZ/- indol-2-yl)methyl)carbamate (122A-4)

To a solution of l-([l,l'-biphenyl]-4-yl)cyclopropanamine (80.8 mg, 329 pmol, 1.0 eq) and 2- (((tert-butoxycarbonyl)amino)methyl)-5-methyl-17/-indole-6-c arboxylic acid (100 mg, 329 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (99.8 mg, 987 pmol, 137 pL, 3 eq), EDCI (157 mg, 823 pmol, 2.5 eq) and HOBt (111 mg, 823 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.5). te/7-Butyl ((6-((l-([l,l'-biphenyl]-4- yl)cyclopropyl)carbamoyl)-5-methyl-lH-indol-2-yl)methyl)carb amate (70.0 mg, 141 pmol, 43% yield) was obtained as a white solid. M + H ⁺ = 496.3 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 10.94 (s, 1H), 8.91 (s, 1H), 7.63 (dd, J= 7.9, 19.9 Hz, 4H), 7.50 - 7.42 (m, 3H), 7.41 - 7.30 (m, 4H), 7.29 - 7.24 (m, 1H), 6.41 - 5.88 (m, 1H), 4.55 - 4.08 (m, 2H), 2.38 (s, 3H), 1.41 (s, 9H), 1.30 (s, 4H).

Step 4: \-(l-(| 1.1 '-Biphenyl |-4-yl)cyclopropyl)-2-(:iininoinethyl)-5-inetliyl-l//-indole -6- carboxamide (Compound 244)

To a stirred solution of /e/7-butyl ((6-((l-([l,l'-biphenyl]-4-yl)cyclopropyl)carbamoyl)-5- methyl-U/-indol-2-yl)methyl)carbamate (60.0 mg, 121 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-([l,l'-Biphenyl]-4-yl)cyclopropyl)-2-(aminomethyl)-5-me thyl- UT-indole-6-carboxamide (24.8 mg, 57.4 pmol, 47% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 396.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 11.24 (s, 1H), 8.94 (s, 1H), 8.37 (br s, 3H), 7.79 - 7.56 (m, 4H), 7.54 - 7.42 (m, 3H), 7.38 - 7.33 (m, 3H), 6.48 (s, 1H), 4.20 (s, 2H), 2.40 (s, 3H), 1.31 (s, 4H).

Example 123: 2-(Aniinomethyl)- \-( l-(3-broniophenyl)cyclopropyl)-5-methyl-l //-indole- 6-carboxamide (Compound 232)

Compound 232

Step 1: tert-Butyl ((6-(( l-(3-bromophenyl)cyclopropyl)carbamoyl)-5-methyl-LH-indol-2- yl)methyl)carbamate (123A-2)

To a solution of l-(3-bromophenyl)cyclopropanamine (209 mg, 990 pmol, 1.0 eq) and 2- (((tert-butoxycarbonyl)amino)methyl)-5-methyl-l/7-indole-6-c arboxylic acid (300 mg, 990 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (299 mg, 2.96 mmol, 412 pL, 3.0 eq), EDCI (472 mg, 2.46 mmol, 2.5 eq) and HOBt (333 mg, 2.46 mmol, 2.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert- Butyl ((6-((l- (3 -bromophenyl) cyclopropyl)carbamoyl)-5-methyl-l/7-indol-2-yl)methyl)carbam ate (200 mg, 401 pmol, 41% yield) was obtained as a yellow solid. M + H ⁺ = 498.1 (LCMS).

Step 2: 2-(Aininoniethyl)-\-( 1 -(3-broniophenyl)cyclopropyl)-5-niethyl-l //-indole-6- carboxamide (Compound 232)

To a stirred solution of tert-butyl ((6-((l-(3-bromophenyl)cyclopropyl)carbamoyl)-5-methyl- l//-indol-2-yl)methyl)carbamate (70.0 mg, 140 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-(Aminomethyl)-7V-(l-(3-bromophenyl)cyclopropyl)-5-methyl-l Z/-indole-6-carboxamide (20.0 mg, 46.0 pmol, 33% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 398.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.95 (s, 1H), 8.56 - 8.20 (m, 3H), 7.49 - 7.42 (m, 2H), 7.41 - 7.35 (m, 2H), 7.28 (t, J = 7.9 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.48 (s, 1H), 4.38 - 4.03 (m, 2H), 2.38 (s, 3H), 1.30 (s, 4H). Example 124: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l- yl)cyclopropyl)indoline-6-carboxamide (Compound 221)

Step 1: te/7- Butyl methyl(prop-2-yn-l-yl)carbamate (124A-2)

A mixture of tert-butyl prop-2-yn-l-ylcarbamate (500 mg, 3.22 mmol, 1.0 eq) in THF (15 mL) was degassed and purged with N2 three times. To the mixture was added sodium hydride (177 mg, 4.43 mmol, 60% purity, 1.5 eq) at 0 °C and the mixture was stirred at the same temperature for 30 min, then Mel (629 mg, 4.43 mmol, 276 pL, 1.5 eq) was added. The mixture was stirred at 25 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH4CI (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl methyl(prop-2-yn-l-yl)carbamate (430 mg, 2.54 mmol, 79% yield) as a yellow oil, which was used in the next step without any further purification. NMR (400 MHz, CDCh) 6 4.13 - 3.97 (m, 2H), 2.94 - 2.90 (m, 3H), 2.24 - 2.19 (m, 1H), 1.49 - 1.46 (m, 9H).

Step 2: Methyl 5-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)prop-l-yn-l -yl)-2- methylbenzoate (124A-3)

To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (700 mg, 2.40 mmol, 1.0 eq), tertbutyl methyl(prop-2-yn-l-yl)carbamate (427 mg, 2.53 mmol, 1.1 eq), Cui (91.6 mg, 481 pmol, 0.2 eq) and Pd(PPh3)2Ch (169 mg, 240 pmol, 0.1 eq) was added TEA (8.4 mL). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (20 mL) and extracted with DCM (15 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 5-amino-4-(3 -((tert-butoxy carbonyl)(methyl)amino)prop- 1 -yn- 1 -yl)-2- methylbenzoate (500 mg, 1.50 mmol, 63% yield) was obtained as a yellow solid. M + H ⁺ = 333.2 (LCMS); ^X H NMR (400 MHz, CDCh) 8 7.29 - 7.27 (m, 1H), 7.15 - 7.13 (m, 1H), 4.36

- 4.28 (m, 2H), 3.90 - 3.85 (m, 3H), 2.99 - 2.98 (m, 3H), 2.46 - 2.39 (m, 3H), 1.51 - 1.47 (m, 9H).

Step 3: Methyl 2-(((tert-biitoxycarbonyl)(methyl)ainino)methyl)-5-methyl-l/ /-indole-6- carboxylate (124A-4)

To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)(methyl)amino)prop-l-yn-l -yl)- 2-methylbenzoate (500 mg, 1.50 mmol, 1.0 eq) in DCE (15 mL) was added Cu(OAc)2 (683 mg, 3.76 mmol, 2.5 eq). The mixture was stirred at 90 °C for 6 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(((tert- butoxycarbonyl)(methyl)amino) methyl)-5-methyl-U/-indole-6-carboxylate (500 mg, 1.50 mmol, 100% yield) was obtained as yellow oil. 'H NMR (400 MHz, CDCh) 6 9.13 - 8.98 (m, 1H), 8.04 - 7.98 (m, 1H), 7.41 - 7.37 (m, 1H), 6.36 - 6.25 (m, 1H), 4.52 - 4.35 (m, 2H), 3.96

- 3.85 (m, 3H), 2.90 - 2.85 (m, 3H), 2.72 - 2.62 (m, 3H), 1.51 (br s, 9H). Step 4: 2-(((/ /7-Biitoxyc:irboiiyl)(inetliyl):iiniiio)inethyl)-5-niethyl- 1 //-indole-6- carboxylic acid (124A-5)

To a stirred solution of methyl 2-(((terLbutoxycarbonyl)(methyl)amino)methyl)-5-methyl-UT- indole-6-carboxylate (200 mg, 602 pmol, 1.0 eq) in a mixture of MeOH (2.0 mL) and THF (6.0 mL) was added NaOH (2 M aqueous, 4.0 mL, 14 eq). The resulting mixture was stirred at 20 °C for 2 h, then at 70 °C for another 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with TBME (5.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with DCM (5.0 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(((lerl- butoxycarbonyl)(methyl)amino)methyl)-5-methyl-U/-indole-6-ca rboxylic acid (200 mg) as a red solid, which was used in the next step without any further purification. M + H ⁺ = 319.2 (LCMS); ^X H NMR (400 MHz, CDCh) 8 7.42 - 7.39 (m, 1H), 6.99 - 6.98 (m, 1H), 6.34 - 6.32 (m, 1H), 2.89 - 2.88 (m, 2H), 2.73 - 2.70 (m, 3H), 2.29 - 2.27 (m, 3H), 1.44 (s, 9H).

Step 5: tert-Butyl melhyl((5-melhyl-6-(( 1 -(naphlhalen- 1 -yl )cyclopropyl )carbamoyl)- 1 //- indol-2-yl)methyl)carbamate (124A-6)

To a solution of 2-(((ter/-butoxycarbonyl)(methyl)amino)methyl)-5-methyl-UT-i ndole-6- carboxylic acid (200 mg, 314 pmol, 1.0 eq) in DCM (8.0 mL) were added 1 -(naphthal en-1- yl)cyclopropanamine (57.6 mg, 314 pmol, 1.0 eq) and TEA (95.4 mg, 942 pmol, 131 pL, 3.0 eq), followed by EDCI (90.3 mg, 471 pmol, 1.5 eq) and HOBt (63.7 mg, 471 pmol, 1.5 eq). The resulting mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL). The product was extracted with DCM (10 mL x 4) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Zc/V-Butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l)- U/-indol-2-yl)m ethyl)carbamate (60.0 mg, 124 pmol, 40% yield) was obtained as a yellow oil. M + H ⁺ = 484.3 (LCMS).

Step 6: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l-yl)cycl opropyl)indoline- 6-carboxamide (Compound 221)

To a solution of /c/7-butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l)- U/-indol-2-yl)methyl)carbamate (60.0 mg, 124 pmol, 1.0 eq) in EtOAc (4.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-A-(l -(naphthal en-l-yl)cyclopropyl) indoline-6- carboxamide (10.7 mg, 26.9 pmol, 22% yield) was obtained as a white solid. M + H ⁺ = 384.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.67 - 8.60 (m, 1H), 7.95 - 7.88 (m, 2H), 7.84 - 7.78 (m, 1H), 7.62 - 7.55 (m, 1H), 7.54 - 7.41 (m, 2H), 7.32 - 7.29 (m, 1H), 7.16 - 7.12 (m, 1H), 6.55 - 6.50 (m, 1H), 4.32 - 4.26 (m, 2H), 2.72 - 2.67 (m, 3H), 2.20 - 2.13 (m, 3H), 1.50 - 1.43 (m, 2H), 1.35 - 1.27 (m, 2H).

Example 125: 2-((Dimethylamino)methyl)-5-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl)- l//-indole-6-carboxamide (Compound 173)

Compound 170 Compound 173

Step 1: 2-( ( I)im et hy la ni ino )met Iiy 1 )-5-m et hyl- X-( 1 -( na pli t Iialen- 1 -y I )cy clopropy 1 )- 1 //- indole-6-carboxamide (Compound 173)

To a solution of 2-(aminomethyl)-5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)- U/-indole-6- carboxamide (90.0 mg, 244 pmol, 1.0 eq) in MeOH (6.0 mL) was added TEA (50.0 pL), followed by the addition of formaldehyde (2.94 g, 36.3 mmol, 2.7 mL, 37% purity in water, 149 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, and then NaBH ₃ CN (123 mg, 1.95 mmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (8.0 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-((Dimethylamino)methyl)-5-methyl-A-(l- (naphthalen-l-yl)cyclopropyl)-U/-indole-6-carboxamide (32.8 mg, 81.1 pmol, 33% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 398.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 11.20 - 11.16 (m, 1H), 9.10 - 9.06 (m, 1H), 8.70 - 8.63 (m, 1H), 7.97 - 7.90 (m, 1H), 7.86 - 7.81 (m, 2H), 7.61 - 7.43 (m, 3H), 7.33 - 7.29 (m, 1H), 7.14 - 7.10 (m, 1H), 6.57 - 6.52 (m, 1H), 4.38 - 4.33 (m, 2H), 2.73 - 2.70 (m, 6H), 2.14 - 2.11 (m, 3H), 1.39 - 1.34 (m, 2H), 1.20 - 1.16 (m, 2H).

Example 126: 2-(l-Aminoethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )-LH- indole-6-carboxamide (Compound 273)

Step 1: Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)but-l-yn-l-yl)-2-me thy

Ibenzoate (126A-1)

To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (400 mg, 1.37 mmol, 1.0 eq), tert- butyl but-3-yn-2-ylcarbamate (244 mg, 1.44 mmol, 90.0 pL, l. l eq), Cui (5.23 mg, 27.5 pmol, 0.02 eq) and Pd(PPh3)2C12 (19.3 mg, 27.5 pmol, 0.02 eq) was added TEA (3.48 g, 34.4 mmol,

4.78 mL, 25 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)but-l-yn-l-yl)-2-me thylbenzoate (410 mg, 1.23 mmol, 90% yield) was obtained as a yellow solid. ^T H NMR (400 MHz, CDCh) 8 7.32 - 7.28 (m, 1H), 7.13 (s, 1H), 4.78 - 4.68 (m, 1H), 3.88 - 3.85 (m, 3H), 2.47 - 2.40 (m, 3H), 1.53 - 1.50 (m, 3H), 1.49 - 1.44 (m, 9H).

Step 2: Methyl 2-( 1 -((/c/7-biitoxycarbonyl)ainino)ethyl)-5-niethyl-l //-indole-6- carboxylate (126A-2)

To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)but-l-yn-l-yl)-2- methylbenzoate (410 mg, 1.23 mmol, 1.0 eq) in DCE (30 mL) was added Cu(OAc)2 (560 mg, 3.09 mmol, 2.5 eq). The mixture was stirred at 130 °C for 6 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with DCM (20 mL x 5). The combined organic layers were dried over TsfeSCL, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(l-((tert- butoxycarbonyl)amino)ethyl)-5-methyl-U/-indole-6-carboxylate (320 mg, 963 pmol, 64% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCh) 6 9.13 - 8.96 (m, 1H), 7.94 - 7.87 (m, 1H), 7.18 - 7.10 (m, 1H), 6.19 - 6.12 (m, 1H), 4.90 - 4.80 (m, 1H), 4.78 - 4.68 (m, 1H), 3.81 - 3.78 (m, 3H), 2.61 - 2.52 (m, 3H), 1.52 (d, J= 6.9 Hz, 3H), 1.40 - 1.35 (m, 9H).

Step 3: 2-( l-((tert-Butoxycarbonyl)amino)ethyl)-5-methyl-lH-indole-6-ca rboxylic acid (126A-3)

To a solution of methyl 2-(l-((ter/-butoxycarbonyl)amino)ethyl)-5-methyl-UT-indole-6 - carboxylate (120 mg, 361 pmol, 1.0 eq) in a mixture of THF (7.0 mL) and MeOH (1.8 mL) was added NaOH (2 M in aqueous, 1.8 mL, 10 eq). The mixture was stirred at 20 °C for 16 h. Then stirred at 70 °C for another 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with MTBE (10 mL x 2). The aqueous was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with DCM (15 mL x 5). The combined organic layers were dried over TsfeSCL, filtered, and concentrated under vacuum to give 2-(l-((terLbutoxycarbonyl)amino)ethyl)-5-methyl-U7-indole-6- carboxylic acid (90.0 mg, 283 pmol, 78% yield) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 319.2 (LCMS).

Step 4: tert-Butyl ( l-(5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-lH-indol- 2-yl)ethyl)carbamate (126A-4)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (44.0 mg, 240 pmol, 1.0 eq) in DCM (5.0 mL) were added 2-(l-((ter/-butoxycarbonyl)amino)ethyl)-5-methyl-17/-indole- 6- carboxylic acid (90.0 mg, 240 pmol, 1.0 eq), TEA (72.9 mg, 721 pmol, 100 pL, 3.0 eq), EDCI (69.1 mg, 360 pmol, 1.5 eq) and HOBt (48.7 mg, 360 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.5). Zc/V-Butyl (l-(5-methyl-6-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)-U/-indol-2-yl)ethyl)carbamate (100 mg, 207 pmol, 86% yield) was obtained as a yellow oil. M + H ⁺ = 484.2 (LCMS).

Step 5: 2-( l-Aininoethyl)-5-methyl-\-( 1 -(ii:iphth:ileii-l-yl)cyclopropyl)-l//-indole-6- carboxamide (Compound 273)

To a solution of Zc/V-butyl (l-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-U T- indol-2-yl)ethyl)carbamate (80.0 mg, 165.43 pmol, 1.0 eq) in EtOAc (4.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15%

- 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- (1 -Aminoethyl)-5-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)-17/-indole-6-carboxamide (25.0 mg, 59.5 pmol, 36% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 384.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 11.32 - 11.24 (m, 1H), 9.08 - 9.01 (m, 1H), 8.76

- 8.68 (m, 1H), 8.63 - 8.47 (m, 3H), 7.98 - 7.90 (m, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.44 (m, 3H), 7.30 - 7.23 (m, 1H), 7.14 - 7.07 (m, 1H), 6.44 - 6.35 (m, 1H), 4.60 - 4.49 (m, 1H), 2.19 - 2.13 (m, 3H), 1.61 - 1.54 (m, 3H), 1.40 - 1.35 (m, 2H), 1.22 - 1.13 (m, 2H). Example 127 : 5-Met hyl-2-( morpholin-3-yl )- \-( 1 -( napht halen- 1 -yl )cyclopropyl )- 1 //- indole-6-carboxamide (Compound 260)

Compound 260

Step 1: tc/7- Butyl 3-formylmorpholine-4-carboxylate (127A-2)

To a stirred solution of (COC1)2 (643 mg, 5.06 mmol, 0.40 mL, 1.1 eq) in DCM (18 mL) was added DMSO (863 mg, 11.1 mmol, 0.80 mL, 2.4 eq) at -78°C. After 15 min, a solution of tert- butyl 3-formylmorpholine-4-carboxylate (1.00 g, 4.60 mmol, 1.0 eq) in DCM (10 mL) was added to the mixture dropwise. The reaction mixture was stirred at -78 °C for another 2 h. TEA (2.33 g, 23.0 mmol, 3.20 mL, 5.0 eq) was added and the reaction mixture was stirred at -78°C for 30 min then was warmed to 20 °C and stirred for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3- formylmorpholine-4-carboxylate (1.00 g, 70% purity) as a colorless oil, which was used in the next step without any further purification.

Step 2: tert-Butyl 3-ethynylmorpholine-4-carboxylate (127A-3)

To a solution of tert-butyl 3-formylmorpholine-4-carboxylate (1.00 g, 4.65 mmol, 1.0 eq) and dimethyl (l-diazo-2-oxopropyl)phosphonate (1.34 g, 6.97 mmol, 1.5 eq) in MeOH (30 mL) was added K2CO3 (2.57 g, 18.6 mmol, 4.0 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tertbutyl 3-ethynylmorpholine-4-carboxylate (800 mg, 85% purity) as a colorless oil, which was used in the next step without any further purification.

Step 3: tert-Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)mor pholine-4-carboxylate (127A-4)

A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (317 mg, 1.09 mmol, 1.0 eq), tert-butyl 3-ethynylmorpholine-4-carboxylate (230 mg, 1.09 mmol, 1.0 eq), Pd(PPh3)2C12 (76.4 mg, 109 prnol, 0.1 eq) and Cui (10.4 mg, 54.4 pmol, 0.05 eq) in TEA (5.0 mL) was degassed and purged with N2 three times. The mixture was stirred at 70 °C for 3 h under a N2 atmosphere. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. tert-Butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)morph oline-4-carboxylate (400 mg, 1.07 mmol, 49% yield) was obtained as a brown oil. M - 56+ H ⁺ = 319.1 (LCMS).

Step 4: tert-Butyl 3-(5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-lH-indol- 2-yl)morpholine-4-carboxylate (127A-5)

To a solution of tert-butyl 3-((2-amino-4-(methoxycarbonyl)-5-methylphenyl)ethynyl)mor pholine-4-carboxylate (100 mg, 267 pmol, 1.0 eq) in DCE (10 mL) was added Cu(OAc)2 (97.0 mg, 534 pmol, 2.0 eq) under a N2 atmosphere. The mixture was stirred at 100 °C for 1 h in a microwave (400 W). TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 2/1, R/= 0.7). /c/V-Butyl 3-(5-methyl-6-((l-(naphthalen-l-yl) cyclopropyl)carbamoyl)-U/-indol-2-yl)morpholine-4-carboxylat e (80.0 mg, 214 pmol, 40% yield) was obtained as a white solid.

Step 5: 2-(4-(tert-Butoxyc:irboiiyl)niorpliolin-3-yl)-5-nietliyl-l //-indole-6-carboxylic acid (127A-6)

To a solution of tert-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-UT - indol-2-yl)morpholine-4-carboxylate (70.0 mg, 187 pmol, 1.0 eq) in a mixture of THF (4.0 mL) and MeOH (1.0 mL) was added NaOH (2 M aqueous, 500 pL, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and washed with MTBE (2.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(4-(tert-butoxycarbonyl)morpholin-3-yl)-5-methyl-UT- indole-6-carboxylic acid (70.0 mg, 80% purity) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 361.1 (LCMS)

Step 6: tert-Butyl 3-(5-m et hy l-6-(( 1 -( na ph t halen- 1 -y 1 )cy clopropy 1 )ca rbam oy 1 )- 1 //-indol- 2-yl)morpholine-4-carboxylate (127A-7)

To a solution of 2-(4-(tert-butoxycarbonyl)morpholin-3-yl)-5-methyl-l _J H-indole-6-carboxylic acid (70.0 mg, 194 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cyclopropanamine (28.5 mg, 155 pmol, 0.8 eq) in DCM (5.0 mL) were added TEA (39.3 mg, 388 pmol, 54.4 pL, 2.0 eq), EDCI (44.7 mg, 233 pmol, 1.2 eq) and HOBt (31.5 mg, 233 pmol, 1.2 eq). The mixture was stirred at 20 °C for 18 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.6). tert-Butyl 3-(5-methyl-6-((l-(naphthalen-l-yl) cyclopropyl)carbamoyl)-lJ/-indol-2-yl)morpholine-4-carboxyla te (70.0 mg, 133 pmol, 69% yield) was obtained as a white solid. M + H ⁺ = 526.2 (LCMS) Step 7: 5-Methyl-2-(morpholin-3-yl)-/V-( l-(naphthalen-l-yl)cyclopropyl)-LH-indole-6- carboxamide (Compound 260)

To a stirred solution of tert-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)- 17/-indol-2-yl)morpholine-4-carboxylate (50.0 mg, 95.1 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-2-(morpholin-3-yl)-7V-(l -(naphthal en-l-yl)cy cl opropyl)-17/-indole-6-carboxamide (16.9 mg, 35.7 pmol, 38% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 426.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 11.29 (br s, 1H), 9.84 (br s, 2H), 9.16 - 8.96 (m, 1H), 8.78 - 8.63 (m, 1H), 7.98 - 7.92 (m, 1H), 7.86 - 7.80 (m, 2H), 7.62 - 7.44 (m, 3H), 7.32 - 7.28 (m, 1H), 7.15 - 7.10 (m, 1H), 6.58 - 6.50 (m, 1H), 4.73 - 4.50 (m, 1H), 4.17 - 3.94 (m, 2H), 3.91 - 3.75 (m, 2H), 3.31 - 3.19 (m, 2H), 2.16 (s, 3H), 1.43 - 1.32 (m, 2H), 1.23 - 1.13 (m, 2H).

Example 128: 2-(2-Aminoethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )-LH- indole-6-carboxamide (Compound 202)

128A-2 128A-3

128A-4 Compound 202

Step 1: Methyl 5-amino-4-(4-((tert-butoxycarbonyl)amino)but-l-yn-l-yl)-2- methylbenzoate (128A-1)

To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (500 mg, 1.72 mmol, 1.0 eq), tertbutyl but-3-yn-l-ylcarbamate (349 mg, 2.06 mmol, 1.2 eq), Cui (65.4 mg, 344 pmol, 0.2 eq) and Pd(PPh3)2Ch (121 mg, 172 pmol, 0.1 eq) was added TEA (4.35 g, 42.9 mmol, 6.0 mL, 25 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)but-l-yn-l-yl)-2 -methyl benzoate (420 mg, 1.26 mmol, 74% yield) was obtained as a yellow oil. M + H ⁺ = 333.2 (LCMS).

Step 2: Methyl 2-(2-((tert-biitoxycarbonyl)ainino)ethyl)-5-niethyl-l //-indole-6- carboxylate (128A-2)

To a solution of methyl 5-amino-4-(3-((tert-butoxycarbonyl)amino)but-l-yn-l-yl)-2 -methyl benzoate (300 mg, 903 pmol, 1.0 eq) in DCE (15 mL) was added Cu(OAc)2 (410 mg, 2.26 mmol, 2.5 eq). The mixture was stirred at 90 °C for 6 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 2-(2-((tert-butoxycarbonyl)amino)ethyl)-5- methyl-lJT-indole-6-carboxylate (210 mg, 632 pmol, 70% yield) was obtained as a yellow oil. 'H NMR (400 MHz, CDCh) 8 8.84 - 8.58 (m, 1H), 8.02 - 7.96 (m, 1H), 7.35 (s, 1H), 6.27 - 6.15 (m, 1H), 3.91 - 3.88 (m, 3H), 3.55 - 3.43 (m, 2H), 3.05 - 2.92 (m, 2H), 2.69 - 2.63 (m, 3H), 1.46 - 1.42 (m, 9H). Step 3: 2-(2-((tert-Butoxycarbonyl)amino)ethyl)-5-methyl-LH-indole-6 -carboxylic acid (128A-3)

To a solution of methyl 2-(2-((ter/-butoxycarbonyl)amino)ethyl)-5-methyl-lJT-indole- 6- carboxylate (200 mg, 602 pmol, 1.0 eq) in a mixture of THF (6.0 mL) and MeOH (2.0 mL) was added NaOH (2 M in aqueous, 4.2 mL, 14 eq). The mixture was stirred at 20 °C for 2 h, then at 70 °C for another 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with MTBE (10 mL x 2). The aqueous was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give crude product 2-(2-((terLbutoxycarbonyl)amino)ethyl)-5-methyl-U/-indole-6- carboxylic acid (210 mg, 90% purity) as a yellow solid, which was used in the next step without any further purification. M - H“ = 317.2 (LCMS).

Step 4: tert-Butyl (2-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-l H-indol- 2-yl)ethyl)carbamate (128A-4)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (104 mg, 569 pmol, 1.0 eq) and 2-(2- ((/c/7-butoxycarbonyl)amino)ethyl)-5-methyl- l7/-indole-6-carboxylic acid (201 mg, 569 pmol, 90% purity, 1.0 eq) in DCM (5.0 mL) were added TEA (173 mg, 1.71 mmol, 237 pL, 3.0 eq), EDCI (164 mg, 853 pmol, 1.5 eq) and HOBt (115 mg, 853 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert- Butyl (2-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-U /-indol-2- yl)ethyl)carbamate (170 mg, 352 pmol, 62% yield) was obtained as a yellow oil. M + H ⁺ = 484.3 (LCMS).

Step 5: 2-(2-Aininoethyl)-5-methyl-\-( 1 -(ii:iphth:ilen-l-yl)cyclopropyl)-l//-indole-6- carboxamide (Compound 202)

To a solution of Zc/V-butyl (2-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-U T- indol-2-yl)ethyl)carbamate (170 mg, 352 pmol, 1.0 eq) in DCM (10 mL) was added TFA (10.0 g, 87.8 mmol, 6.50 mL, 250 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 30 mm, 5 pm); flow rate: 60 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(2- Aminoethyl)-5-methyl-A-(l-(naphthalen-l-yl) cyclopro pyl)-l//-indole-6-carboxamide (120 mg, 313 pmol, 89% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 384.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.66 - 8.61 (m, 1H), 7.94 - 7.88 (m, 2H), 7.83 - 7.78 (m, 1H), 7.61 - 7.55 (m, 1H), 7.53 - 7.41 (m, 2H), 7.22 - 7.19 (m, 1H), 7.07 - 7.05 (m, 1H), 6.22 - 6.19 (m, 1H), 3.28 - 3.23 (m, 2H), 3.11 - 3.05 (m, 2H), 2.18 - 2.14 (m, 3H), 1.48 - 1.43 (m, 2H), 1.34 - 1.28 (m, 2H). Example 129: 5-Methyl-2-(2-(methylamino)ethyl)-/V-(l-(naphthalen-l-yl)cyc lopropyl)- l//-indole-6-c:irboxamide (Compound 222)

129A-6 Compound 222 Step 1: te/7- Butyl but-3-yn-l-yl(methyl)carbamate (129A-2)

To a mixture of tert-butyl but-3-yn-l-ylcarbamate (500 mg, 2.95 mmol, 1.0 eq) in THF (15 mL) was addede sodium hydride (177 mg, 4.43 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min under a N2 atmosphere, and Mel (629 mg, 4.43 mmol, 276 pL, 1.5 eq) was added. The resulting mixture was stirred at 25 °C for 4 h. TLC indicated that the starting material was completely consumed. The reaction mixture was quenched with saturated aqueous NH4CI (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl but-3-yn- l-yl(methyl) carbamate (520 mg, 2.84 mmol, 96% yield) as a yellow oil, which was used in the next step without any further purification. ^T H NMR (400 MHz, CDCL) 6 3.45 - 3.36 (m, 2H), 3.35 - 3.25 (m, 1H), 2.94 - 2.91 (m, 3H), 2.45 - 2.38 (m, 2H), 1.47 (s, 9H).

Step 2: Methyl 5-amino-4-(4-((tert-butoxycarbonyl)(methyl)amino)but-l-yn-l- yl)-2- methylbenzoate (129A-3)

To a mixture of methyl 5-amino-4-iodo-2-methylbenzoate (700 mg, 2.40 mmol, 1.0 eq), tertbutyl but-3-yn-l-yl(methyl)carbamate (507 mg, 2.77 mmol, 1.2 eq), Pd(PPh3)2Ch (169 mg, 240 pmol, 0.1 eq) and Cui (91.6 mg, 481 pmol, 0.2 eq) was added TEA (6.08 g, 60.1 mmol, 8.40 mL, 25 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (20 mL) and extracted with DCM (15 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. Methyl 5-amino-4-(4-((tert- butoxycarbonyl)(methyl)amino)but-l-yn-l-yl)-2-methylbenzoate (570 mg, 1.65 mmol, 68% yield) was obtained as a yellow oil. M + H ⁺ = 347.2 (LCMS); 'H NMR (400 MHz, CDCL) 8 7.27 - 7.24 (m, 1H), 7.12 - 7.09 (m, 1H), 3.89 - 3.84 (m, 3H), 3.56 - 3.44 (m, 2H), 3.01 - 2.91 (m, 3H), 2.75 - 2.66 (m, 2H), 2.46 - 2.39 (m, 3H), 1.50 - 1.44 (m, 9H).

Step 3: Methyl 2-(2-((te/7-biitoxycarbonyl)(niethyl)ainino)ethyl)-5-niethyl -l//-indole-6- carboxylate (129A-4)

To a solution of methyl 5-amino-4-(4-((ter/-butoxycarbonyl)(methyl)amino)but-l-yn-l- yl)-2- methylbenzoate (570 mg, 1.65 mmol, 1.0 eq) in DCE (20 mL) was added Cu(OAc)2 (747 mg, 4.11 mmol, 2.5 eq). The mixture was stirred at 90 °C for 6 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 2-(2-((/c77-butoxycarbonyl) (methyl)amino) ethyl)-5-methyl-l//-indole-6-carboxylate (440 mg, 1.27 mmol, 77% yield) was obtained as a yellow solid. flTNMR (400 MHz, CDCh) 8 8.05 - 7.95 (m, 1H), 7.36 - 7.32 (m, 1H), 7.13 - 7.07 (m, 1H), 6.23 - 6.18 (m, 1H), 3.88 - 3.85 (m, 3H), 3.14 - 3.01 (m, 2H), 2.89 - 2.79 (m, 3H), 2.73 - 2.69 (m, 2H), 2.44 - 2.41 (m, 3H), 1.47 (s, 9H).

Step 4: 2-(2-((/c/7-Biitoxycarbonyl)(niethyl)ainino)ethyl)-5-niethyl - 1 //-indole-6- carboxylic acid (129A-5)

To a solution of methyl 2-(2-((/c77-butoxycarbonyl) (methyl)amino)ethyl)-5-methyl- l//- indole-6-carboxylate (440 mg, 1.27 mmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 8.9 mL, 14 eq). The resulting mixture was stirred 20 °C for 2 h, then at 70 °C for another 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with MTBE (5.0 mL x 3). The aqueous was acidified to pH 5 with HC1 (1 M aqueous) and extracted with DCM (10 mL x 8), the combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give 2-(2-((/c77-butoxycarbonyl)(methyl)amino)ethyl)-5-methyl- l//-indole-6- carboxylic acid (410 mg, 1.23 mmol, 97% yield) as a red solid, which was used in the next step without any further purification. M - H“ = 331.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.21 - 8.16 (m, 1H), 7.43 - 7.39 (m, 1H), 6.24 - 6.21 (m, 1H), 3.56 - 3.47 (m, 2H), 3.12 - 3.00 (m, 2H), 2.73 - 2.70 (m, 3H), 2.49 - 2.46 (m, 3H), 1.46 - 1.42 (m, 9H).

Step 5: tc/7- Butyl methyl(2-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbam oyl)- l//-iiidol-2-yl)ethyl)carbaniate (129A-6)

To a solution of 2-(2-((terLbutoxycarbonyl)(methyl)amino)ethyl)-5-methyl-l//- indole-6- carboxylic acid (100 mg, 301 pmol, 1.0 eq) in DCM (8.0 mL) were added 1 -(naphthal en-1- yl)cyclopropanamine (55.1 mg, 301 pmol, 1.0 eq), TEA (91.3 mg, 903 pmol, 126 pL, 3.0 eq), EDCI (86.5 mg, 451 pmol, 1.5 eq) and HOBt (61.0 mg, 451 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.4). /c/V-Butyl methyl(2-(5-methyl-6-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)-lZ/-indol-2-yl)ethyl)carbamate (90.0 mg, 181 pmol, 60% yield) was obtained as a yellow oil. M + H ⁺ = 498.2 (LCMS).

Step 6: 5-Methyl-2-(2-(methylamino)ethyl)-/V-(l-(naphthalen-l-yl)cyc lopropyl)-lH- indole-6-carboxamide (Compound 222)

To a solution of tert-butyl methyl(2-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)- l//-indol-2-yl)ethyl)carbamate (90.0 mg, 181 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (3.08 g, 27.0 mmol, 2.00 mL, 149 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-Methyl-2-(2-(methylamino)ethyl)-A-(l-(naphthalen-l- yl)cyclopropyl)-l/7-indole-6-carboxamide (18.6 mg, 46.8 pmol, 26% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 398.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.22 - 9.10 (m, 1H), 8.60 - 8.54 (m, 1H), 7.92 - 7.86 (m, 2H), 7.84 - 7.77 (m, 1H), 7.60 - 7.53 (m, 1H), 7.52 - 7.40 (m, 2H), 7.01 - 6.97 (m, 1H), 6.52 - 6.47 (m, 1H), 3.27 - 3.19 (m, 2H), 2.96 - 2.86 (m, 2H), 2.77 - 2.72 (m, 3H), 1.92 - 1.87 (m, 3H), 1.46 - 1.38 (m, 2H), 1.33 - 1.25 (m, 2H).

Example 130: 5-Methyl-2-(morpholinomethyl)-N-(l-(naphthalen-l-yl)cyclopro pyl)-LH- indole-6-carboxamide (Compound 213) ompoun

Step 1: 5-Metliyl-2-(inorpholinoinethyl)- \-( l-(n:iphth:ilen- l-yl)cyclopropyl)-l //-indole- 6-carboxamide (Compound 213)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (90.2 mg, 492 pmol, 1.0 eq) and 5- methyl-2-(morpholinomethyl)-lZ7-indole-6-carboxylic acid (135 mg, 492 pmol, 1.0 eq) in DCM (10 mL) were added TEA (149 mg, 1.48 mmol, 206 pL, 3.0 eq), EDCI (142 mg, 738 pmol, 1.5 eq) and HOBt (99.8 mg, 738 pmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 55% - 75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-2-(morpholinomethyl)-A- (l-(naphthalen-l-yl)cyclopropyl)-U/-indole-6-carboxamide (24.6 mg, 55.7 pmol, 11% yield, FA salt) was obtained as a white solid. M + H ⁺ = 440.2 (LCMS); 'H NMR (400 MHz, CDCh)

8 9.09 - 8.90 (m, 1H), 8.48 (d, J= 8.3 Hz, 1H), 7.97 (d, J = 7.0 Hz, 1H), 7.91 (d, J= 7.7 Hz, 1H), 7.81 (d, J= 8.4 Hz, 1H), 7.62 - 7.45 (m, 3H), 7.26 (s, 1H), 7.18 (s, 1H), 6.54 (s, 1H), 6.27 (s, 1H), 3.86 - 3.67 (m, 6H), 2.56 (br s, 4H), 2.29 (s, 3H), 1.61 - 1.55 (m, 2H), 1.45 - 1.36 (m, 2H). Example 131: 2-((Benzylamino)methyl)-5-methyl-/V-(l-(naphthalen-l-yl)cycl opropyl)- l//-indole-6-carboxamide (Compound 229)

131A-4 131A-5

Compound 229

Step 1: tert- Butyl benzyl(prop-2-yn-l-yl)carbamate (131 A-2)

A solution of tert-butyl prop-2-yn-l-ylcarbamate (500 mg, 3.22 mmol, 1.0 eq) in THF (10 mL) was degassed and purged with N2 three times. To the mixture was added sodium hydride (193 mg, 4.83 mmol, 60% purity, 1.5 eq) in portions at 0 °C. The mixture was stirred at the same temperature for 30 min. Then (bromomethyl)benzene (827 mg, 4.83 mmol, 574 pL, 1.5 eq) was added and the resulting mixture was stirred at 25 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into ice water (15 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl benzyl(prop-2-yn-l- yl)carbamate (260 mg, 1.06 mmol, 33% yield) was obtained as a white solid. M - 56 + H ⁺ = 190.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.37 - 7.31 (m, 2H), 7.28 (br dd, J = 4.0, 6.3 Hz, 3H), 4.57 (s, 2H), 4.20 - 3.80 (m, 2H), 2.22 (br s, 1H), 1.58 - 1.43 (m, 9H).

Step 2: Methyl 5-amino-4-(3-(benzyl(tert-butoxycarbonyl)amino)prop-l-yn-l-y l)-2- methylbenzoate (131A-3)

To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (150 mg, 515 pmol, 1.0 eq) and tert-butyl benzyl(prop-2-yn-l-yl)carbamate (164 mg, 670 pmol, 1.3 eq) in THF (2.0 mL) were added Pd(PPh3)4 (11.9 mg, 10.3 pmol, 0.02 eq), copper(I) iodide (1.96 mg, 10.3 pmol, 0.02 eq) and TEA (130 mg, 1.29 mmol, 179 pL, 2.5 eq) at 20 °C. The resulting mixture was stirred at 25 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 5-amino-4-(3-(benzyl(/er/-butoxycarbonyl)amino)prop-l-yn-l-y l)-2- methylbenzoate (150 mg, 367 pmol, 71% yield) was obtained as a colorless oil. M + H ⁺ = 409.3 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.63 - 7.39 (m, 7H), 4.80 (s, 2H), 4.57 - 4.36 (m, 2H), 4.06 (s, 3H), 2.62 (s, 3H), 1.69 (br s, 9H).

Step 3: Methyl 2-((benzyl(/c/7-biitoxycarbonyl)ainino)niethyl)-5-niethyl-l/ /-indole-6- carboxylate (131A-4)

A solution of methyl 5-amino-4-(3-(benzyl(/er/-butoxycarbonyl)amino)prop-l-yn-l-y l)-2- methylbenzoate (150 mg, 367 pmol, 1.0 eq) in THF (30 mL) was degassed and purged with N2 three times. To the mixture was added Cu(OAc)2 (167 mg, 918 pmol, 2.5 eq) at 20 °C. The resulting mixture was stirred at 130 °C for 5 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.6). Methyl 2-((benzyl(/er/-butoxycarbonyl)amino) methyl)-5-methyl- 17/-indole-6-carboxylate (90.0 mg, 220 pmol, 60% yield) was obtained as a colorless oil. 'H NMR (400 MHz, CDCh) 5 9.18 - 9.02 (m, 1H), 8.02 (br s, 1H), 7.38 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 7.31 (br d, J = 6.7 Hz, 1H), 7.22 (br d, J= 5.5 Hz, 2H), 6.24 (s, 1H), 4.40 (s, 4H), 3.91 (s, 3H), 2.68 (s, 3H), 1.51 (br s, 9H).

Step 4: 2-((Benzyl(tert-butoxycarbonyl)amino)methyl)-5-methyl-l //-indole-6-carboxylic acid (131A-5)

To a solution of methyl 2-((benzyl(/c/7-butoxycarbonyl)amino)methyl)-5-methyl- l7/-indole- 6-carboxylate (80.0 mg, 196 pmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 3.0 mL, 31 eq). The mixture was stirred at 70 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with MTBE (5.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2- ((benzyl(tert-butoxycarbonyl) amino)methyl)-5-methyl-U/-indole-6-carboxylic acid (90.0 mg), which was used in the next step without any further purification. M + H ⁺ = 395.2 (LCMS).

Step 5: tert-Butyl benzyl((5-melhyl-6-(( 1 -(naphlhalen- 1 -yl )cyclopropyl )carbamoyl)- 1 //- indol-2-yl)methyl)carbamate (131A-6)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (40.0 mg, 218 pmol, 1.0 eq) and 2- ((benzyl(/c77-butoxycarbonyl)amino)methyl)-5-methyl- l7/-indole-6-carboxylic acid (86.1 mg, 218 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (66.3 mg, 655 pmol, 91.2 pL, 3.0 eq), EDCI (83.7 mg, 437 pmol, 2.0 eq) and HOBt (59.0 mg, 437 pmol, 2.0 eq). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/5, R/= 0.4). /c/V-Butyl benzyl((5-methyl-6-((l-(naphthalen- l-yl)cyclopropyl)carbamoyl)-U/-indol-2-yl)methyl)carbamate (70.0 mg, 125 pmol, 57% yield) was obtained as a colorless oil. M + H ⁺ = 560.4 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.90 (br s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 7.98 (d, J= 7.0 Hz, 1H), 7.91 (d, J= 8.3 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.55 - 7.46 (m, 2H), 7.36 - 7.28 (m, 3H), 7.25 (s, 1H), 7.22 - 7.13 (m, 2H), 6.54 (s, 1H), 6.16 (s, 1H), 4.40 - 4.32 (m, 4H), 2.29 (s, 3H), 1.48 (br s, 9H), 1.43 - 1.38 (m, 2H), 1.27 (t, J= 7.2 Hz, 2H).

Step 6: 2-( ( Benzy la in ino )ni el by 1 )-5-ni el by l-\-( 1 -( na phi halen- 1 -y 1 )cy clopropy 1 )- 1 //- indole-6-carboxamide (Compound 229)

To a stirred solution of tert-butyl benzyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)- U/-indol-2-yl)methyl)carbamate (50.0 mg, 89.3 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-((Benzylamino)methyl)-5-methyl-A-(l-(naphthalen-l-yl)cyclo propyl)-UT- indole-6-carbox amide (4.80 mg, 9.14 pmol, 10% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 460.1 (LCMS); 'H NMR (400 MHz, CDCL) 6 9.99 - 9.68 (m, 3H), 8.58 (br d, J= 7.5 Hz, 1H), 7.91 (br dd, J= 7.2, 14.7 Hz, 2H), 7.81 (br d, J= 8.6 Hz, 1H), 7.55 - 7.38 (m, 5H), 7.34 (br s, 3H), 6.89 (br s, 1H), 6.70 - 6.53 (m, 1H), 6.05 (br d, J= 1.8 Hz, 1H), 3.97 - 3.75 (m, 4H), 2.07 (s, 3H), 1.56 (br d, J= 3.4 Hz, 2H), 1.39 (br s, 2H).

Example 132: 5-Methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-LH-in dole-2- carboxylic acid (Compound 204)

Step 1

Compound 216 Compound 204

Step 1 : 5-M et hyl-6-(( 1 -( napht halen- 1 -yl)cyclopropyl)c:irbamoyl )- 1 //-indole-2-carboxylic acid (Compound 204)

To a solution of 5-amino-4-iodo-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 226 pmol, 1.0 eq) and 2-oxopropanoic acid (99.6 mg, 1.13 mmol, 79.6 pL, 5.0 eq) in DMF (8.0 mL) was added l,4-diazabicyclo[2.2.2]octane (76.1 mg, 678 pmol, 74.6 pL, 3.0 eq). The mixture was stirred at 20 °C for 30 min. Then the mixture was added Pd(OAc)2 (2.54 mg, 11.3 pmol, 0.05 eq) and stirred at 105 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 2) then dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-U/-in dole-2-carboxylic acid (9.73 mg, 25.3 pmol, 11% yield, FA salt) was obtained as a yellow solid. M + H ⁺ = 385.1 (LCMS); ¹ H NMR (400 MHz, DMSO ) 6 11.72 - 11.61 (m, 1H), 9.16 - 9.09 (m, 1H), 8.71 - 8.65 (m, 1H), 7.98 - 7.91 (m, 1H), 7.87 - 7.81 (m, 2H), 7.62 - 7.51 (m, 3H), 7.50 - 7.44 (m, 1H), 7.37 - 7.34 (m, 1H), 7.13 - 7.10 (m, 1H), 2.13 - 2.09 (m, 3H), 1.40 - 1.34 (m, 2H), 1.21 - 1.16 (m, 2H). Example 133: 5-Methyl-\ ’-(l-(naphthalen-l-yl)cyclopropyl)-l II-indole-2.6- dicarboxamide (Compound 205)

Compound 205

Step 1: 6-(Methoxycarbonyl)-5-niethyl-l//-indole-2-carboxylic acid (133 A-l)

To a solution of methyl 5-amino-4-iodo-2-methylbenzoate (500 mg, 1.72 mmol, 1.0 eq) and 2- oxopropanoic acid (756 mg, 8.59 mmol, 605 pL, 5.0 eq) in DMF (15 mL) was added 1,4- diazabicyclo[2.2.2]octane (578 mg, 5.15 mmol, 567 pL, 3.0 eq). The reaction mixture was stirred at 20 °C for 30 min, then Pd(OAc)2 (19.3 mg, 85.9 pmol, 0.05 eq) was added. The mixture was stirred at 105 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 x 3 mL), were dried over ISfeSCU, filtered, and concentrated under vacuum to give crude product 6-(methoxycarbonyl)-5-methyl-17/-indole-2-carboxylic acid (420 mg, 92% purity) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 233.9 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 12.04 - 11.92 (m, 1H), 8.03 - 7.99 (m, 1H), 7.97 - 7.93 (m, 1H), 7.57 - 7.51 (m, 1H), 7.06 - 6.99 (m, 1H), 3.85 - 3.82 (m, 3H), 2.57 - 2.54 (m, 3H). Step 2: Methyl 2-carbamoyl-5-methyl-l //-indole-6-carboxylate (133A-2)

To a solution of 6-(methoxycarbonyl)-5-methyl-U/-indole-2-carboxylic acid (200 mg, 858 pmol, 1.0 eq) and HOBt (151 mg, 1.11 mmol, 1.3 eq) in DMF (10 mL) was added EDCI (214 mg, 1.11 mmol, 1.3 eq). The reaction mixture was stirred at 20 °C for 0.6 h, then NH3.H2O (5.46 g, 39.0 mmol, 6.0 mL, 25% purity in water, 46 eq) was added. The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were washed with brine (20 x 2 mL) then the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product methyl 2-carbamoyl-5-methyl-U/-indole-6-carboxylate (270 mg, 70% purity) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 233.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.80 - 11.75 (m, 1H), 8.08 - 8.04 (m, 1H), 8.01 - 7.98 (m, 1H), 7.96 - 7.94 (m, 1H), 7.52 - 7.49 (m, 1H), 6.89 - 6.84 (m, 1H), 3.84 - 3.80 (m, 3H), 2.57 - 2.55 (m, 3H).

Step 3: 2-Carbamoyl-5-methyl-l//-indole-6-carboxylic acid (133A-3)

To a solution of methyl 2-carbamoyl-5-methyl-lJ/-indole-6-carboxylate (200 mg, 603 pmol, 70% purity, 1.0 eq) in MeOH (10 mL) was added NaOH (1 M, 3.1 mL, 5.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and washed with MTBE (10 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product 2- carbamoyl-5-methyl-U/-indole-6-carboxylic acid (150 mg, 80% purity) as a yellow solid, which was used in the next step without any further purification. M - H“ = 217.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 11.76 - 11.67 (m, 1H), 8.08 - 7.97 (m, 2H), 7.50 - 7.42 (m, 2H), 7.10 - 7.05 (m, 1H), 6.91 - 6.84 (m, 1H), 2.57 - 2.55 (m, 3H).

Step 4: 5-Methyl-\ ⁶ -( l-(n:iphth:ileii-l-yl)cyclopropyl)-l//-indole-2.6-dicarboxai nide (Co mpound 205)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (67.2 mg, 367 pmol, 1.0 eq) and 2- carbamoyl-5-methyl-U/-indole-6-carboxylic acid (100 mg, 367 pmol, 1.0 eq) were added TEA (111 mg, 1.10 mmol, 153 pL, 3.0 eq), EDCI (105 mg, 550 pmol, 1.5 eq) and HOBt (74.3 mg, 550 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over ISfeSCL, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (70 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-A ⁶ -(l-(naphthalen-l-yl)cyclopropyl)-l//-indole-2,6- dicarboxamide (29.0 mg, 75.6 pmol, 21% yield, FA salt) was obtained as a white solid. M + H ⁺ = 384.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 8 11.50 - 11.43 (m, 1H), 9.12 - 9.05 (m, 1H), 8.71 - 8.64 (m, 1H), 7.98 - 7.88 (m, 2H), 7.87 - 7.79 (m, 2H), 7.62 - 7.43 (m, 3H), 7.35 - 7.27 (m, 2H), 7.14 - 7.08 (m, 1H), 7.01 - 6.95 (m, 1H), 2.12 - 2.08 (m, 3H), 1.36 (br s, 2H), 1.20 - 1.12 (m, 2H).

Example 134: \ ² -Methoxy-\ ² .5-dimethyl-\ ⁶ -(l-(naphthalen-l-yl)cyclopropyl)-l//- indole-2,6-dicarboxamide (Compound 225)

Step 1: V ² -Methoxy-\ ² .5-dimethyl-\ ⁶ -( l-(naphthalen- l-yl)cyclopropyl)-l //-indole-2.6-di carboxamide (Compound 225)

To a solution of 5-methyl-6-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)-l//-indole-2- carboxylic acid (70.0 mg, 182 pmol, 1.0 eq) and A,O-dimethylhydroxylamine (26.6 mg, 273 pmol, 1.5 eq, HC1 salt) in DCM (3.0 mL) were added TEA (55.3 mg, 546 pmol, 76.0 pL, 3.0 eq) and T3P (232 mg, 364 pmol, 217 pL, 50% purity in EtOAc, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N ² - Methoxy-A ² ,5-dimethyl-A ⁶ -(l-(naphthalen-l-yl)cyclopropyl)-l//-indole-2,6-dicar boxamide (18.6 mg, 41.7 pmol, 23% yield) was obtained as a white solid. M + H ⁺ = 428.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.5 (s, 1H), 9.1 (s, 1H), 8.7 (d, J = 8.19 Hz, 1H), 8.0 (d, J = 7.95 Hz, 1H), 7.8 - 7.9 (m, 2H), 7.5 - 7.6 (m, 2H), 7.5 (t, J= 7.64 Hz, 1H), 7.4 (s, 1H), 7.2 (s, 1H), 7.0 (d, J = 1.34 Hz, 1H), 3.8 (s, 3H), 3.3 (s, 3H), 2.1 (s, 3H), 1.4 (s, 2H), 1.2 - 1.2 (m, 2H).

Example 135: 5-Methyl-\-(l-(n:iphthalen-l-yl)cyclopropyl)-2-phenyl-l //-indole-6- carboxamide (Compound 226)

Compound 226

Step 1: Methyl 5-amino-2-methyl-4-(phenylethynyl)benzoate (135A-1)

A solution of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq), ethynylbenzene (158 mg, 1.55 mmol, 170 pL, 1.5 eq) and TEA (209 mg, 2.06 mmol, 287 pL, 2.0 eq) in a mixture of H2O (7.5 mL) and toluene (15 mL) was degassed and purged with N2 three times. To the mixture were added Pd(PPh3)2C12 (21.7 mg, 30.9 pmol, 0.03 eq) and Cui (1.96 mg, 10.3 pmol, 0.01 eq). The resulting mixture was stirred at 70 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/2. Methyl 5-amino-2-methyl-4-(phenylethynyl)benzoate (250 mg, 942 pmol, 91% yield) was obtained as a brown solid. M + H ⁺ = 266.1 (LCMS); ¹ H NMR (400 MHz, CDCh) 8 7.57 - 7.51 (m, 2H), 7.41 - 7.35 (m, 3H), 7.33 (s, 1H), 7.25 (s, 1H), 3.89 (s, 3H), 2.47 (s, 3H).

Step 2: Methyl 5-methyl-2-phenyl-l//-indole-6-carboxylate (135A-2)

A mixture of methyl 5-amino-2-methyl-4-(phenylethynyl)benzoate (216 mg, 814 pmol, 1.0 eq) in DCE (20 mL) was degassed and purged with N2 three times. To the mixture was added CU(OAC)2 (370 mg, 2.04 mmol, 2.5 eq) dropwise at 20 °C. The resulting mixture was stirred at 90 °C for 5 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.7). Methyl 5-methyl-2-phenyl- IT/- indole-6-carboxylate (150 mg, 565 pmol, 69% yield) was obtained as a brown solid. 'H NMR (400 MHz, CDCh) 6 8.50 (br s, 1H), 8.10 (s, 1H), 7.51 - 7.44 (m, 3H), 7.40 - 7.34 (m, 2H), 7.27 - 7.24 (m, 1H), 6.77 (d, J= 1.1 Hz, 1H), 3.93 (s, 3H), 2.70 (s, 3H).

Step 3: 5-Methyl-2-phenyl-l//-indole-6-carboxylic acid (135A-3)

To a solution of methyl methyl 5-methyl-2-phenyl-lH-indole-6-carboxylate (70 mg, 264 pmol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (5.0 mL) was added NaOH (2 M aqueous, 1.5 mL, 10 eq). The mixture was stirred at 70 °C for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, diluted with H2O (5.0 mL) and washed with MTBE (3.0 mL x 3). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-methyl-2-phenyl-U/-indole-6-carboxylic acid (70 mg) as a white solid, which was used in the next step without any further purification.

Step 4: 5-Methyl- \-( l-(n:iphthalen-l-yl)cyclopropyl)-2-phenyl-l//-indole-6-carbo xamide (Compound 226)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (58.3 mg, 318 pmol, 1.0 eq) and 5- methyl-2-phenyl-lH-indole-6-carboxylic acid (80.0 mg, 318 pmol, 1.0 eq) in DCM (5 mL) were added TEA (96.7 mg, 955 pmol, 133 pL, 3.0 eq), EDCI (122 mg, 637 pmol, 2.0 eq) and HOBt (86.0 mg, 637 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 45% - 75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)-2-phenyl-17/-indole-6-carboxamide (21.1 mg, 50.7 pmol, 16% yield) was obtained as a yellow solid. M + H ⁺ = 417.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 11.47 (s, 1H), 9.09 (s, 1H), 8.73 (d, J= 8.5 Hz, 1H), 7.96 (d, J= 7.5 Hz, 1H), 7.89 - 7.79 (m, 4H), 7.65 - 7.53 (m, 2H), 7.52 - 7.41 (m, 3H), 7.35 - 7.24 (m, 2H), 7.11 (s, 1H), 6.80 (d, J= 1.4 Hz, 1H), 2.18 (s, 3H), 1.43 - 1.35 (m, 2H), 1.23 - 1.16 (m, 2H).

Example 136: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-(pyridin-2-yl )-LH-indole- 6-carboxamide (Compound 234)

Step 4

Compound 234

Step 1: Methyl 5-amino-2-methyl-4-(pyridin-2-ylethynyl)benzoate (136 A-l)

A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (1.00 g, 3.44 mmol, 1.0 eq), TEA (695 mg, 6.87 mmol, 956 pL, 2.0 eq), Pd(PPh3)2C12 (72.3 mg, 103 pmol, 0.03 eq), Cui (6.54 mg, 34.3 pmol, 0.01 eq) and 2-ethynylpyridine (531 mg, 5.15 mmol, 521 pL, 1.5 eq) in a mixture of toluene (50 mL) and H2O (25 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 70 °C for 3 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-amino-2-methyl-4-(pyridin-2-ylethynyl) benzoate (800 mg, 3.00 mmol, 87% yield) was obtained as a yellow solid.

Step 2: Methyl 5-methyl-2-(pyridin-2-yl)-l//-indole-6-carboxylate (136A-2)

To the solution of methyl 5-amino-2-methyl-4-(pyridin-2-ylethynyl)benzoate (150 mg, 564 pmol, 1.0 eq) inDMF (7.5 mL) was added Z-BuOK (1 M in THF, 1.18 mL, 2.1 eq). The reaction mixture was stirred at 90 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), and then dried over Na2SO4, concentrated under vacuum to give methyl 5- methyl-2-(pyridin-2-yl)-U/-indole-6-carboxylate (45.0 mg, 169 pmol, 10% yield) as a yellow gum. M + H ⁺ = 267.2 (LCMS).

Step 3: 5- ethyl-2-(pyridin-2-yl)-l//-indole-6-carboxylic acid (136A-3)

To a solution of methyl 5-methyl-2-(pyridin-2-yl)-U/-indole-6-carboxylate (45.0 mg, 169 pmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (3.0 mL) was added NaOH (2 M in aqueous, 845 pL, 10 eq). The mixture was stirred at 25 °C for 1 h and then at 70 °C for another 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and the pH was adjusted to 6 using HC1 (I M aqueous), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H2O (5.0 mL), dried under vacuum to give the crude product 5- methyl-2-(pyri din-2 -yl)-U/-indole-6-carboxylic acid (40.0 mg) as a yellow solid.

Step 4: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-(pyridin-2-yl )-lH-indole-6- carboxamide (Compound 234)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (29.1 mg, 159 pmol, 1.0 eq) and 5- methyl-2-(pyridin-2-yl)-U/-indole-6-carboxylic acid (40.0 mg, 157 pmol, 1.0 eq) in DMF (4.0 mL) were added TEA (48.1 mg, 477 pmol, 66.2 pL, 3.0 eq), EDCI (60.8 mg, 317 pmol, 2.0 eq) and HOBt (42.9 mg, 317 pmol, 2.0 eq). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-2-(pyridin-2-yl) -U/-indole-6-carboxamide (9.20 mg, 21.5 pmol, 14% yield) was obtained as a yellow solid. M + H ⁺ = 418.1 (LCMS); ^T H NMR (400 MHz, DMSO-t/e) 8 11.63 (d, = 0.9 Hz, 1H), 9.08 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.59 (d, J= 4.1 Hz, 1H), 7.95 (dd, J= 3.8, 7.7 Hz, 2H), 7.88 - 7.81 (m, 3H), 7.63 - 7.51 (m, 2H), 7.51 - 7.45 (m, 1H), 7.29 (s, 2H), 7.17 (s, 1H), 7.03 (d, J= 1.4 Hz, 1H), 2.13 (s, 3H), 1.42 - 1.34 (m, 2H), 1.21 - 1.15 (m, 2H).

Example 137: 1.5-l)imethyl-\-(l-(n:iphth:ilen-l-yl)cyclopropyl)-l//-indol e-6- carboxamide (Compound 201)

Compound 199 Compound 201

Step 1: 1 ,5-Dimethyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-lH-indole-6-carboxamide

(Compound 201)

To a solution of 5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-U/-indole-6-carb oxamide (100 mg, 294 pmol, 1.0 eq) in THF (4.0 mL) was added sodium hydride (23.5 mg, 294 pmol, 60% purity, 2.0 eq) at 0°C for 30 min, followed by Mel (41.7 mg, 294 pmol, 9.14 pL, 1.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 50% - 80% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 1 , 5-Dimethyl-A-(l -(naphthalen- 1 -yl)cyclopropyl)- U/-indole-6-carboxamide (60.0 mg, 166 pmol, 63% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 355.0 (LCMS); ^NMR W MHz, CDCh) 5 8.65 - 8.57 (m, 1H), 8.16 - 8.08 (m, 1H), 8.03 (d, J= 8.1 Hz, 1H), 7.93 (br d, J= 8.4 Hz, 1H), 7.73 - 7.56 (m, 3H), 7.41 (d, J= 18.6 Hz, 2H), 7.14 (d, J= 2.0 Hz, 1H), 6.70 (br s, 1H), 6.46 (br s, 1H), 3.79 (s, 3H), 2.40 (s, 3H), 1.72 (br s, 2H), 1.54 (s, 2H).

Example 138: l-Cyclobutyl-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-LH -indole-6- carboxamide (Compound 296)

Compound 199 Compound 296

Step 1 : 1 -( yclobutyl-5-inet hyl-\-( 1 -(napht halen- 1 -yl)cyclopropyl )- 1 //-indole-6- carboxamide (Compound 296)

To a solution of 5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-lZ/-indole-6-car boxamide (80.0 mg, 235 pmol, 1.0 eq) and cyclobutanol (50.8 mg, 705 pmol, 3.0 eq) in toluene (4.0 mL) was added CMBP (56.7 mg, 235 pmol, 1.0 eq). The mixture was stirred at 90 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 40% - 70% B over 7 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give l-cyclobutyl-5-methyl-A-[l-(l-naphthyl)cyclopropyl]indole-6- carboxamide (18.4 mg, 46.3 pmol, 20% yield) as a white solid. M + H ⁺ = 395.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.01 (s, 1H), 8.72 (d, J= 8.3 Hz, 1H), 8.01 - 7.91 (m, 1H), 7.84 (d, J= 7.5 Hz, 2H), 7.66 - 7.51 (m, 3H), 7.47 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.18 (s, 1H), 6.34 (d, J = 3.0 Hz, 1H), 4.83 (quin, J = 8.5 Hz, 1H), 2.42 - 2.27 (m, 4H), 2.11 (s, 3H), 1.86 - 1.73 (m, 2H), 1.44 - 1.36 (m, 2H), 1.24 - 1.14 (m, 2H). Example 139: l-(Azetidin-3-yl)-5-methyl-\-( l-(naphthalen-l-yl)cyclopropyl)-l//-indole- 6-carboxamide (Compound 218)

Compound 218

Step 1: tert-Butyl 3-(5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-lH-indol- l-yl)azetidine-l-carboxylate (139A-1)

To a mixture of 5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-l/Z-indole-6-ca rboxamide (200 mg, 588 pmol, 1.0 eq), tert-butyl 3 -iodoazetidine- 1 -carboxylate (332 mg, 1.76 mmol, 2.0 eq) and CS2CO3 (384 mg, 1.76 mmol, 2.0 eq) in DMF (2.5 mL) was stirred at 150 °C for 30 min in a microwave (400 W). TLC indicated that 30% of the starting material still remained and 40% of the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.6). tert-Butyl 3-(5-methyl-6-((l-(naphthalen-l- yl)cy cl opropyl)carbamoyl)-17/-indol-l-yl)azeti dine- 1 -carboxylate (60.0 mg, 100 pmol, 18% yield) was obtained as a yellow gum.

Step 2: l-(Azetidin-3-yl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-LH-indole-6- carboxamide (Compound 218)

To a solution of tert-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-17 T- indol-l-yl)azetidine-l -carboxylate (55.0 mg, 111 pmol, 1.0 eq) in DCM (10 mL) was added TFA (2.3 mL). The resulting mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). l-(Azetidin-3-yl)-5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )-l//-indole-6-carboxamide (19.7 mg, 38.8 pmol, 35% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 396.1 (LCMS); flT NMR (400 MHz, DMSO ) 8 9.00 (s, 2H), 8.69 (d, J= 8.3 Hz, 1H), 7.94 (d, J= 7.6 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.79 (d, J= 3.3 Hz, 1H), 7.62 - 7.45 (m, 3H), 7.30 (s, 1H), 7.25 (s, 1H), 6.52 (d, J = 3.1 Hz, 1H), 5.50 (br t, J= 7.9 Hz, 1H), 4.50 - 4.29 (m, 4H), 2.09 (s, 3H), 1.39 (br s, 2H), 1.24 - 1.16 (m, 2H).

Example 140: 5-Methyl-l-(l-methylazetidin-3-yl)-/V-(l-(naphthalen-l-yl)cy clopropyl)-

TH-indole-6-carboxamide (Compound 290)

Compound 218 Compound 290

Step 1: 5-Methyl-l-( l-methylazetidin-3-yl)-/V-(l-(naphthalen-l-yl)cyclopropyl)-l H- indole-6-carboxamide (Compound 290)

To a solution of l-(azetidin-3-yl)-5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )-l//-indole-6- carboxamide (50.0 mg, 83.4 pmol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (50 pL), followed by the addition of formaldehyde (27.1 mg, 334 pmol, 24.8 pL, 37% purity in water, 4.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (42.0 mg, 667 pmol, 8.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (8.0 mL) and extracted with EtOAc (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5 -Methyl -1-(1- methylazeti din-3 -yl)-7V-(l -(naphthal en-l-yl)cy cl opropyl)-U/-indole-6-carboxamide (11.0 mg, 26.6 pmol, 16% yield) was obtained as a yellow solid. M + H ⁺ = 410.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.02 - 8.96 (m, 1H), 8.74 - 8.67 (m, 1H), 7.97 - 7.91 (m, 1H), 7.88 - 7.78 (m, 2H), 7.64 - 7.44 (m, 3H), 7.29 - 7.20 (m, 2H), 6.41 - 6.35 (m, 1H), 5.02 - 4.89 (m, 1H), 3.75 - 3.60 (m, 2H), 3.30 - 3.25 (m, 2H), 2.32 (br d, J= 2.4 Hz, 3H), 2.16 - 2.07 (m, 3H), 1.44 - 1.34 (m, 2H), 1.15 (br s, 2H).

Example 141: l-(Azetidin-3-ylmethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cycl opropyl)-lH- indole-6-carboxamide (Compound 239)

Compound 239

Step 1: /crt- Butyl 3-((5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-TH-indol- l-yl)methyl)azetidine-l-carboxylate (141A-1)

A mixture of 5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-U/-indole-6-car boxamide (150 mg, 441 pmol, 1.0 eq), tert-butyl 3 -(iodomethyl)azetidine-l -carboxylate (262 mg, 881 pmol, 2.0 eq) and cesium carbonate (287 mg, 881 pmol, 2.0 eq) in DMF (2 mL) was stirred at 150 °C for 30 min in a microwave (400 W). LCMS indicated that 50% starting material remained and 50% desired mass was detected. The mixture reaction was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.6). /crt-Butyl 3-((5-methyl- 6-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)-U/-indol-l-yl)methyl)azeti dine- 1- carboxylate (120 mg, crude) was obtained as a white solid. M + H ⁺ = 510.3 (LCMS). Step 2: l-(Azetidin-3-ylmethyl)-5-methyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-LH-indole- 6-carboxamide (Compound 239)

To a stirred solution of tert-butyl 3-((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) -lJ/-indol-l-yl)methyl)azetidine-l -carboxylate (120 mg, 235 pmol, 1.0 eq) in DCM (10 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 1 -(Azeti din-3 -ylmethyl)-5-methyl-7V-(l -(naphthal en- 1 -yl)cyclopropyl)- 1 JT-indole-6- carboxamide (22.9 mg, 43.7 pmol, 6% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 410.1 (LCMS); ^X HNMR (400 MHz, DMSO ) 8 9.00 (s, 1H), 8.68 (d, J= 8.4 Hz, 1H), 8.61 (br dd, J= 2.5, 4.1 Hz, 1H), 8.55 - 8.44 (m, 1H), 7.98 - 7.91 (m, 1H), 7.90 - 7.80 (m, 2H), 7.60 - 7.44 (m, 3H), 7.38 (d, J= 3.1 Hz, 1H), 7.27 (s, 2H), 6.35 (d, J= 3.0 Hz, 1H), 4.34 (d, J = 7.4 Hz, 2H), 3.94 - 3.80 (m, 2H), 3.75 - 3.63 (m, 2H), 2.08 (s, 3H), 1.43 - 1.35 (m, 2H), 1.24 - 1.15 (m, 2H).

Example 142: 5-Methyl-\-(l-(naphth:ilen-l-yl)cyclopropyl)-l-(oxetan-3-ylm ethyl)-l//- indole-6-carboxamide (Compound 295)

Compound 199 Compound 295

Step 1: 5-Methyl-\-( l-(naphthalen- l-yl)cyclopropyl)-l-(oxetan-3-ylmethyl)-l //-indole-6- carboxamide (Compound 295)

To a solution of 5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-lZ/-indole-6-ca rboxamide (80.0 mg, 235 pmol, 1.0 eq) in DMF (4.0 mL) were added CS2CO3 (230 mg, 705 pmol, 3.0 eq) and 3-(iodomethyl)oxetane (93.1 g, 470 pmol, 2.0 eq). The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna Cl 8 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 43% - 73% B over 7 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 5-methyl-7V-(l-(naphthalen-l-yl) cyclopropyl)- l-(oxetan-3-ylmethyl)- 1H- indole-6-carboxamide (39.3 mg, 95.4 pmol, 41% yield) as a white solid. M + H ⁺ = 411.1 (LCMS); flT NMR (400 MHz, DMSO ) 8 9.00 (s, 1H), 8.71 (d, J= 8.4 Hz, 1H), 7.98 - 7.90 (m, 1H), 7.84 (dd, J= 2.3, 7.7 Hz, 2H), 7.61 - 7.45 (m, 3H), 7.40 (d, J= 3.0 Hz, 1H), 7.23 (d, J= 12.8 Hz, 2H), 6.30 (d, J= 2.8 Hz, 1H), 4.56 (dd, J= 6.1, 7.8 Hz, 2H), 4.44 - 4.30 (m, 4H), 3.42 - 3.34 (m, 1H), 2.09 (s, 3H), 1.46 - 1.37 (m, 2H), 1.24 - 1.15 (m, 2H).

Example 143: l-(2-Aminoethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )-LH- indole-6-carboxamide (Compound 203)

Compound 199 Compound 203

Step 1: l-(2-Aminoethyl)-5-methyl-\-( 1 -(naphth:ilen-l-yl)cyclopropyl)-l //-indole-6- carboxamide (Compound 203)

To a mixture of 5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-lZ/-indole-6-ca rboxamide (80.0 mg, 235 pmol, 1.0 eq) in acetonitrile (4.0 mL) was added sodium hydride (18.8 mg, 470 pmol, 60% purity, 2.0 eq). The mixture was degassed and purged with N2 three times and stirred at 0 °C for 10 min. To the mixture was added 2-chloroethanamine (27.3 mg, 235 pmol, 1.0 eq, HCI salt), followed by TEA (23.8 mg, 235 pmol, 32.7 pL, 1.0 eq). The mixture was stirred at 20 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HCI, mobile phase B: acetonitrile). 1 -(2- Aminoethyl)-5-methyl-7V-( 1 -(naphthal en- 1 -yl)cyclopropyl)- lZZ-indole-6-carboxamide (10.6 mg, 25.2 pmol, 11% yield, HCI salt) was obtained as a white solid. M + H ⁺ = 384.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.02 (s, 1H), 8.70 (d, J= 8.2 Hz, 1H), 7.95 - 7.82 (m, 5H), 7.60 - 7.45 (m, 3H), 7.38 (d, J= 3.1 Hz, 1H), 7.29 (d, J = 9.4 Hz, 2H), 6.38 (d, J = 2.9 Hz, 1H), 4.30 (t, J= 6.8 Hz, 2H), 3.16 - 3.09 (m, 1H), 3.18 - 3.08 (m, 1H), 2.10 (s, 3H), 1.44 - 1.36 (m, 2H), 1.22 - 1.15 (m, 2H).

Example 144: 3,5-Dimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-LH-indole-6 - carboxamide (Compound 212)

Compound 212

Step 1: Methyl 5-(allylamino)-4-iodo-2-methylbenzoate (144A-1)

To a solution of methyl 5 -amino-4-iodo-2-m ethylbenzoate (300 mg, 1.03 mmol, 1.0 eq) and K2CO3 (427 mg, 3.09 mmol, 3.0 eq) in DMF (5.0 mL) was added 3 -bromoprop- 1-ene (125 mg, 1.03 mmol, 1.0 eq) slowly. The mixture was stirred at 25 °C for 60 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. Methyl 5-(allylamino)-4-iodo-2-methylbenzoate (103 mg, 311 pmol, 30% yield) was obtained as a white oil. M + H ⁺ = 331.9 (LCMS). Step 2: Methyl 3.5-dimethyl-l//-indole-6-carboxylate (144A-2)

To a solution of methyl 5-(allylamino)-4-iodo-2-methylbenzoate (103 mg, 311 pmol, 1.0 eq) in DMF (8.0 mL) were added ISfeCCh (82.4 mg, 778 pmol, 2.5 eq), TBAC (95.1 mg, 342 pmol, 95.7 pL, 1.1 eq) and Pd(OAc)2 (6.98 mg, 31.1 pmol, 0.1 eq). The resulting mixture was stirred at 100 °C for 2 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/5, R/= 0.5). Methyl 3,5-dimethyl- lJT-indole-6-carboxylate (30.0 mg, 148 pmol, 47% yield) was obtained as a brown solid.

Step 3: 3.5-l)imethyl-l//-indole-6-carboxylic acid (144A-3)

To a solution of methyl 3,5-dimethyl-lJ/-indole-6-carboxylate (70.0 mg, 344 pmol, 1.0 eq) in a mixture of THF (3.5 mL) and MeOH (3.5 mL) was added NaOH (2 M aqueous, 1.72 mL, 10 eq). The mixture was stirred at 25 °C for 1 h then at 70 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 3,5-dimethyl-17/-indole-6-carboxylic acid (60.0 mg, 317 pmol, 92% yield) as a white solid.

Step 4: 3,5-Dimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-lH-indole-6 -carboxamide (Compound 212)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (58.1 mg, 317 pmol, 1.0 eq) and 3,5- dimethyl-lJ/-indole-6-carboxylic acid (60.0 mg, 317 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (96.3 mg, 951 pmol, 132 pL, 3.0 eq), EDCI (91.2 mg, 476 pmol, 1.5 eq) and HOBt (64.3 mg, 476 pmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna Cl 8 column (100 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 55% - 75% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 3,5-Dimethyl-7V-(l-(naphthalen-l- yl)cyclopropyl)- l//-indole-6-carboxamide (32.1 mg, 81.9 pmol, 26% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 355.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.48 (br d, J= 8.7 Hz, 1H), 7.98 (d, J= 6.8 Hz, 1H), 7.91 (d, J= 7.8 Hz, 1H), 7.81 (br d, J= 8.2 Hz, 2H), 7.64 - 7.55 (m, 1H), 7.48 (s, 2H), 7.14 (s, 1H), 6.95 (s, 1H), 6.54 (br s, 1H), 2.33 (s, 3H), 2.26 (s, 3H), 1.58 - 1.56 (m, 2H), 1.41 (s, 2H).

Example 145: 3-(2-Aminoethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )-lH- indole-6-carboxamide (Compound 292)

145A-4 Compound 292

Step 1: (E)-Methyl 5-methyl-3-(2-nitrovinyl)-lH-indole-6-carboxylate (145A-1)

To a solution of methyl 5 -methyl- l //-indole-6-carboxylate (460 mg, 2.43 mmol, 1.0 eq) and E)-A, A-dimethyl-2-nitroethenamine (282 mg, 2.43 mmol, 1.0 eq) in DCM (5.0 mL) was added TFA (277 mg, 2.43 mmol, 0.18 mL, 1.0 eq). The mixture was stirred at 20 °C for 5 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by trituration from EtOAc (5 mL). (£)-Methyl 5-methyl-3-(2-nitrovinyl)- l //-indole- 6-carboxylate (300 mg, 1.15 mmol, 47% yield) was obtained as a yellow solid. M + H ⁺ = 261.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.40 - 8.33 (m, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.95 - 7.89 (m, 1H), 7.72 (s, 1H), 3.90 (s, 3H), 2.71 (s, 3H).

Step 2: Methyl 5-methyl-3-(2-nitroethyl)-lH-indole-6-carboxylate (145A-2)

To a solution of (£)-methyl 5-methyl-3-(2-nitrovinyl)-U/-indole-6-carboxylate (300 mg, 1.15 mmol, 1.0 eq) in a mixture of THF (15 mL) and MeOH (5.0 mL) was added NaBH4 (131 mg, 3.46 mmol, 3.0 eq) at 0 °C. Then the mixture was stirred at 20 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. Methyl 5-methyl-3-(2-nitroethyl)- IT/-indole-6- carboxylate (230 mg, 877 pmol, 76% yield) was obtained as a white solid. M + H ⁺ = 263.1 (LCMS); ^X H NMR (400 MHz, CDCI3) 8 8.21 - 8.11 (m, 1H), 8.09 - 8.04 (m, 1H), 7.41 - 7.37 (m, 1H), 7.22 - 7.17 (m, 1H), 4.79 - 4.53 (m, 2H), 4.01 - 3.77 (m, 3H), 3.64 - 3.35 (m, 2H), 2.83 - 2.59 (m, 3H).

Step 3: 5-Methyl-3-(2-nitroethyl)-lH-indole-6-carboxylic acid (145A-3)

A solution of methyl 5-methyl-3-(2-nitroethyl)-lJ/-indole-6-carboxylate (70.0 mg, 267 pmol, 1.0 eq) in HC1 (2 M aqueous, 2.0 mL) was stirred at 110 °C for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with NaOH (2 M aqueous) to adjust the pH to 6. The mixture was concentrated under vacuum to remove the water completely. The mixture was treated with MeOH/DCM (V/V = 10/1, 2.0 mL) then filtered. The filter cake was washed with MeOH/DCM (V/V = 10/1, 2.0 mL x 2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give crude product 5-methyl-3-(2-nitroethyl)-U/-indole-6-carboxylic acid (100 mg, 80% purity) as a grey solid. M + H ⁺ = 249.1 (LCMS).

Step 4: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-3-(2-nitroethyl )-lZ7-indole-6- carboxamide (145A-4)

To a solution of 5-methyl-3-(2-nitroethyl)-U/-indole-6-carboxylic acid (100 mg, 403 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (73.8 mg, 403 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (81.5 mg, 806 pmol, 0.12 mL, 2.0 eq), EDCI (92.7 mg, 483 pmol, 1.2 eq) and HOBt (65.3 mg, 483 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.4). 5 -Methyl -7V-(1 -(naphthal en-l-yl)cy clopropyl)-3-(2-nitroethyl)- UT-indole-6- carboxamide (15.0 mg, 36.3 pmol, 9% yield) was obtained as a white solid. M + H ⁺ = 414.2 (LCMS).

Step 5: 3-(2-Ainiiioethyl)-5-niethyl-\-( 1 -(ii:iplith:ileii-l-yl)cyclopropyl)-l//-indole-6- carboxamide (Compound 292)

To a solution of 5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-3-(2-nitroethyl) -U/-indole-6- carboxamide (15.0 mg, 36.3 pmol, 1.0 eq) in a mixture of MeOH (2.0 mL) and H2O (0.5 mL) were added iron powder (10.1 mg, 181 pmol, 5.0 eq) and NH4CI (9.70 mg, 181 pmol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) the mixture was filtered through a pad of Celite and the slurry was washed with EtOAc several times and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 3-(2-Aminoethyl)-5-methyl-A-(l- (naphthalen-l-yl)cyclopropyl)-U/-indole-6-carboxamide (1.2 mg, 3.13 pmol, 9% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 384.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.64 (d, J= 8.5 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.53 - 7.42 (m, 2H), 7.31 (s, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 3.16 (br d, J= 7.3 Hz, 2H), 3.05 (d, J= 7.4 Hz, 2H), 2.21 (s, 3H), 1.52 - 1.42 (m, 2H), 1.31 (br d, J= 1.9 Hz, 2H).

Example 146: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)indoline-6-carbo xamide (Compound 207)

Compound 199 Compound 207 Step 1 : 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)indoline-6-carbo xamide (Compound 207)

To a solution of 5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-U/-indole-6-carb oxamide (100 mg, 294 pmol, 1.0 eq) in AcOH (10 mL) was added NaBHiCN (36.9 mg, 588 pmol, 2.0 eq), the resulting mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)indoline-6-carbox amide (40.0 mg, 116 pmol, 40% yield) was obtained as a white solid. M + H ⁺ = 343.0 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.19 (s, 1H), 8.62 (d, J= 8.4 Hz, 1H), 7.94 (d, J= 7.5 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.61 - 7.44 (m, 3H), 7.16 (s, 1H), 6.92 (s, 1H), 3.60 (br t, J= 7.9 Hz, 2H), 3.06 (br t, J= 7.7 Hz, 2H), 2.00 (s, 3H), 1.36 (br d, J= 1.5 Hz, 2H), 1.21 - 1.15 (m, 2H).

Example 147: l,5-Dimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)indoline-6-c arboxamide (Compound 210)

Compound 201 Compound 210

Step 1: l,5-Dimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)indoline-6-c arboxamide (Comp ound 210)

To a solution of l,5-dimethyl-A-(l-(naphthalen-l-yl)cyclopropyl)-U/-indole-6- carboxamide (50.0 mg, 141 pmol, 1.0 eq) in AcOH (1.0 mL) was added NaBHsCN (17.7 mg, 282 pmol, 2.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vaccum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 1,5-Dimethyl-7V-(1 -(naphthal en-l-yl)cy cl opropyl)indoline-6- carboxamide (31.7 mg, 80.7 pmol, 57% yield, HCI salt) was obtained as a white solid. M + H ⁺ = 357.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.04 - 8.97 (m, 1H), 8.66 (d, J= 8.3 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.82 (t, J = 6.7 Hz, 2H), 7.46 (s, 3H), 6.98 - 6.79 (m, 1H), 6.55 - 6.35 (m, 1H), 3.33 - 3.25 (m, 2H), 2.89 - 2.81 (m, 2H), 2.70 - 2.66 (m, 3H), 1.91 (s, 3H), 1.35

(br d, J= 1.0 Hz, 2H), 1.17 (s, 2H).

Example 148: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-oxoindoline-6 - carboxamide (Compound 249)

Compound 249

Step 1: Methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (148A-2)

To a solution of methyl 2-methyl-5-nitrobenzoate (5.00 g, 25.6 mmol, 1.0 eq) and methyl 2- chloroacetate (3.06 g, 28.2 mmol, 1.1 eq) in DMF (50 mL) was slowly added a solution of t- BuOK (7.19 g, 64.1 mmol, 2.5 eq) in DMF (100 mL) at 0 °C and the mixture was stirred at 0 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 4-(2- methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (4.00 g, 15.0 mmol, 29% yield) was obtained as a yellow solid. M + H ⁺ = 268.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.73 (s, 1H), 7.25 (s, 1H), 4.05 (s, 2H), 3.95 (s, 3H), 3.73 (s, 3H), 2.70 (s, 3H).

Step 2: Methyl 5-methyl-2-oxoindoline-6-carboxylate (148A-3)

A solution of methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (400 mg, 1.69 mmol, 1.0 eq) in HC1 (1 M aqueous, 16 mL, 9.5 eq) was stirred at 100 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-methyl-2-oxoindoline-6-carboxylate (200 mg, 975 pmol, 58% yield) was obtained as a brown solid. M + H ⁺ = 206.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.43 (s, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 3.81 (s, 3H), 3.51 (s, 2H), 2.45 (s, 3H).

Step 3: 5-Methyl-2-oxoindoline-6-carboxylic acid (148A-4)

A solution of methyl 5-methyl-2-oxoindoline-6-carboxylate (150 mg, 731 pmol, 1.0 eq) in HC1 (2 M aqueous, 5.0 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-methyl-2-oxoindoline-6-carboxylic acid (100 mg), which was used in the next step without any further purification. M + H ⁺ = 192.0 (LCMS); 'H NMR (400 MHz, DMSO ) 8 10.39 (s, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 3.49 (s, 2H), 2.46 (s, 3H).

Step 4: 5-Methyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-2-oxoindoline-6-carboxamide (Compound 249)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (47.9 mg, 262 pmol, 1.0 eq) and 5- methyl-2-oxoindoline-6-carboxylic acid (50.0 mg, 262 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (79.4 mg, 785 pmol, 109 pL, 3.0 eq), EDCI (100 mg, 523 pmol, 2.0 eq) and HOBt (70.7 mg, 523 mmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)-2-oxoindoline-6-carboxamide (13.5 mg, 37.9 pmol, 14% yield, FA salt) was obtained as a white solid. M + H ⁺ = 357.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.26 (s, 1H), 9.10 (s, 1H), 8.64 (d, = 8.4 Hz, 1H), 7.93 (d, = 8.1 Hz, 1H), 7.82 (t, J= 7.4 Hz, 2H), 7.61 - 7.42 (m, 3H), 6.96 (s, 1H), 6.46 (s, 1H), 3.40 (s, 2H), 1.98 (s, 3H), 1.33 (s, 2H), 1.19 - 1.13 (m, 2H). Example 149: 3,3,5-Trimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-oxoind oline-6- carboxamide (Compound 243)

Compound 243 Step 1: Methyl 4-(l-methoxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-nitrobenz oate (149A-1)

To a solution of methyl 4-(2-methoxy-2-oxoethyl)-2-methyl-5-nitrobenzoate (500 mg, 1.87 mmol, 1.0 eq) in DMF (50 mL) was slowly added Mel (664 mg, 4.68 mmol, 291 pL, 2.5 eq), 15-crown-5 (103 mg, 468 pmol, 92.8 pL, 0.25 eq) and sodium hydride (187 mg, 4.68 mmol, 60% purity, 2.5 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 4-(l -methoxy -2-methyl-l -oxopropan-2-yl)- 2-methyl-5-nitrobenzoate (600 mg, crude) was obtained as a white solid. M + H ⁺ = 296.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.54 (s, 1H), 7.46 (s, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 2.73 (s, 3H), 1.68 (s, 6H).

Step 2: Methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (149A-2)

To a solution of methyl 4-(l-methoxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-nitrobenz oate (300 mg, 1.02 mmol, 1.0 eq) in MeOH (60 mL) was added 10% palladium on carbon (300 mg). The mixture was degassed and purged with H2 three times, and then the mixture was stirred at 50 °C for 16 h under a H2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum to give the crude product methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (200 mg, 857 pmol, 84% yield) as a yellow oil. M + H ⁺ = 234.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.06 (br s, 1H), 7.48 (s, 1H), 7.08 (s, 1H), 3.90 (s, 3H), 2.59 (s, 3H), 1.42 (s, 6H).

Step 3: 3,3,5-Trimethyl-2-oxoindoline-6-carboxylic acid (149A-3)

To a solution of methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (100 mg, 429 pmol, 1.0 eq) in a mixture of MeOH (2.5 mL) and THF (7.5 mL) was added NaOH (2 M aqueous, 4.5 mL, 21 eq). The mixture was stirred at 70 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with MTBE (3.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with 2-methyltetrahydrofuran (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-(2-((terL butoxycarbonyl) amino)ethoxy)-2-methyl benzoic acid (90.0 mg), which was used in the next step without any further purification. M + H ⁺ = 220.0 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 12.88 - 12.61 (m, 1H), 10.38 (s, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 2.47 (s, 3H), 1.25 (s, 6H). Step 4: 3,3,5-Trimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-oxoind oline-6- carboxamide (Compound 243)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (75.2 mg, 411 pmol, 1.0 eq) and 5-(2- ((/ert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (90.0 mg, 411 pmol, 1.0 eq) in DCM (10 mL) were added TEA (125 mg, 1.23 mmol, 171 pL, 3.0 eq), EDCI (157 mg, 821 pmol, 2.0 eq) and HOBt (111 mg, 821 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 3,3,5-Trimethyl- 7V-(1 -(naphthal en-l-yl)cy cl opropyl)-2-oxoindoline-6-carboxamide (45.3 mg, 117 pmol, 28% yield) was obtained as a white solid. M + H ⁺ = 385.1 (LCMS); ^T H NMR (400 MHz, DMSO- d ₆ ) 6 10.22 (s, 1H), 9.12 (s, 1H), 8.62 (d, J= 8.2 Hz, 1H), 7.93 (d, J= 7.7 Hz, 1H), 7.82 (dd, J = 1.8, 10.3 Hz, 2H), 7.61 - 7.42 (m, 3H), 7.05 (s, 1H), 6.47 (s, 1H), 1.97 (s, 3H), 1.32 (br s, 2H), 1.21 - 1.14 (m, 8H).

Example 150: 3,3,5-Trimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)indoline- 6- carboxamide (Compound 262)

Step 3

Compound 262

Step 1: Methyl 3,3,5-trimethylindoline-6-carboxylate (150A-1)

To a solution of methyl 3,3,5-trimethyl-2-oxoindoline-6-carboxylate (200 mg, 857 pmol, 1.0 eq) in THF (50 mL) was slowly added BH3.THF (1 M, 2.14 mL, 2.5 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. MeOH (5.0 mL) was added and stirred at 70 °C for 1 h. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 3,3,5-trimethylindoline-6-carboxylate (160 mg, 730 pmol, 85% yield) was obtained as a white solid. M + H ⁺ = 220.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.19 (s, 1H), 6.90 (s, 1H), 3.86 (s, 3H), 3.33 (s, 2H), 2.51 (s, 3H), 1.31 (s, 6H).

Step 2: 3,3,5-Trimethylindoline-6-carboxylic acid (150A-2)

A solution of methyl 3,3,5-trimethylindoline-6-carboxylate (100 mg, 456 pmol, 1.0 eq) in HC1 (2 M aqueous, 1 mL) was stirred at 100 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 3,3,5-trimethylindoline-6-carboxylic acid (50.0 mg), which was used in the next step without any further purification. M + H ⁺ = 206.1 (LCMS).

Step 3: 3,3,5-Trimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)indoline- 6-carboxamide (Compound 262)

To a solution of 1 -(naphthal en-l-yl)cyclopropanamine (44.6 mg, 244 pmol, 1.0 eq) and 3,3,5- trimethylindoline-6-carboxylic acid (50.0 mg, 244 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (49.3 mg, 487 pmol, 67.8 pL, 2.0 eq), EDCI (56.0 mg, 292 pmol, 1.2 eq) and HOBt (39.5 mg, 292 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 3,3,5-Trimethyl-A-(l-(naphthalen-l- yl)cyclopropyl) indoline-6-carboxamide (7.50 mg, 17.2 pmol, 7% yield) was obtained as a yellow solid. M + H ⁺ = 371.2 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 8.96 (s, 1H), 8.64 (d, J= 8.1 Hz, 1H), 7.92 (d, J= 7.6 Hz, 1H), 7.80 (dd, J= 7.7, 9.9 Hz, 2H), 7.59 - 7.41 (m, 4H), 6.72 (s, 1H), 6.15 (s, 1H), 3.09 (s, 2H), 1.90 (s, 3H), 1.30 (br s, 2H), 1.15 (s, 8H).

Example 151: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) indoline-6- carboxamide (Compound 190)

Step 1: tert-Butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)indo lin-2- yl)methyl)carbamate (151A-1)

To a solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-l/Z - indol-2-yl)methyl)carbamate (225 mg, 479 pmol, 1.0 eq) in HO Ac (15 mL) was added NaBHiCN (60.2 mg, 958 pmol, 2.0 eq). The resulting mixture was stirred at 25 °C for 16 h. TLC indicated that that the starting material was completely consumed. The mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5), and the combined organic layers were washed with saturated aqueous NazCO, solution (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/1. tert-Butyl((5-methyl-6-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl) indolin-2-yl)methyl)carbamate (115 mg, 243.86 pmol, 51% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCh) 8 8.43 (d, J = 8.5 Hz, 1H), 7.91 (dd, J= 7.8, 15.6 Hz, 2H), 7.80 (d, J= 8.3 Hz, 1H), 7.60 - 7.43 (m, 4H), 6.81 (s, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.89 - 4.74 (m, 1H), 3.98 (br dd, J= 2.4, 4.1 Hz, 1H), 3.27 - 3.15 (m, 1H), 3.04 (dd, J= 8.9, 16.4 Hz, 1H), 2.67 (dd, J= 7.6, 16.1 Hz, 1H), 2.O7 (s, 3H), 1.54 (br d, J= 1.8 Hz, 2H), 1.42 (s, 9H), 1.38 (br s, 2H). Step 2: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) indoline-6- carboxamide (Compound 190)

To a solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) indolin- 2-yl)methyl)carbamate (110 mg, 188 pmol, 1.0 eq) in DCM (7.0 mL) was added TFA (1.56 mL). The mixture was stirred at 25 °C for 10 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- (Aminomethyl)-5-methyl-7V-(l-(naphthalen-l-yl) cyclopropyl)indoline-6-carboxamide (12.1 mg, 29.8 pmol, 16% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 372.3 (LCMS); 'H NMR (400 MHz, DMSO ) 8 8.92 (s, 1H), 8.63 (d, J= 8.3 Hz, 1H), 7.97 - 7.86 (m, 4H), 7.83 - 7.74 (m, 2H), 7.61 - 7.29 (m, 3H), 6.79 (s, 1H), 6.21 (s, 1H), 3.99 - 3.87 (m, 1H), 3.04 - 2.96 (m, 1H), 2.88 - 2.75 (m, 2H), 2.69 (br d, J= 7.1 Hz, 1H), 1.89 (s, 3H), 1.30 (m, 2H), 1.18 - 1.09 (m, 2H).

Example 152: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l- yl)cyclopropyl)indoline-6-carboxamide (Compound 231)

Compound 231

Step 1: te/7- Butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l) indolin-2-yl)methyl)carbamate (152A-1)

To a solution of tert-butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l)- U/-indol-2-yl)methyl)carbamate (90.0 mg, 186 pmol, 1.0 eq) in AcOH (5.0 mL) was added NaBHiCN (23.4 mg, 372.21 pmol, 2.0 eq). The resulting mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by the addition of saturated aqueous ISfeCCh (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product tert-butyl methyl((5- methyl-6-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl) indolin-2-yl)methyl)carbamate (420 mg, 92% purity) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 486.2 (LCMS).

Step 2: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l-yl)cycl opropyl)indoline- 6-carboxamide (Compound 231)

To a solution of tert-butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l) indolin-2-yl)methyl)carbamate (110 mg, 181 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 2.4 mL), the mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-A-(l -(naphthal en-l-yl)cy cl opropyl) indo line-6- carboxamide (15.4 mg, 36.0 pmol, 20% yield, HC1 salt) was obtained as a yellow solid solid. M + H ⁺ = 386.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 8 8.97 - 8.90 (m, 1H), 8.65 (br d, J = 8.5 Hz, 2H), 7.98 - 7.89 (m, 1H), 7.85 - 7.75 (m, 2H), 7.60 - 7.41 (m, 3H), 6.83 - 6.78 (m, 1H), 6.25 - 6.20 (m, 1H), 4.05 - 3.97 (m, 1H), 3.64 - 3.62 (m, 3H), 3.15 - 2.65 (m, 5H), 1.95 - 1.87 (m, 3H), 1.36 - 1.28 (m, 2H), 1.19 - 1.10 (m, 2H).

Example 153: 5-Methyl-/V-(l-(naphthalen-l-yl)cydopropyl)-lH-indazole-6-ca rboxamide (Compound 176)

31A-3 ^{Step 1} Compound 176 Step 1: 5-Methyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-TH-indazole-6-carboxamide (Compound 176)

To a solution of 5-methyl-U/-indazole-6-carboxylic acid (50.0 mg, 284 pmol, 1.0 eq) and 1- (naphthalen-l-yl)cyclopropanamine (52.0 mg, 284 pmol, 1.0 eq) in DMF (5.0 mL) were added TEA (86.2 mg, 851 pmol, 119 pL, 3.0 eq), EDCI (81.6 mg, 426 pmol, 1.5 eq) and HOBt (57.5 mg, 426 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) at 25 °C and extracted with EtOAc (2.0 mL x 3). The combined organic layers were washed with brine (2.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- Methyl-A-(1 -(naphthal en-l-yl)cy cl opropyl)-lJ/-indazole-6-carboxamide (15.5 mg, 45.0 pmol, 16% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 342.1 (LCMS); NMR (400 MHz, DMSO-tL) 8 9.24 - 9.19 (m, 1H), 8.18 - 8.14 (m, 1H), 7.98 - 7.91 (m, 2H), 7.88 - 7.80 (m, 2H), 7.61 - 7.45 (m, 5H), 6.64 (s, 1H), 2.12 (s, 3H), 1.42 - 1.35 (m, 2H), 1.22 - 1.15 (m, 2H).

Example 154: l-(Azetidin-3-yl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-lH- indazole-6-carboxamide (Compound 304) and 2-(azetidin-3-yl)-5-methyl-/V-(l- (naphthalen-l-yl)cyclopropyl)-2H-indazole-6-carboxamide (Compound 305)

Boc

154A-2

154A-2 Compound 305

Step 1: te/7- Butyl 3-(5-methyl-6-(( l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-TH- indazol-l-yl)azetidine-l-carboxylate (154A-1) and tert-butyl 3-(5-methyl-6-((l- (naphthalene-l-yl)cyclopropyl)carbamoyl)-2Z/-indazol-2-yl)az etidine-l -carboxylate (154A-2)

To a solution of 5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-U/-indazole-6-ca rboxamide (150 mg, 439 pmol, 1.0 eq) and tert-butyl 3 -iodoazetidine- 1 -carboxylate (249 mg, 879 pmol, 2.0 eq) in DMF (5.0 mL) was added cesium carbonate (429 mg, 1.32 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, Rp = 0.4, R/2 = 0.6). tert-Butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-U/ -indazol-l-yl) azetidine- 1 -carboxylate (140 mg, 282 pmol, 64% yield) was obtained as a colorless oil. M + H ⁺ = 497.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.20 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 8.11 (s, 1H), 7.97 - 7.91 (m, 1H), 7.85 (dd, J= 3.0, 7.6 Hz, 2H), 7.60 - 7.45 (m, 4H), 7.39 (s, 1H), 5.64 - 5.53 (m, 1H), 4.33 - 4.26 (m, 2H), 4.18 (br s, 2H), 2.05 (s, 3H), 1.41 (s, 11H), 1.23 - 1.19 (m, 2H). tert-Butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-2J T- indazol -2 -yl)azeti dine- 1 -carboxylate (50.0 mg, 101 pmol, 23% yield) was obtained as a colorless oil. M - 56 + H ⁺ = 441.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 8 9.21 (s, 1H), 8.69 (d, J= 8.5 Hz, 1H), 8.38 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.63 - 7.57 (m, 1H), 7.56 - 7.51 (m, 1H), 7.47 (t, J= 7.6 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 5.54 - 5.40 (m, 1H), 4.36 (br t, J= 8.2 Hz, 2H), 4.20 (br d, J= 4.0 Hz, 2H), 2.10 (s, 3H), 1.42 (s, 9H), 1.38 (br s, 2H), 1.19 (s, 2H).

Step 2: l-(Azetidin-3-yl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-lH-indazole-6- carboxamide (Compound 304)

To a stirred solution of tert-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)- U/-indazol-l-yl)azetidine-l -carboxylate (70.0 mg, 141 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). l-(Azetidin-3-yl)-5-methyl-7V-(l-(naphthalen-l-yl)cyclopropy l)-U/-indazole- 6-carboxamide (22.3 mg, 50.9 pmol, 36% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 397.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.38 - 9.23 (m, 2H), 9.20 (s, 1H), 8.66 (d, J= 8.1 Hz, 1H), 8.21 (s, 1H), 7.97 - 7.92 (m, 1H), 7.86 (dd, J= 4.1, 7.6 Hz, 2H), 7.62 - 7.44 (m, 5H), 5.78 (t, J= 7.6 Hz, 1H), 4.45 - 4.31 (m, 4H), 2.07 (s, 3H), 1.46 - 1.36 (m, 2H), 1.27 - 1.16 (m, 2H).

Step 3: 2-(Azetidin-3-yl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-2Z/-indazole-6- carboxamide (Compound 305)

To a stirred solution of tert-butyl 3-(5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)- 27/-indazol-2-yl)azetidine- l -carboxylate (70.0 mg, 141 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (800 pL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2- (Azetidin-3-yl)-5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl) -2J/-indazole-6-carboxamide (20.9 mg, 40.9 pmol, 51% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 397.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.23 (s, 1H), 9.15 (br d, J= 10.1 Hz, 1H), 8.97 - 8.86 (m, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H), 7.96 (d, J= 7.9 Hz, 1H), 7.84 (t, J= 8.1 Hz, 2H), 7.64 - 7.51 (m, 2H), 7.51 - 7.42 (m, 2H), 7.32 (s, 1H), 5.67 (quin, J= 7.5 Hz, 1H), 4.54 - 4.34 (m, 4H), 2.10 (s, 3H), 1.39 (s, 2H), 1.26 - 1.17 (m, 2H).

Example 155: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzofuran-6-carboxamide (Compound 197)

Step 5

155A-4 Compound 197

Step 1: Methyl 5-hydroxy-4-iodo-2-methylbenzoate (155A-1)

To a solution of methyl 5 -hydroxy-2-m ethylbenzoate (1.00 g, 6.02 mmol, 1.0 eq) in AcOH (10 mL) was added NIS (1.49 g, 6.62 mmol, 1.1 eq). The mixture was stirred at 20 °C for 16 h.

LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. Methyl 5 -hydroxy -4-iodo-2- methylbenzoate (1.70 g, 5.82 mmol, 97% yield) was obtained as a white solid. M + H ⁺ = 293.0 (LCMS). Step 2: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6- carboxylate (155A-2)

To a solution of methyl 5-hydroxy-4-iodo-2-methylbenzoate (1.70 g, 5.82 mmol, 1.0 eq) and tert-butyl prop-2-yn-l-ylcarbamate (903 mg, 5.82 mmol, 1.0 eq) in a mixture of H2O (10 mL) and toluene (20 mL) were added TEA (1.18 g, 11.6 mmol, 1.62 mL, 2.0 eq), Pd(PPh3)2Ch (123 mg, 175 pmol, 0.03 eq) and Cui (111 mg, 582 pmol, 0.1 eq). The mixture was stirred at 70 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/7. Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6- carboxylate (1.00 g, 3.13 mmol, 54% yield) was obtained as a yellow oil. M - 56+ H ⁺ = 264.1 (LCMS).

Step 3: 2-(((tert-Butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6- carboxylic acid (155A-3)

To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6- carboxylate (800 mg, 2.51 mmol, 1.0 eq) in a mixture of THF (5.0 mL) and EtOH (5.0 mL) was added NaOH (2 M in aqueous, 3.2 mL).The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with MTBE (2.0 mL x 3). The aqueous layer was basified to pH 4 using HC1 (1 M aqueous) and extracted with EtOAc (8.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(((tert- butoxycarbonyl) amino)methyl)-5-methylbenzofuran-6-carboxylic acid (700 mg) as a white solid. M - 56 + H ⁺ = 250.1 (LCMS).

Step 4: tert-Butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)benz ofuran- 2-yl)methyl)carbamate (155A-4)

To a solution of 2-(((tert-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6- carboxylic acid (700 mg, 2.29 mmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (441 mg, 2.41 mmol, 20.0 pL, 1.0 eq) in DCM (10 mL) were added TEA (696 mg, 6.88 mmol, 957 pL, 3.0 eq), EDCI (879 mg, 4.59 mmol, 2.0 eq) and HOBt (620 mg, 4.59 mmol, 2.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert- Butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)benz ofuran-2- yl)methyl)carbamate (800 mg, 1.70 mmol, 74% yield) was obtained as a white solid. M + H ⁺ = 471.3 (LCMS); flTNMR (400 MHz, CDCh) 8 8.42 - 8.36 (m, 1H), 7.91 - 7.79 (m, 2H), 7.76 - 7.70 (m, 1H), 7.54 - 7.37 (m, 3H), 7.16 - 7.12 (m, 2H), 6.47 - 6.36 (m, 2H), 4.87 - 4.79 (m, 1H), 4.46 - 4.22 (m, 2H), 2.22 - 2.15 (m, 3H), 1.41 - 1.39 (m, 2H), 1.35 (br s, 9H), 1.35 - 1.31 (m, 2H).

Step 5: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) benzofuran-6- carboxamide (Compound 197)

To a solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) benzofuran-2-yl)methyl)carbamate (80.0 mg, 640 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- (Aminomethyl)-5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)ben zofuran-6-carboxamide (26.6 mg, 65.5 pmol, 19% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 371.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.18 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 8.54 (br s, 2H), 7.97 - 7.91 (m, 1H), 7.83 (s, 2H), 7.62 - 7.44 (m, 3H), 7.43 - 7.41 (m, 1H), 7.27 - 7.22 (m, 1H), 6.96 - 6.90 (m, 1H), 4.40 - 4.16 (m, 2H), 2.13 (s, 3H), 1.60 - 1.31 (m, 2H), 1.27 - 1.06 (m, 2H).

Example 156: 2-((Dimethylamino)methyl)-5-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzofuran-6-carboxamide (Compound 198)

Compound 197 Compound 198 Step 1: 2-((Dimethylamino)methyl)-5-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl) benzofuran-6-carboxamide (Compound 198)

To a solution of 2-(aminomethyl)-5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)b enzofuran-6- carboxamide (70.0 mg, 189 pmol, 1.0 eq, HC1 salt) in MeOH (2.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (15.3 mg, 189 pmol, 14.1 pL, 37% purity, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (11.9 mg, 189 pmol, 1.0 eq) was added. The reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luma C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-((Dimethylamino)methyl)-5-methyl-A-(l-(naphthalen-l- yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carboxamide (30.9 mg, 77.5 pmol, 41% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 399.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 6 9.19 (s, 1H), 8.70 - 8.61 (m, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.63 - 7.43 (m, 4H), 7.30 - 7.26 (m, 1H), 7.13 - 7.09 (m, 1H), 4.51 (br s, 2H), 2.74 (br s, 6H), 2.11 (s, 3H), 1.42 - 1.33 (m, 2H), 1.24 - 1.14 (m, 2H).

Example 157: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l- yl)cyclopropyl)benzofuran-6-carboxamide (Compound 220)

157A-2

157A-3 Compound 220

Step 1: Methyl 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzo furan-6- carboxylate (157A-1)

To a solution of methyl 2-(((ter/-butoxycarbonyl)amino)methyl)-5-methylbenzofuran-6- carboxylate (200 mg, 626 pmol, 1.0 eq) in DMF (5.0 mL) was degassed and purged with N2 three times. To the mixture was added sodium hydride (50.1 mg, 1.25 mmol, 60% purity, 2.0 eq) dropwise at 0 °C for 30 min, then iodomethane (88.9 mg, 626 pmol, 39.0 pL, 1.0 eq) was added and the mixture was stirred at 0 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 2-(((ter/-butoxycarbonyl)(methyl)amino) methyl)-5-methylbenzofuran-6-carboxylate (220 mg, 660 pmol, 53% yield) was obtained as a colorless oil. M - 56 + H ⁺ = 278.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.05 (s, 1H), 7.37 (s, 1H), 6.61 - 6.44 (m, 1H), 4.61 - 4.47 (m, 2H), 3.92 (s, 3H), 3.01 - 2.91 (m, 3H), 2.70 - 2.64 (m, 3H), 1.52 - 1.46 (m, 9H).

Step 2: 2-(((tert-Butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzo furan-6- carboxylic acid (157A-2)

To a solution of methyl 2-(((/c/7-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzo furan -6-carboxylate (200 mg, 600 pmol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (15 mL) was added NaOH (2 M aqueous, 6.3 mL, 21 eq). The mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, H2O (20 mL) was added, and the mixture was washed with MTBE (5.0 mL x 3). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with 2-methyltetrahydrofuran (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-(2- ((/ -butoxycarbonyl) amino)ethoxy)-2-methyl benzoic acid (180 mg), which was used in the next step without any further purification. M + H ⁺ = 320.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.20 (s, 1H), 7.40 (s, 1H), 6.61 - 6.49 (m, 1H), 4.56 (br d, J= 14.8 Hz, 2H), 2.98 (br s, 3H), 2.73 (s, 3H), 1.54 - 1.46 (m, 9H).

Step 3: tert-Butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l) benzofuran-2-yl)methyl)carbamate (157A-3)

To a solution of l-(naphthalen-l-yl)cyclopropanamine (100 mg, 546 pmol, 1.0 eq) and 2- (((tert-butoxycarbonyl)(methyl)amino)methyl)-5-methylbenzofu ran-6-carboxylic acid (174 mg, 546 pmol, 1.0 eq) in DCM (10 mL) were added TEA (166 mg, 1.64 mmol, 228 pL, 3.0 eq), EDCI (209 mg, 1.09 mmol, 2.0 eq) and HOBt (148 mg, 1.09 mmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtO Ac/petroleum ether from 1/100 to 1/1. tert- Butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l)benzofuran-2- yl)methyl) carbamate (150 mg, 311 pmol, 57% yield) was obtained as a white solid. M + H ⁺ =

485.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.47 (d, J= 8.4 Hz, 1H), 8.00 - 7.88 (m, 2H), 7.81 (d, J= 8.2 Hz, 1H), 7.64 - 7.45 (m, 3H), 7.23 (s, 2H), 6.55 - 6.38 (m, 2H), 4.53 - 4.40 (m, 2H), 2.97 - 2.84 (m, 3H), 2.27 (s, 3H), 1.46 (br s, 9H), 0.91 - 0.83 (m, 4H).

Step 4: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l-yl)cycl opropyl) benzofuran-6-carboxamide (Compound 220)

To a stirred solution of tert-butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)benzofuran-2-yl)methyl)carbamate (50.0 mg, 103 pmol, 1.0 eq) in EtO Ac (1.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-7V-(l-(naphthalen-l-yl)cycl opropyl) benzofuran-6-carboxamide (9.04 mg, 21.5 pmol, 21% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 385.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 8 9.20 (s, 1H), 8.67 (d, J =

8.2 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.84 (t, J = 7.6 Hz, 2H), 7.62 - 7.44 (m, 4H), 7.26 (s, 1H), 7.01 (s, 1H), 4.36 (s, 2H), 2.57 (s, 3H), 2.13 (s, 3H), 1.39 (s, 2H), 1.25 - 1.17 (m, 2H). Example 158: ( )-2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)-2,3- dihydrobenzofuran-6-carboxamide (Compound 235) and (l?)-2-(Aminomethyl)-5- methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2,3-dihydrobenzof uran-6-carboxamide (Compound 236)

Compound 235 Compound 236

Step 1: tert-Butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-2,3 - dihydrobenzofuran-2-yl)methyl)carbamate (158A-1) To a solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)nben zo furan-2-yl)methyl)carbamate (200 mg, 425 pmol, 1.0 eq) in z-PrOH (20 mL) was added 10% palladium on carbon (100 mg) under a N2 atmosphere. The suspension was degassed and purged with H2 for three times. The mixture was stirred at 20 °C for 16 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with z-PrOH (4.0 mL x 5). The combined filtrates were concentrated under vacuum to give the crude product tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (400 mg) as a colorless oil. M - 56 + H ⁺ = 417.2 (LCMS). Step 2: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) -2,3-dihydro benzofuran-6-carboxamide (158A-2)

To a solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-2,3 - dihydrobenzofuran-2-yl)methyl)carbamate (400 mg, 846 pmol, 1.0 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 498 pL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- ( Aminomethyl)-5-methyl-7V-(l-(naphthal en-l-yl)cy cl opropyl)-2, 3-dihy drobenzofuran-6- carboxamide (120 mg, 293 pmol, 17% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 373.3 (LCMS).

Step 3: (5)-2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopro pyl)-2,3- dihydrobenzofuran-6-carboxamide (Compound 235) and (7?)-2-(Aminomethyl)-5- methyl -N-( l-(naphthalen-l-yl)cyclopropyl)-2,3-dihydrobenzofuran-6-carb oxamide (Compound 236)

2-(Aminomethyl)-5-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)-2, 3-dihy drobenzofuran-6- carboxamide (120 mg, 293 pmol, HC1 salt) was further separated by SFC (DAICEL CHIRALPAK AD column (250 x 30 mm, 10 pm); flow rate: 3.4 mL/min; gradient: 42% - 42% B over 8 min; mobile phase A: CO2, mobile phase B: 0.1% isopropyl amine in EtOH). (R)-2-(Aminomethyl)-5-methyl-7V-(l -(naphthal en- 1 -yl)cy cl opropyl)-2, 3-dihy drobenzofuran- 6-carb oxamide (17.8 mg) was obtained as a white solid. M + H ⁺ = 373.1 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.47 - 8.42 (m, 1H), 7.95 - 7.85 (m, 2H), 7.82 - 7.76 (m, 1H), 7.64 - 7.40 (m, 3H), 6.87 (s, 1H), 6.53 (s, 1H), 4.88 - 4.65 (m, 1H), 3.17 (br dd, J= 9.2, 16.1 Hz, 1H), 3.00 - 2.71 (m, 3H), 2.09 (s, 3H), 1.57 - 1.51 (m, 2H), 1.42 - 1.34 (m, 2H). (S)-2- ( Aminomethyl)-5-methyl-7V-(l-(naphthal en-l-yl)cy cl opropyl)-2, 3-dihy drobenzofuran-6- carboxamide (15.4 mg) was obtained as a white solid. M + H ⁺ = 373.1 (LCMS); 'H NMR (400 MHz, CDCL) 6 8.47 - 8.42 (m, 1H), 7.95 - 7.85 (m, 2H), 7.82 - 7.76 (m, 1H), 7.64 - 7.40 (m, 3H), 6.87 (s, 1H), 6.53 (s, 2H), 4.88 - 4.65 (m, 1H), 3.17 (br dd, J= 9.2, 16.1 Hz, 1H), 3.00 - 2.71 (m, 3H), 2.09 (s, 3H), 1.57 - 1.51 (m, 2H), 1.42 - 1.34 (m, 2H). Example 159: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(quinoli n-5- yl)cyclopropyl)benzamide (Compound 230)

Compound 230

Step 1: tert-Butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l)-2,3- dihydrobenzofuran-2-yl)methyl)carbamate (159A-1)

To a solution of tert-butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoy l) benzofuran-2-yl)methyl)carbamate (60.0 mg, 61.9 pmol, 1.0 eq) in z-PrOH (20 mL) was added 10% palladium on carbon (60.0 mg). The mixture was degassed and purged with H2 three times and then the mixture was stirred at 25 °C for 4 h under a H2 atmosphere. LCMS indicated that 40% starting material still remained and 50% desired mass was detected. The combined organic layers were filtered through a pad of Celite and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.3). tert- Butylmethyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)car bamoyl)-2,3-dihydro benzofuran-2-yl)methyl) carbamate (40.0 mg, 41.1 pmol, 33% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 431.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.44 (d, J = 8.4 Hz, 1H), 7.92 (dd, J= 7.6, 15.7 Hz, 2H), 7.80 (d, J= 7.5 Hz, 1H), 7.61 - 7.44 (m, 3H), 6.90 (s, 1H), 6.54 (s, 1H), 6.43 (s, 1H), 4.99 - 4.84 (m, 1H), 3.67 - 3.48 (m, 1H), 3.22 - 3.11 (m, 1H), 2.93 - 2.88 (m, 3H), 2.85 (d, = 7.2 Hz, 1H), 2.81 (d, = 7.2 Hz, 1H), 2.10 (s, 3H), 1.44 (br s, 9H), 1.41 - 1.37 (m, 2H), 1.30 - 1.25 (m, 2H).

Step 2: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l-yl)cycl opropyl)-2,3- dihydrobenzofuran-6-carboxamide (Compound 230)

To a stirred solution of tert-butyl methyl((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)-2,3-dihydrobenzofuran-2-yl)methyl)carbamate (30.0 mg, 61.7 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-A-(l-(naphthalen-l- yl)cyclopropyl) -2,3-dihydrobenzofuran-6-carboxamide (8.20 mg, 19.0 pmol, 31% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 387.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.06 (s, 2H), 8.89 - 8.75 (m, 1H), 8.64 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.7 Hz, 1H), 7.81 (dd, J= 7.6, 13.6 Hz, 2H), 7.62 - 7.49 (m, 2H), 7.48 - 7.43 (m, 1H), 7.01 (s, 1H), 6.44 (s, 1H), 5.14 - 4.96 (m, 1H), 3.30 (dd, J= 9.4, 16.6 Hz, 1H), 3.23 - 3.14 (m, 1H), 3.08 (ddd, J= 4.6, 8.5, 12.7 Hz, 1H), 2.90 (dd, J= 6.5, 16.2 Hz, 1H), 2.56 (br t, J= 5.3 Hz, 3H), 1.98 (s, 3H), 1.33 (s, 2H), 1.24 - 1.10 (m, 2H).

Example 160: 2-((Dimethylamino)methyl)-5-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl)- 2,3-dihydrobenzofuran-6-carboxamide (Compound 224)

158A-2 Compound 224

Step 1: 2-((Dimethylamino)methyl)-5-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl)-2,3- dihydrobenzofuran-6-carboxamide (Compound 224)

To a solution of 2-(aminomethyl)-5-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)- 2,3- dihydrobenzofuran-6-carboxamide (101 mg, 270 pmol, 1.0 eq, HC1 salt) in MeOH (3.0 mL) was added TEA (50 pL), followed by the addition of formaldehyde (46.7 mg, 540 mmol, 59.1 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (33.9 mg, 540 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luma C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-((Dimethylamino)methyl)-5- methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)-2, 3 -dihydrobenzo furan-6-carboxamide (17.5 mg, 42.8 pmol, 16% yield HC1 salt) was obtained as a white solid. M + H ⁺ = 401.1 (LCMS); ^T H NMR (400 MHz, CDCh) 8 12.80 - 12.43 (m, 1H), 8.55 - 8.42 (m, 1H), 7.90 (br dd, J= 7.7, 11.2 Hz, 2H), 7.79 (br d, J= 8.1 Hz, 1H), 7.62 - 7.41 (m, 3H), 6.90 - 6.80 (m, 1H), 6.57 - 6.47 (m, 1H), 5.40 (br s, 1H), 3.47 - 3.24 (m, 2H), 3.19 - 3.05 (m, 1H), 2.98 - 2.83 (m, 6H), 2.79 - 2.68 (m, 1H), 2.11 - 1.97 (m, 3H), 1.63 - 1.47 (m, 2H), 1.44 - 1.30 (m, 2H).

Example 161: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-3-propyl-2,3- dihydrobenzofuran-6-carboxamide (Compound 397)

161A-4 Compound 397

Step 1: (Z)-Methyl 4-iodo-2-methyl-5-(pent-2-en-l-yloxy)benzoate (161 A-l)

A mixture of methyl 5-hydroxy-4-iodo-2-methylbenzoate (500 mg, 1.71 mmol, 1.0 eq) and (Z)-pent-2-en-l-ol (221 mg, 2.57 mmol, 1.5 eq) in toluene (25 mL) was degassed and purged with N2 three times. To the mixture was added CMBP (620 mg, 2.57 mmol, 1.5 eq) dropwise at 20 °C. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (Z)-Methyl 4-iodo-2-methyl-5-(pent-2-en- 1-yloxy) benzoate (400 mg, 1.11 mmol, 65% yield) was obtained as a colorless oil. M + H ⁺ = 361.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.77 (s, 1H), 7.35 - 7.27 (m, 1H), 5.70 - 5.50 (m, 2H), 4.73 - 4.58 (m, 2H), 3.84 - 3.78 (m, 3H), 2.44 - 2.35 (m, 3H), 2.17 - 2.08 (m, 2H), 1.00 - 0.94 (m, 3H).

Step 2: Methyl 5-methyl-3-propylbenzofuran-6-carboxylate (161A-2)

A mixture of methyl (Z)-methyl 4-iodo-2-methyl-5-(pent-2-en-l-yloxy)benzoate (500 mg, 1.71 mmol, 1.0 eq) in DMF (25 mL) was degassed and purged with N2 three times. To the mixture were added Pd(OAc)2 (24.9 mg, 111 pmol, 0.1 eq), TBAC (340 mg, 1.22 mmol, 342 pL, 1.1 eq) and sodium carbonate (294 mg, 2.78 mmol, 2.5 eq). The mixture was stirred at 100 °C for 18 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-methyl-3-propylbenzofuran-6-carboxylate (200 mg, 861 pmol, 78% yield) was obtained as a yellow oil. 'H NMR (400 MHz, DMSO-tL) 6 7.97 (s, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 3.87 - 3.81 (m, 3H), 2.64 - 2.57 (m, 5H), 1.74 - 1.59 (m, 2H), 0.96 - 0.91 (m, 3H).

Step 3: Methyl 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylate (161A-3)

To a solution of methyl 5-methyl-3-propylbenzofuran-6-carboxylate (160 mg, 689 pmol, 1.0 eq) in z-PrOH (10 mL) was added 10% palladium on carbon (100 mg). The mixture was degassed and purged with H2 three times. The resulting mixture was stirred at 20 °C for 16 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The combined organic layers were filtered through Celite pad and the filtrate was concentrated under vacuum to give the crude product methyl 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylate (80.0 mg, 341 pmol, 50% yield) as a yellow oil. M + H ⁺ = 235.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 7.31 (s, 1H), 7.03 (s, 1H), 4.65 (t, J= 8.8 Hz, 1H), 4.22 (dd, J= 6.6, 8.7 Hz, 1H), 3.87 (s, 3H), 3.52 - 3.35 (m, 1H), 2.53 (s, 3H), 1.82 - 1.71 (m, 1H), 1.61 - 1.32 (m, 3H), 0.97 (t, J= 7.3 Hz, 3H). Step 4: 5-Methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylic acid (161A-4)

To a solution of methyl 5-methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylate (80.0 mg, 196 pmol, 1.0 eq) in a mixture of MeOH (1.6 mL) and THF (3.2 mL) was added NaOH (2 M aqueous, 3.6 mL, 21 eq). The mixture was stirred at 70 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with MTBE (3.0 mL x 3). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-methyl-3-propyl- 2,3-dihydro benzofuran-6-carboxylic acid (80.0 mg) as a yellow oil, which was used in the next step without any further purification. 'H NMR (400 MHz, DMSO-tL) 6 12.57 (br s, 1H), 7.13 (d, J= 3.4 Hz, 2H), 4.62 (t, J = 8.9 Hz, 1H), 4.18 (dd, J = 6.7, 8.8 Hz, 1H), 3.49 - 3.39 (m, 1H), 2.43 (s, 3H), 1.35 (s, 4H), 0.91 (t, J= 7.2 Hz, 3H).

Step 5: 5-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-3-propyl-2,3-di hydrobenzofuran- 6-carboxamide (Compound 397)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (58.2 mg, 318 pmol, 1.0 eq) and 5- methyl-3-propyl-2,3-dihydrobenzofuran-6-carboxylic acid (70.0 mg, 318 pmol, 1.0 eq) in DMF (8 mL) were added TEA (64.3 mg, 636 pmol, 88.5 pL, 2 eq), EDCI (73.1 mg, 381 pmol, 1.2 eq) and HOBt (51.5 mg, 381 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 40% - 70% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Methyl-7V-(l-(naphthalen-l-yl) cyclopropyl)-3-propyl-2,3-dihydrobenzofuran-6-carboxamide (45.5 mg, 117 pmol, 37% yield) was obtained as a white solid. M + H ⁺ = 386.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.01 (s, 1H), 8.64 (d, J= 8.4 Hz, 1H), 7.92 (d, J= 7.8 Hz, 1H), 7.81 (dd, J= 7.7, 10.8 Hz, 2H), 7.60 - 7.42 (m, 3H), 6.96 (s, 1H), 6.41 (s, 1H), 4.54 (t, J = 8.9 Hz, 1H), 4.11 (dd, J= 6.4, 8.7 Hz, 1H), 3.39 - 3.33 (m, 1H), 1.95 (s, 3H), 1.67 - 1.56 (m, 1H), 1.46 - 1.24 (m, 5H), 1.16 (br d, J = 3.5 Hz, 2H), 0.92 - 0.84 (m, 3H). Example 162: 6-Methyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-lH-indole-5-carboxamide (Compound 223)

Step 1: 6-Methyl-/V-( l-(naphthalen-l-yl)cyclopropyl)-LH-indole-5-carboxamide (Compound 223)

To a mixture of 6-methyl-U/-indole-5-carboxylic acid (60.0 mg, 343 pmol, 1.0 eq) and 1- (naphthalen-l-yl)cyclopropanamine (62.8 mg, 343 pmol, 8.75 pL, 1.0 eq) in DCM (5.0 mL) was added TEA (104 mg, 1.03 mmol, 143 pL, 3.0 eq), followed by EDCI (98.5 mg, 514 pmol, 1.5 eq) and HOBt (69.4 mg, 514 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 45% - 75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 6-Methyl- A-(l-(naphthalen-l-yl)cyclopropyl)-U/-indole-5-carboxamide (64.2 mg, 186 pmol, 54% yield) was obtained as a white solid. M + H ⁺ = 341.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 11.08 - 10.87 (m, 1H), 9.01 - 8.90 (m, 1H), 8.78 - 8.64 (m, 1H), 7.97 - 7.91 (m, 1H), 7.87 - 7.79 (m, 2H), 7.63 - 7.43 (m, 3H), 7.32 - 7.28 (m, 1H), 7.27 - 7.18 (m, 1H), 7.13 - 7.05 (m, 1H), 6.37 - 6.31 (m, 1H), 2.22 - 2.15 (m, 3H), 1.43 - 1.30 (m, 2H), 1.22 - 1.11 (m, 2H). Example 163: 2-(Am inoniel Iiyl )-5-niel Iiyl-\-( 1 -( naplil Iialen- 1 -yl )cyclopropyl )- 1 //- benzo [J|imidazole-6-carboxamide (Compound 280) Compound 280

Step 1: Methyl 5-amino-4-(2-((tert-butoxycarbonyl)amino)acetamido)-2-methyl benzoate (163A-1)

To a solution of methyl 4,5-diamino-2-methylbenzoate (300 mg, 1.66 mmol, 1.0 eq) and 2- ((/c77-butoxycarbonyl)amino)acetic acid (292 mg, 1.66 mmol, 1.0 eq) in THF (9.0 mL) was added TV, jV-methanediylidenedicyclohexanamine (687 mg, 3.33 mmol, 674 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/4. Methyl

5-amino-4-(2-((tert-butoxycarbonyl)amino)acetamido)-2-met hylbenzoate (200 mg, 593 mmol, 53% yield) was obtained as a white solid. M + H ⁺ = 338.3 (LCMS); NMR (400 MHz, CDCh) 6 7.95 (s, 1H), 7.80 (s, 1H), 6.56 (s, 1H), 5.40(br t, J = 5.7 Hz, 1H), 3.94 (d, J = 5.7 Hz, 2H), 3.81 (s, 3H), 2.51 (s, 3H), 1.48 (s, 9H).

Step 2: Methyl 2-(((/c/7-biitoxycarboiiyl)ainiiio)inethyl)-5-inetliyl-l//-b eiizo|7|imidazole- 6-carboxylate (163A-2)

A solution of methyl 5-amino-4-(2-((tert-butoxycarbonyl)amino)acetamido)-2- methylbenzoate (200 mg, 593 pmol, 1.0 eq) in acetic acid (7.0 mL) was stirred at 80 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product methyl 2-(((lerl- butoxycarbonyl)amino)methyl)-5-methyl-U/-benzo[J]imidazole-6 -carboxylate (200 mg) was obtained as a white solid. M + H ⁺ = 320.3 (LCMS).

Step 3: 2-(((/c/7-Biitoxycarbonyl):iinino)niethyl)-5-niethyl-l //-benzo|7|iinidazole-6- carboxylic acid (163A-3)

To a solution of methyl 2-(((/c/7-butoxy carbonyl)amino)methyl)-5-m ethyl- IT/-benzo[t/] imidazole-6-carboxylate (180 mg, 564 pmol, 1.0 eq) in a mixture of H2O (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 845 pL, 3.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with MTBE (15 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(((terLbutoxycarbonyl)amino)methyl)-5-methyl- U/-benzo[ d]imidazole-6- carboxylic acid (150 mg), which was used in the next step without any further purification. M + H ⁺ = 306.3 (LCMS).

Step 4: tert-Butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-lH- benzo [J|imidazol-2-yl)methyl)carbamate (163A-4)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (32.7 mg, 179 pmol, 0.8 eq) and 2- (((/c/7-butoxycarbonyl)amino)methyl)-5-methyl- l7/-benzo[t/]imidazole-6-carboxylic acid (100 mg, 328 pmol, 1.0 eq) in DCM (10 mL) were added TEA (45.2 mg, 446 pmol, 62.1 pL, 2.0 eq), EDCI (51.3 mg, 268 pmol, 1.2 eq) and HOBt (36.2 mg, 268 pmol, 1.2 eq). The mixture was stirred at 20 °C for 18 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1 , R/= 0.7). Zc/V-Butyl ((5 -methyl-6-((l -(naphthal en-1- yl) cyclopropyl)carbamoyl)-U/-benzo[J]imidazol-2-yl)methyl)carba mate (100 mg, crude) was obtained as a colorless oil. M + H ⁺ = 471.3 (LCMS).

Step 5: 2-(Aminomethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) -LH-benzo[ | imidazole-6-carboxamide (Compound 280)

To a stirred solution of tert-butyl ((5-methyl-6-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)- U/-benzo[J]imidazol-2-yl)methyl)carbamate (30.0 mg, 63.8 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B : acetonitrile). 2-(Aminomethyl)-5-methyl-7V-( 1 -(naphthal en- 1 -yl )cycl opropyl )- l 7/- benzo[t ]imidazole-6-carboxamide (11.7 mg, 31.6 pmol, 50% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 371.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 8 9.15 (s, 1H), 8.73 - 8.54 (m, 4H), 7.95 (d, J= 7.8 Hz, 1H), 7.83 (dd, J= 2.7, 7.7 Hz, 2H), 7.62 - 7.51 (m, 2H), 7.47 (t, J= 7.6 Hz, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 4.30 (br s, 2H), 2.19 (s, 3H), 1.39 (s, 2H), 1.23 - 1.14 (m, 2H).

Example 164: 2-(Aminomethyl)-6-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) benzo[ | thiazole-5-carboxamide (Compound 245) p

20A-1 Stepl 164A-1

Compound 245

Step 1: Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[</|t hiazole-5- carboxylate (164A-1)

A mixture of methyl 5-amino-4-iodo-2-methylbenzoate (300 mg, 1.03 mmol, 1.0 eq), tert-butyl (2-amino-2-thioxoethyl)carbamate (196 mg, 1.03 mmol, 1.0 eq) and CuO (82.0 mg, 1.03 mmol, 1.0 eq) in DMF (6.0 mL) was degassed and purged with N2 three times. Pd2(dba)3 (18.9 mg, 21.6 pmol, 1.1 eq) and DPPF (28.6 mg, 51.5 pmol, 0.05 eq) were added and the mixture was stirred at 60 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/3. Methyl 2-(((tert-butoxycarbonyl)amino)methyl)-6- methylbenzo[d]thiazole-5-carboxylate (340 mg, 1.11 mmol, 99% yield) was obtained as a white solid. M + H ⁺ = 337.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 8.32 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 4.51 (br d, J= 6.1 Hz, 2H), 3.87 (s, 3H), 2.61 (s, 3H), 1.42 (s, 9H).

Step 2: 2-(((tert-Butoxycarbonyl)amino)methyl)-6-methylbenzo[J|thiaz ole-5-carboxylic acid (164A-2)

To a solution of methyl 2-(((tert-butoxycarbonyl)amino)methyl)-6-methylbenzo[J]thiaz ole-5- carboxylate (340 mg, 1.11 mmol, 1.0 eq) in a mixture of THF (10 mL) and H2O (5.0 mL) was added LiOH.H2O (102 mg, 2.71 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and washed with MTBE (15 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (I M aqueous). The product was extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-(((terLbutoxycarbonyl)amino)methyl)- 6-rnethylbenzo[d]thiazole-5-carboxylic acid (340 mg), which was used in the next step without any further purification. M + H ⁺ = 323.0 (LCMS).

Step 3: tert-Butyl((6-methyl-5-((l-(naphthalen-l-yl)cyclopropyl)carb amoyl)benzo[ ] thiazol-2-yl)methyl)carbamate (164A-3)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (56.8 mg, 310 pmol, 1.0 eq) and 2- (((ter/-butoxycarbonyl)amino)methyl)-6-methylbenzo[ ]thiazole-5-carboxylic acid (100 mg, 310 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (94.2 mg, 931 pmol, 130 pL, 3.0 eq), EDCI (119 mg, 620 pmol, 2.0 eq) and HOBt (83.8 mg, 620 pmol, 2.0 eq). The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tert-butyl((6-methyl-5-((l- (naphthalen- l -yl)cy cl opropyl)carbam oyl )benzo[t/]thi azol -2-yl )methyl)carbam ate (110 mg), which was used in the next step without any further purification. M + H ⁺ = 488.3 (LCMS).

Step 4: 2-(Aminomethyl)-6-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) benzo[J]thiazole- 5-carboxamide (Compound 245)

To a stirred solution of ZerLbutyl((6-methyl-5-((l-(naphthalen-l-yl)cyclopropyl)carba moyl) benzo[d]thiazol-2-yl)methyl)carbamate (100 mg, 205 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 5% - 35% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-(Aminomethyl)-6-methyl-A-(l -(naphthal en-l-yl)cyclopropyl) benzo [ ]thiazole-5-carboxamide (74.7 mg, 173 pmol, 84% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 388.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 9.32 (s, 1H), 8.78 - 8.53 (m, 4H), 7.99 - 7.93 (m, 2H), 7.85 (t, J = 7.9 Hz, 2H), 7.65 - 7.45 (m, 4H), 4.58 (br s, 2H), 2.21 (s, 3H), 1.46 - 1.20 (m, 4H). Example 165: 6-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-oxo-2,3-dihyd ro-lH- benzo [ |imidazole-5-carboxamide (Compound 238)

165A-2 Compound 238

Step 1: Methyl 6-methyl-2-oxo-2.3-dihydro-l//-benzo| |imid:izole-5-c:irboxyl:ite (165A- 1)

To a solution of methyl 4,5-diamino-2-methylbenzoate (400 mg, 2.22 mmol, 1.0 eq) in MeCN (40 mL) was added CDI (396 mg, 2.44 mmol, 1.1 eq). The resulting mixture was stirred at 70 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. Methyl 6- methyl-2-oxo-2,3-dihydro-U/-benzo[J]imidazole-5-carboxylate (340 mg, 1.65 mmol, 74% yield) was obtained as a white solid. M + H ⁺ = 207.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 10.89 (br s, 1H), 10.71 (s, 1H), 7.41 (s, 1H), 6.84 (s, 1H), 3.78 (s, 3H), 2.55 - 2.52 (m, 3H).

Step 2: 6-Methyl-2-oxo-2.3-dihydro-l //-benzo| |iniidazole-5-carboxylic acid (165A-2)

To a solution of methyl 6-methyl-2-oxo-2,3 -dihydro- U/-benzo[t ]imidazole-5 -carboxylate (120 mg, 582 pmol, 1.0 eq) in MeOH (5.0 mL) was added NaOH (2 M aqueous, 1.08 mL, 3.5 eq). The mixture was stirred at 50 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (3.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 6-methyl-2-oxo-2,3-dihydro-l//-benzo[J]imidazole-5-carboxyli c acid (110 mg) as a white solid. M + H ⁺ = 193.2 (LCMS).

Step 3: 6-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-oxo-2,3-dihyd ro-LH-benzo[ | imidazole-5-carboxamide (Compound 238)

To a solution of l-(naphthalen-l-yl)cyclopropanamine (105 mg, 572 pmol, 1.0 eq) and 6- methyl-2-oxo-2,3-dihydro-l//-benzo[t/]imidazole-5-carboxylic acid (110 mg, 572 pmol, 1.0 eq) in DCM (18 mL) were added TEA (174 mg, 1.72 mmol, 239 pL, 3.0 eq), EDCI (219 mg, 1.14 mmol, 2.0 eq) and HOBt (155 mg, 1.14 mmol, 2.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 6-Methyl- A-(l-(naphthalen-l-yl)cyclopropyl)-2-oxo-2,3-dihydro-l//-ben zo[J]imidazole-5- carboxamide (20.0 mg, 56.0 pmol, 10% yield) was obtained as a white solid. M + H ⁺ = 358.1 (LCMS); flT NMR (400 MHz, DMSO ) 8 10.59 (s, 1H), 10.49 (s, 1H), 8.99 (s, 1H), 8.67 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.4 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.62 - 7.42 (m, 3H), 6.64 (d, J = 13.0 Hz, 2H), 2.07 (s, 3H), 1.40 - 1.29 (m, 2H), 1.20 - 1.08 (m, 2H).

Example 166: l,3,6-Trimethyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-2-oxo-2, 3-dihydro- lH-benzo[ |imidazole-5-carboxamide (Compound 237)

Step 1 Step 2

165A-1 166A-1

166A-2 Compound 237

Step 1: Methyl 1.3.6-1 riniet hyl-2-oxo-2.3-dihydro- 1 //-benzo |7| ini idazole-5-carboxylate (166A-1)

To a solution of methyl 6-methyl-2-oxo-2,3 -dihydro- l//-benzo[t/]imidazole-5 -carboxylate (100 mg, 485 pmol, 1.0 eq) in DMF (5.0 mL) were added CH3I (413 mg, 2.91 mmol, 181 pL, 6.0 eq) and K2CO3 (402 mg, 2.91 mmol, 6.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.2). Methyl l,3,6-trimethyl-2-oxo-2,3-dihydro-l//-benzo[J]imidazole-5-ca rboxylate (88.0 mg, 376 pmol, 77% yield) was obtained as a white solid. M + H ⁺ = 235.2 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 7.59 (s, 1H), 7.11 (s, 1H), 3.82 (s, 3H), 3.34 (s, 6H), 2.58 (s, 3H).

Step 2: 1.3.6- l r ini et hyl-2-oxo-2.3-d ihy dr o-l //-benzo |7|iin idazole-5-car boxy lie acid (166A-2)

To a solution of methyl l,3,6-trimethyl-2-oxo-2,3-dihydro-l//-benzo[t/]imidazole-5- carboxylate (70.0 mg, 299 pmol, 1.0 eq) in MeOH (3.5 mL) was added NaOH (2 M aqueous, 523 pL, 3.5 eq). The mixture was stirred at 50 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (3.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 5), the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product l,3,6-trimethyl-2-oxo-2,3-dihydro-U/-benzo[t/]imidazole-5-ca rboxylic acid (60.0 mg) as a white solid. M + H ⁺ = 221.0 (LCMS). Step 3: 1 >-Triinethyl-\-( l-(iiaplithalen-l-yl)cyclopropyl)-2-oxo-2.3-dihydro-l //-benzo [</|imidazole-5-carboxamide (Compound 237)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (83.2 mg, 454 pmol, 1.0 eq) and 1,3,6- trimethyl-2-oxo-2,3-dihydro-17/-benzo[t ]imidazole-5-carboxylic acid (100 mg, 454 pmol, 1.0 eq) in DCM (15 mL) were added TEA (138 mg, 1.36 mmol, 190 pL, 3.0 eq), EDCI (174 mg, 908 pmol, 2.0 eq) and HOBt (123 mg, 908 pmol, 2.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 1,3,6- Trimethyl-A-(1 -(naphthal en-l-yl)cy cl opropyl)-2-oxo-2, 3-dihy dro-l//-benzo[t/]imidazole-5- carboxamide (36.8 mg, 95.5 pmol, 21% yield) was obtained as a white solid. M + H ⁺ = 386.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.00 (s, 1H), 8.69 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.84 (dd, J= 3.7, 7.6 Hz, 2H), 7.61 - 7.44 (m, 3H), 6.91 (d, J= 5.0 Hz, 2H), 3.26 (d, J= 8.4 Hz, 6H), 2.10 (s, 3H), 1.42 - 1.34 (m, 2H), 1.23 - 1.15 (m, 2H).

Example 167: 7-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-l,2,3,4- tetrahydroquinoxaline-6-carboxamide (Compound 297)

167A-2 167A-3

167A-4 Compound 297

Step 1: Methyl 7-methyl-l,2,3,4-tetrahydroquinoxaline-6-carboxylate (167A-1)

To a solution of methyl 4,5-diamino-2-methylbenzoate (400 mg, 2.22 mmol, 1.0 eq) in DMA (8.0 mL) were added NaHCCh (1.86 g, 22.2 mmol, 10 eq) and 1,2-dibromoethane (500 mg, 2.66 mmol, 200 pmL, 1.2 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 7-methyl-l,2,3,4-tetrahydro quinoxaline-6-carboxylate (200 mg, 969 prnol, 44% yield) was obtained as a yellow solid. M + H ⁺ = 207.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 7.01 (s, 1H), 6.18 (s, 1H), 6.12 (br s, 1H), 5.36 (br s, 1H), 3.67 (s, 3H), 3.26 (br d, J= 2.8 Hz, 2H), 3.16 - 3.10 (m, 2H), 1.96 (s, 3H).

Step 2: 1-tert-Butyl 7-methyl 6-methyl-3,4-dihydroquinoxaline-l,7(2ZZ)-dicarboxylate (167A-2)

To a solution of methyl 7-methyl-l,2,3,4-tetrahydroquinoxaline-6-carboxylate (200 mg, 969 prnol, 1.0 eq) in DMF (20 mL) was added sodium hydride (96.9 mg, 2.42 mmol, 60% purity, 2.5 eq) at 0 °C, followed by di-/c/7-butyl dicarbonate (529 mg, 2.42 mmol, 557 pL, 2.5 eq). The resulting mixture was stirred at 25 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1-tert-Butyl 7-methyl 6-methyl-3,4-dihydroquinoxaline-l,7(2J7)-dicarboxylate (150 mg, 489 pmol, 50% yield) was obtained as a yellow gum. 'H NMR (400 MHz, DMSO-tL) 6 7.99 (s, 1H), 6.82 (br s, 1H), 6.39 (s, 1H), 3.71 (s, 3H), 3.58 (br t, J= 4.9 Hz, 2H), 3.28 (br d, J= 3.0 Hz, 2H), 2.38 (s, 3H), 1.46 (s, 9H). Step 3: 4-(tert-Butoxycarbonyl)-7-methyl-l,2,3,4-tetrahydroquinoxali ne-6-carboxylic acid (167A-3)

To a solution of 1 -tert-butyl 7-methyl 6-methyl-3,4-dihydroquinoxaline-l,7(2rt)-dicarboxylate (150 mg, 489 pmol, 1.0 eq) in a mixture of THF (7.5 mL) and MeOH (7.5 mL) was added NaOH (2 M aqueous, 1.22 mL, 5.0 eq). The resulting mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and adjust the pH to 6 using HC1 (I M aqueous), and a precipitate was formed. The mixture was filtered, and the filter cake was washed with H2O (5.0 mL) and dried under vacuum to give 4-(tert-butoxycarbonyl)-7-methyl- l,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (100 mg, 342 pmol, 70% yield) as an orange solid, which was used in the next step without any further purification. M - H“ = 291.0 (LCMS).

Step 4: tert-Butyl 6-methyl-7-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-3,4-d ihydro quinoxaline- l(2ZZ)-carboxylate (167A-4)

To a solution of 4-(tert-butoxycarbonyl)-7-methyl-l,2,3,4-tetrahydroquinoxali ne-6-carboxylic acid (100 mg, 342 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (62.7 mg, 342 pmol, 1.0 eq) in DMF (10 mL) were added TEA (104 mg, 1.03 mmol, 143 pL, 3.0 eq), EDCI (78.7 mg, 411 pmol, 1.2 eq) and HOBt (55.5 mg, 411 pmol, 1.2 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL), and a precipitate was formed. The mixture was filtered and the filter cake was washed with H2O (5.0 mL) and dried under vacuum to give tert-butyl 6-methyl-7-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl) -3,4-dihydroquin oxaline- l (2rt)-carboxylate (130 mg, 284 pmol, 83% yield) as an orange solid. M + H ⁺ = 458.2 (LCMS).

Step 5: 7-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-l,2,3,4-tetrahy droquinoxaline-6- carboxamide (Compound 297)

To a solution of tert-butyl 6-methyl-7-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-3,4- dihydroquin oxaline- l (2rt)-carboxylate (130 mg, 284 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 10 mL). The resulting mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated at 30 °C under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7-Methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-l, 2,3,4- tetrahydroquinoxaline-6-carboxamide (35.9 mg, 90.5 pmol, 32% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 358.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.93 (br s, 1H), 8.65 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.87 - 7.74 (m, 2H), 7.63 - 7.37 (m, 3H), 6.83 - 6.66 (m, 1H), 6.46 (br s, 1H), 3.40 - 3.25 (m, 4H), 1.99 (s, 3H), 1.32 (br s, 2H), 1.15 (br s, 2H).

Example 168: 6-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-l,2,3,4- tetrahydroquinoline-7-carboxamide (Compound 227)

Step 3

168A-2 Compound 227

Step 1: Methyl 6-methyl-l,2,3,4-tetrahydroquinoline-7-carboxylate (168A-1)

To a solution of methyl 6-methylquinoline-7-carboxylate (51.0 mg, 254 pmol, 1.0 eq) in i- PrOH (12 mL) was added 10% palladium on carbon (10 mg, 254 pmol, 1.0 eq) at 20 °C under a N2 atmosphere. The mixture was degassed and purged with H2 three times, then stirred at 50 °C for 4 h under a H2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was allowed to cool to room temperature, filtered through a pad of Celite and the filter cake was washed with i- PrOH (4.0 mL x 3). The combined filtrates were concentrated to give the crude product methyl 6-methyl-l,2,3,4-tetrahydroquinoline-7-carboxylate (70.0 mg), which was used in the next step without any further purification. M + H ⁺ = 206.2 (LCMS).

Step 2: 6-Methyl-l,2,3,4-tetrahydroquinoline-7-carboxylic acid (168A-2)

To a solution of methyl 6-methyl-l,2,3,4-tetrahydroquinoline-7-carboxylate (70.0 mg, 341 pmol, 1.0 eq) in THF (2.0 mL) was added a mixture of LiOH (24.5 mg, 1.02 mmol, 3.0 eq) in H2O (1.0 mL). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with MTBE (1.0 mL x 3). The aqueous layer was basified to pH 5 using HC1 (1 M aqueous) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 6-methyl-l,2,3,4-tetrahydroquinoline-7-carboxylic acid (50.0 mg), which was used in the next step without any further purification. M + H ⁺ = 192.1 (LCMS).

Step 3: 6-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-l,2,3,4-tetrahy droquinoline-7-carb oxamide (Compound 227)

To a solution of 6-methyl-l,2,3,4-tetrahydroquinoline-7-carboxylic acid (26.1 mg, 136 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (25.0 mg, 136 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (41.1 mg, 409 pmol, 57.0 pL, 3.0 eq), EDCI (65.4 mg, 341 pmol, 1.5 eq) and HOBt (46.1 mg, 341 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 6-Methyl-A-(l -(naphthal en-1- yl)cyclopropyl)-l,2,3,4-tetrahydro quinoline-7-carboxamide (11.5 mg, 28.2 pmol, 10% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 357.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 9.04 (br s, 1H), 8.63 (d, J= 8.3 Hz, 1H), 7.96 - 7.90 (m, 1H), 7.86 - 7.77 (m, 2H), 7.61 - 7.42 (m, 3H), 6.88 - 6.78 (m, 1H), 6.61 - 6.49 (m, 1H), 3.25 - 3.12 (m, 3H), 1.93-1.71 (s, 6H), 1.33 (br s, 2H), 1.22 - 1.11 (m, 2H).

Example 169: 7-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-3-oxo-l, 2,3,4- tetrahydrocyclopenta[/>]indole-6-carboxamide (Compound 334)

Step 1: 3-(6-(Methoxycarbonyl)-5-methyl-lH-indol-3-yl)propanoic acid (169A-1)

To a solution of methyl 5 -methyl- I T/-indole-6-carboxylate (400 mg, 2.11 mmol, 1.0 eq) in AcOH (2 mL) were added acetyl acetate (432 mg, 4.23 mmol, 396 pL, 2.0 eq) and acrylic acid (381 mg, 5.29 mmol, 2.5 eq). The mixture was stirred at 50 °C for 72 h. LCMS indicated that 40% of the starting material remained and 50% of the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 3-(6- (Methoxycarbonyl)-5-methyl-17/-indol-3-yl)propanoic acid (200 mg, 765 pmol, 36% yield) was obtained as a pale yellow solid. M + H ⁺ = 262.2 (LCMS).

Step 2: Methyl 3-(3-chloro-3-oxopropyl)-5-methyl-l H-indole-6-carboxylate (169A-2)

To a solution of 3-(6-methoxycarbonyl-5-methyl-lJ/-indol-3-yl)propanoic acid (170 mg, 651 pmol, 1.0 eq) in DCM (4.0 mL) was added SOCh (310 mg, 2.60 mmol, 189 pL, 4.0 eq) under a N2 atmosphere. The mixture was stirred at 20 °C for 1 h. LCMS (the sample was quenched with MeOH) indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give methyl 3-(3- chloro-3-oxopropyl)-5-methyl-17/-indole-6-carboxylate (180 mg) as a brown solid, which was used in the next step without any further purification. M+ H ⁺ = 276.2 (LCMS). Step 3: Methyl 7-methyl-3-oxo-l,2,3,4-tetrahydrocyclopenta[/>]indole-6-c arboxylate (169A-3)

To a solution of AlCh (343 mg, 2.57 mmol, 141 pL, 4.0 eq) in DCE (10 mL) was added methyl 3-(3-chloro-3-oxopropyl)-5-methyl-U/-indole-6-carboxylate (180 mg, 644 pmol, 1.0 eq). The mixture was stirred at 20 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NaHCOs (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.6). Methyl 7-methyl-3-oxo-

1.2.3.4-tetrahydrocyclopenta[Z>]indole-6-carboxylate (50.0 mg) was obtained as a crude brown solid. M + H ⁺ = 244.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.86 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 3.85 (s, 3H), 3.06 - 3.01 (m, 2H), 2.96 - 2.90 (m, 2H), 2.58 (s, 3H).

Step 4: 7-Methyl-3-oxo-l,2,3,4-tetrahydrocyclopenta[/>]indole-6-c arboxylic acid (169A-4)

To a solution of 7-methyl-3-oxo-l,2,3,4-tetrahydrocyclopenta[Z>]indole-6-c arboxylate (40.0 mg, 164 pmol, 1.0 eq) in a mixture of THF (3.0 mL) and H2O (1.0 mL) was added NaOH (32.9 mg, 822 pmol, 5.0 eq). The mixture was stirred at 80 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H2O (5.0 mL) and washed with MTBE (5.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 7-methyl-3-oxo-

1.2.3.4-tetrahydrocyclopenta[Z>]indole-6-carboxylic acid (37.0 mg), which was used in the next step without any further purification. M - H“ = 227.8 (LCMS).

Step 5: 7-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-3-oxo-l,2,3,4-t etrahydrocyclopenta [Z>]indole-6-carboxamide (Compound 334)

To a solution of 7-methyl-3-oxo-l,2,3,4-tetrahydrocyclopenta[Z>]indole-6-c arboxylic acid (30.0 mg, 130 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (24.0 mg, 131 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (40.0 mg, 393 pmol, 54.7 pL, 3.0 eq), EDCI (62.7 mg, 327 pmol, 2.5 eq) and HOBt (44.2 mg, 327 pmol, 2.5 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 65% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 7 -Methyl - N-( 1 -(naphthal en- 1 -yl)cy clopropyl)-3 -oxo- 1 ,2,3 ,4-tetrahydrocyclopenta[Z>]indole-6- carboxamide (20.0 mg, 49.5 pmol, 38% yield) was obtained as a white solid. M + H ⁺ = 395.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 1.57 (s, 1H), 9.22 (s, 1H), 8.69 (br d, J= 7.8 Hz, 1H), 7.95 (br d, J= 7.6 Hz, 1H), 7.84 (br d, J= 7.6 Hz, 2H), 7.68 - 7.45 (m, 4H), 7.11 (s, 1H), 2.97 (br s, 2H), 2.86 (br s, 2H), 2.14 (s, 3H), 1.38 (br s, 2H), 1.19 (br s, 2H).

Example 170: 7-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-3-oxo-2,3,9,9a- tetrahydro- lH-imidazo[l,5-a]indole-6-carboxamide (Compound 194)

Compound 190 Compound 194

Step 1 : 7-Met hyl- \-( 1 -( napht halen- 1 -yl)cyclopropyl )-3-oxo-2.3.9.9a-tet rahydro- 1 //- imidazo[l,5-a]indole-6-carboxamide (Compound 194)

To a solution of 2-(aminomethyl)-5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl) indoline-6- carboxamide (90.0 mg, 185 pmol, 1.0 eq, TFA salt) and TEA (467 mg, 4.62 mmol, 643 pL, 25 eq) in acetonitrile (12 mL) at 0 °C was added a solution of triphosgene (55.0 mg, 185 pmol, 1.0 eq) in acetonitrile (3.0 mL) over 5 min under a N2 atmosphere. The mixture was stirred at the same temperature for another 20 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into aqueous NaOH (0.05 M, 60 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 40% - 60% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7-Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-3- oxo-2,3,9,9a-tetrahydro-U/-imidazo[l,5-a]indole-6-carboxamid e (14.6 mg, 33.3 pmol, 18% yield) was obtained as a white solid. M + H ⁺ = 398.0 (LCMS); ^T H NMR (400 MHz, DMSO- d ₆ ) 6 9.08 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.7 Hz, 1H), 7.82 (dd, J= 2.4, 7.8 Hz, 2H), 7.60 - 7.42 (m, 3H), 7.02 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.57 (dd, J = 6.8, 8.9 Hz, 1H), 3.67 (t, J= 9.2 Hz, 1H), 3.27 (br dd, J= 6.9, 9.1 Hz, 1H), 3.16 (dd, J= 9.2, 16.4 Hz, 1H), 2.92 (dd, J= 8.9, 16.5 Hz, 1H), 1.95 (s, 3H), 1.41 - 1.30 (m, 2H), 1.26 - 1.07 (m, 2H).

Example 171: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-fluorophenyl)cyclopropy l)-2- methylbenzamide (Compound 272)

Step 2

Compound 272

Step 1: l-(2-Fluorophenyl)cyclopropanamine (171A-2)

A solution of 2-fluorobenzonitrile (1.00 g, 8.26 mmol, 1.0 eq) in anhydrous Et20 (50 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (2.35 g, 8.26 mmol, 2.44 mL, 1.0 eq) slowly at -78 °C, and then EtMgBr (3 M in Et20, 6.06 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (2.34 g, 16.5 mmol, 2.04 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (10 mL), and extracted with MTBE (30 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(2-Fluorophenyl)cyclopropanamine (400 mg, 2.65 mmol, 32% yield) was obtained as a colorless oil. M + H ⁺ = 152.1 (LCMS). Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-fluorophenyl)cyclopropy l)-2-methyl benzamide (Compound 272)

To a solution of l-(2-fluorophenyl)cyclopropanamine (100 mg, 483 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (108 mg, 483 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (147 mg, 1.45 mmol, 202 pL, 3.0 eq), EDCI (139 mg, 724 pmol, 1.5 eq) and HOBt (78.0 mg, 724 pmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l-(2- fluorophenyl) cyclopropyl)-2-methyl benzamide (109 mg, 288 pmol, 60% yield) was obtained as a white solid. M + H ⁺ = 357.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.23 - 10.10 (m, 1H), 8.98 (s, 1H), 7.62 - 7.55 (m, 1H), 7.32 - 7.24 (m, 1H), 7.17 - 7.09 (m, 3H), 6.94 (dd, J= 2.7, 8.3 Hz, 1H), 6.83 (d, J= 2.8 Hz, 1H), 4.30 (t, J= 4.9 Hz, 2H), 3.47 (q, J= 52 Hz, 2H), 2.82 (d, J= 4.9 Hz, 6H), 2.12 (s, 3H), 1.23 - 1.17 (m, 2H), 1.17 - 1.13 (m, 2H).

Example 172: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-fluorophenyl)cyclopropy l)-2- methylbenzamide (Compound 252)

Step 3

172A-2 Compound 252

Step 1: Methyl 5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (172A-1)

A mixture of methyl 5 -hydroxy -2-methylbenzoate (5.00 g, 30.1 mmol, 1.0 eq), 2- (dimethylamino)ethanol (2.68 g, 30.1 mmol, 3.02 mL, 1.0 eq), TMAD (10.4 g, 60.2 mmol, 2.0 eq) and PPh ₃ (15.8 g, 60.2 mmol, 2.0 eq) in toluene (150 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. Methyl 5-(2- (dimethylamino)ethoxy)-2-methylbenzoate (6.00 g, 25.3 mmol, 84% yield) was obtained as a white solid. ^X H NMR (400 MHz, CD ₃ OD) 8 7.43 (d, J= 2.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.03 (dd, J= 2.8, 8.4 Hz, 1H), 4.18 - 4.03 (m, 2H), 3.87 (s, 3H), 2.76 (t, J= 5.4 Hz, 2H), 2.47 (s, 3H), 2.34 (s, 6H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methylbenzoic acid (172A-2)

A solution of methyl 5-(2-(dimethylamino)ethoxy)-2-methylbenzoate (4.00 g, 16.8 mmol, 1.0 eq) in HC1 (2 M aqueous, 20 mL) was stirred at 110 °C for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, basified to pH 6 using NaOH (2 M aqueous) the mixture was concentrated under vacuum to give the crude product 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (2.00 g, HC1 salt) as a white solid.

Step 3: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-fluorophenyl)cyclopropy l)-2-methylbenza mide (Compound 252)

To a stirred solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (50.0 mg, 224 prnol, 1.0 eq) and l-(3-fluorophenyl)cyclopropanamine (33.9 mg, 224 pmol, 1.0 eq) in DMF (1.0 mL) were added EDCI (64.4 mg, 336 pmol, 1.5 eq), HOBt (45.4 mg, 336 pmol, 1.5 eq) and TEA (68.0 mg, 672 pmol, 3.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-(2- (dimethylamino)ethoxy)-7V-(l -(3 -fluorophenyl)cy cl opropyl)-2-m ethylbenzamide (8.60 mg, 24.1 pmol, 11% yield, HC1 salt) as a white solid. M + H ⁺ = 357.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 12.90 - 12.56 (m, 1H), 7.17 - 7.04 (m, 5H), 6.94 - 6.86 (m, 2H), 4.55 (br d, J = 1.1 Hz, 2H), 3.55 - 3.36 (m, 2H), 2.92 (br s, 6H), 2.36 (s, 3H), 1.48 - 1.35 (m, 4H).

Example 173: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(4-fluorophenyl)cyclopropy l)-2- methylbenzamide (Compound 259)

Step 1

172A-2 Compound 259

Step 1 : 5-(2-(Dimethylamino)ethoxy)-/V-(l-(4-fluorophenyl)cyclopropy l)-2-methyl benzamide (Compound 259)

To a solution of l-(4-fluorophenyl)cyclopropanamine (100 mg, 661 pmol, 1.2 eq) and 5-(2- ((ter/-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (123 mg, 551 pmol, 1.0 eq) in DCM (1.0 mL) were added TEA (167 mg, 1.65 mmol, 230 pL, 3.0 eq), EDCI (159 mg, 827 pmol, 1.5 eq) and HOBt (112 mg, 827 pmol, 1.5 eq). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A- (l-(4-fluorophenyl)cyclopropyl)-2-methyl benzamide (118 mg, 326 pmol, 59% yield) was obtained as a white solid. M + H ⁺ = 357.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 12.97 - 12.63 (m, 1H), 7.46 - 7.38 (m, 2H), 7.11 (d, J= 8.4 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.90 (s, 1H), 6.85 (dd, J= 2.6, 8.4 Hz, 1H), 4.57 - 4.49 (m, 2H), 3.47 - 3.38 (m, 2H), 2.93 (d, J= 4.8 Hz, 6H), 2.33 (s, 3H), 1.42 - 1.35 (m, 2H), 1.34 - 1.28 (m, 2H). Example 174: /V-(l-(2-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2- methylbenzamide (Compound 251)

Step 1

172A-2 Compound 251

Step 1 : /V-(l-(2-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2-methyl benzamide (Compound 251)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (50.0 mg, 224 pmol, 1.0 eq) and l-(2-bromophenyl)cyclopropanamine (47.5 mg, 224 pmol, 1.0 eq) in DMF (5.0 mL) were added TEA (45.3 mg, 448 pmol, 62.3 pL, 2.0 eq), EDCI (51.5 mg, 267 pmol, 1.2 eq) and HOBt (36.3 mg, 269 pmol, 1.2 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 65% B over 8 min; mobile phase A: l 0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-(l-(2-Bromophenyl)cyclopropyl)-5- (2-(dimethylamino)ethoxy)-2-methylbenzamide (20.2 mg, 48.1 pmol, 21% yield) was obtained as a yellow gum. M + H ⁺ = 417.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.80 (dd, J= 1.6, 7.6 Hz, 1H), 7.55 (dd, J= 0.9, 7.9 Hz, 1H), 7.31 (dt, J= 1.1, 7.5 Hz, 1H), 7.15 (dt, J= 1.6, 7.7 Hz, 1H), 7.06 (d, J= 8.1 Hz, 1H), 6.89 - 6.82 (m, 2H), 6.78 (s, 1H), 4.04 (t, J= 5.6 Hz, 2H), 2.73 (t, J= 5.6 Hz, 2H), 2.35 (s, 6H), 2.24 (s, 3H), 1.32 (dd, J= 4.3, 14.1 Hz, 4H).

Example 175: /V-(l-(3-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2- methylbenzamide (Compound 261) p Step 1 : /V-(l-(3-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2-methylbenz amide (Compound 261)

A mixture of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (351 mg, 472 pmol, 2.0 eq), l-(3-bromophenyl)cyclopropanamine (50.0 mg, 236 pmol, 1.0 eq), TEA (71.6 mg, 707 pmol, 98.4 pL, 3.0 eq), HOBt (47.8 mg, 354 pmol, 1.5 eq) and EDCI (67.8 mg, 354 pmol, 1.5 eq) in DCM (3.0 mL) was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy) -2- methylbenzamide (41.6 mg, 100 pmol, 42% yield, HC1 salt) was obtained as a pink solid. M + H ⁺ = 417.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.56 - 10.42 (m, 1H), 9.09 - 9.04 (m, 1H), 7.43 - 7.35 (m, 2H), 7.29 - 7.24 (m, 1H), 7.22 - 7.17 (m, 2H), 7.01 - 6.96 (m, 2H), 4.39 - 4.33 (m, 2H), 3.54 - 3.44 (m, 2H), 2.85 - 2.81 (m, 6H), 2.28 - 2.22 (m, 3H), 1.28 (br d, J = 5.0 Hz, 4H).

Example 176: /V-(l-(4-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2- methylbenzamide (Compound 258)

Compound 258

Step 1: l-(4-Bromophenyl)cyclopropanamine (176A-1)

To a stirred solution of tert-butyl (l-(4-bromophenyl)cyclopropyl)carbamate (300 mg, 961 pmol, 1.0 eq) in EtOAc (6.0 mL) was added HClZEtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 2 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum at 30 °C to give l-(4-bromophenyl)cyclopropanamine (230 mg, 932 pmol, 97% yield, HC1 salt) as a white solid.

Step 2: /V-(l-(4-Bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2-methyl benzamide (Compound 258)

To a solution of l-(4-bromophenyl)cyclopropanamine (80.0 mg, 322 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (71.9 mg, 322 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (97.7 mg, 966 pmol, 134 pL, 3.0 eq), EDCI (154 mg, 805 pmol, 2.5 eq) and HOBt (109 mg, 805 pmol, 2.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-(l-(4-Bromophenyl)cyclopropyl)- 5-(2-(dimethyl amino)ethoxy)-2-methylbenzamide (12.8 mg, 27.9 pmol, 9% yield) was obtained as a yellow gum. M + H+ = 417.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.97 (s, 1H), 7.48 (s, 2H), 7.18 (d, J= 8.5 Hz, 3H), 6.93 (s, 2H), 4.05 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.36 - 2.17 (m, 9H), 1.25 (br d, J= 5.5 Hz, 4H)

Example 177: /V-(l-(2-chlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethox y)-2- methylbenzamide (Compound 326)

Step 4

177A-4

Compound 326 Step 1: l-(2-Chlorophenyl)cyclopropanamine (177A-2)

A mixture of 2-chlorobenzonitrile (500 mg, 2.39 mmol, 1.0 eq) in anhydrous Et20 (35 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (1.14 g, 4.00 mmol, 1.18 mL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 2.67 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (1.03 g, 7.27 mmol, 897 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give crude product l-(2-chlorophenyl)cyclopropanamine (600 mg) as a brown oil. M + H ⁺ = 168.1 (LCMS).

Step 2: tert-Butyl (l-(2-Chlorophenyl)cyclopropyl)carbamate (177A-3)

To a solution of l-(2-chlorophenyl)cyclopropanamine (600 mg, 3.58 mmol, 1.0 eq) in DCM (30 mL) were added TEA (724 mg, 7.16 mmol, 996 pL, 2.0 eq) and BOC2O (937 mg, 4.30 mmol, 987 pL, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product /c/7-butyl (l-(2-chlorophenyl)cyclopropyl)carbamate (360 mg) as a white solid. M - 56 + H ⁺ = 212.0 (LCMS).

Step 3: l-(2-Chlorophenyl)cyclopropanamine (177A-4)

To a stirred solution of Zc/V-butyl (l-(2-chlorophenyl)cyclopropyl)carbamate (360 mg, 1.34 mmol, 1.0 eq) in EtOAc (3.0 mL) was added HClZEtOAc (4 M, 15 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give product l-(2-chlorophenyl)cyclopropanamine (260 mg, HC1 salt) as a brown solid. M + H ⁺ = 168.0 (LCMS). Step 4: /V-(l-(2-Chlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethox y)-2-methyl benzamide (Compound 326)

To a solution of l-(2-chlorophenyl)cyclopropanamine (50.0 mg, 298 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (133 mg, 596 pmol, 2.0 eq) in DMF (2.0 mL) were added TEA (90.5 mg, 895 pmol, 174 pL, 3.0 eq), EDCI (68.6 mg, 501 pmol, 1.2 eq) and HOBt (48.4 mg, 358 pmol, 1.2 eq). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). A-(l-(2-Chlorophenyl)cyclopropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (37.7 mg, 90.6 pmol, 30% yield, FA salt) was obtained as a white solid. M + H ⁺ = 373.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 10.56 (br s, 1H), 8.39 (s, 1H), 7.79 (dd, J= 1.9, 7.4 Hz, 1H), 7.36 (dd, J= 1.4, 7.5 Hz, 1H), 7.25 - 7.18 (m, 1H), 7.06 (d, J= 8.1 Hz, 1H), 6.93 - 6.68 (m, 3H), 4.21 (t, J= 5.1 Hz, 2H), 3.13 (t, J= 5.0 Hz, 2H), 2.62 (s, 6H), 2.22 (s, 3H), 1.32 (d, J= 4.4 Hz, 2H), 1.28 (d, J= 4.4 Hz, 2H).

Example 178: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(o- tolyl)cyclopropyl)benzamidee (Compound 282)

Step 1

172A-2 Compound 282

Step 1 : 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(o-tolyl)cyclopro pyl)benzamide (Compound 282)

To a mixture of 1 -(o-tolyl)cyclopropanamine (100 mg, 679 pmol, 1.1 eq) and 5-(2-(dimethy lamino)ethoxy)-2-methylbenzoic acid (138 mg, 618 pmol, 1.0 eq) in DCM (2.0 mL) were added EDCI (178 mg, 926 pmol, 1.5 eq), HOBt (125 mg, 926 pmol, 1.5 eq) and TEA (187 mg, 1.85 mmol, 3.0 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2- (Dimethylamino)ethoxy)-2-methyl-7V-(l-(o-tolyl)cyclopropyl)b enzamidee (32.4 mg, 91.9 prnol, 15% yield, HC1 salt) was obtained as a yellow gum. M + H ⁺ = 353.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 5 10.51 (br s, 1H), 8.90 (s, 1H), 7.59 (br d, J = 5.9 Hz, 1H), 7.15 - 7.08 (m, 4H), 6.94 - 6.89 (m, 1H), 6.75 (d, J = 2.6 Hz, 1H), 4.30 (br t, J = 5.0 Hz, 2H), 3.49 - 3.42 (m, 2H), 2.80 (d, J = 4.9 Hz, 6H), 2.48 (s, 3H), 2.07 (s, 3H), 1.18 - 1.11 (m, 2H), 1.07 - 0.99 (m, 2H).

Example 179: 5-(2-( Dimet hyl:imino)et hoxy)-2-met hyl-\-(l-(/n- tolyl)cyclopropyl)benzamide (Compound 255)

Compound 255

Step 1: l-(m-Tolyl)cyclopropanamine (179A-2)

A mixture of 3 -methylbenzonitrile (1.00 g, 8.54 mmol, 1.02 mL, 1.0 eq) in anhydrous Et20 (40 mL) was degassed and purged with N2 three times. The mixture was cooled to -78 °C under a N2 atmosphere. To this mixture was added Ti(z-PrO)4 (2.67 g, 9.39 mmol, 2.77 mL, 1.1 eq) slowly, and then EtMgBr (3 M in Et2O, 6.26 mL, 2.2 eq) was added dropwise over 1 h to maintain the temperature between -78 °C and -73 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (2.42 g, 17.1 mmol, 2.11 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (40 mL) and MTBE (10 mL), and extracted with MTBE (40 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. \ -(m- Tolyl)cyclopropanamine (200 mg, 1.36 mmol, 16% yield) was obtained as a yellow oil. M + H ⁺ = 148.1 (LCMS).

Step 2: 5-(2-(l)iinetliylainiiio)ethoxy)-2-niethyl-\-( l-(/n-tolyl)cyclopropyl (benzamide (Compound 255)

To a solution of l-(m-tolyl)cyclopropanamine (70.0 mg, 475 pmol, 1.0 eq) and 5-(2-(dimethyl amino)ethoxy)-2-methylbenzoic acid (106 mg, 475 pmol, 1.0 eq) in DMF (1.0 mL) were added TEA (96.2 mg, 951 pmol, 132 pL, 2.0 eq), EDCI (109 mg, 571 pmol, 1.2 eq) and HOBt (77.1 mg, 571 pmol, 1.2 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/ethanol = 10/1, R/ = 0.2). 5-(2- (Dimethylamino) ethoxy)-2-methyl-A-(l-(m-tolyl)cyclopropyl)benzamide (70.8 mg, 201 pmol, 42% yield) was obtained as a white solid. M + H ⁺ = 353.1 (LCMS); ¹ HNMR (400 MHz, CDCL) 8 7.24 - 7.18 (m, 1H), 7.17 - 7.07 (m, 3H), 7.03 (d, J= 7.4 Hz, 1H), 6.97 (d, J= 2.6 Hz, 1H), 6.88 (dd, J= 2.8, 8.4 Hz, 1H), 6.41 (s, 1H), 4.10 (t, J= 5.5 Hz, 2H), 2.79 (t, J= 5.4 Hz, 2H), 2.40 (s, 6H), 2.36 (s, 3H), 2.35 (s, 3H), 1.36 (s, 4H).

Example 180: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(p- tolyl)cyclopropyl)benzamide (Compound 253)

180A-1 Compound 253 Step 1 : 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(p-tolyl)cyclopro pyl)benzamide (Compound 253)

To a solution of l-(/?-tolyl)cyclopropanamine (69.2 mg, 470 pmol, 1.0 eq) in DCM (8.0 mL) were added 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (100 mg, 448 pmol, 1.0 eq), TEA (136 mg, 1.34 mmol, 187 pL, 3.0 eq), EDCI (129 mg, 672 pmol, 1.5 eq) and HOBt (90.8 mg, 672 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l-(/?- tolyl)cyclopropyl)benzam ide (68.8 mg, 194 pmol, 43% yield) was obtained as a white solid. M + H ⁺ = 353.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.91 - 8.86 (m, 1H), 7.23 - 7.02 (m, 5H), 6.94 - 6.87 (m, 2H), 4.09 - 4.01 (m, 2H), 2.64 - 2.57 (m, 3H), 2.28 - 2.24 (m, 3H), 2.24 - 2.18 (m, 8H), 1.26 - 1.12 (m, 4H).

Example 181: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2- (trifluoromethyl)phenyl)cyclopropyl)benzamide (Compound 321)

Compound 321

Step 1: l-(2-(Trifluoromethyl) phenyl)cyclopropanamine (181A-2)

A mixture of 2-(trifluoromethyl)benzonitrile (200 mg, 1.17 mmol, 1.0 eq) in anhydrous Et2O (15 mL) was degassed and purged with N2 three times. The mixture was stirred with a mechanical stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (365 mg, 1.29 mmol, 379 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 858 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (331 mg, 2.34 mmol, 288 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (2.0 mL) and MTBE (15 mL), and extracted with MTBE (15 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/MeOH = 10/1, R/= 0.2). l-(2-(Trifluoromethyl)phenyl) cyclopropanamine (80.0 mg, 397 pmol, 34% yield) was obtained as a yellow oil. M + H ⁺ = 202.0 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-(trifluorometh yl)phenyl) cyclopropyl)benzamide (Compound 321)

To a solution of l-(2-(trifluoromethyl)phenyl)cyclopropanamine (50.0 mg, 248 pmol, 1.0 eq) and 5-[2-(dimethylamino)ethoxy]-2-methyl-benzoic acid (55.5 mg, 248 pmol, 1.0 eq) in DMF (1.0 mL) were added HATU (142 mg, 372 pmol, 1.5 eq) and DIEA (95.4 mg, 745 pmol, 130 pL, 3.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-[2-(dimethylamino)ethoxy]-2- methyl-A-[l-[2-(trifluoromethyl)phenyl]cyclopropyl]benzamide (55.8 mg, 100 mmol, 51% yield, HC1 salt) as a white solid. M + H ⁺ = 407.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.32 (br d, J= 1.1 Hz, 1H), 8.68 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.69 (d, J= 7.8 Hz, 1H), 7.62 (t, J= 7.6 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.93 (dd, J= 2.6, 8.4 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 4.29 (t, J= 5.0 Hz, 2H), 3.47 (q, J= 5.1 Hz, 2H), 2.81 (d, J = 4.9 Hz, 6H), 2.08 (s, 3H), 1.30 - 1.14 (m, 4H). Example 182: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-ethylphenyl)cyclopropyl )-2- methylbenzamide (Compound 364)

Step 5

Compound 364

Step 1: 2-Ethylbenzonitrile (182A-2)

To a solution of l-bromo-2-ethylbenzene (2.00 g, 10.8 mmol, 1.49 mL, 1.0 eq) in DMF (17 mL) was added CuCN (1.45 g, 16.2 mmol, 3.54 mL, 1.5 eq). The mixture was stirred at 140 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 2- Ethylbenzonitrile (800 mg, 6.10 mmol, 56% yield) was obtained as a white solid. M + H ⁺ = 132.1 (LCMS).

Step 2: l-(2-Ethylphenyl)cyclopropanamine (182A-3)

A mixture of 2-ethylbenzonitrile (400 mg, 3.05 mmol, 411 pL, 1.0 eq) in anhydrous Et2O (28 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (953 mg, 3.35 mmol, 990 pL, 1.1 eq) slowly at -78 °C, and then EtMgBr (3 M in Et2O, 2.24 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (866 mg, 6.10 mmol, 753 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude product l-(2-ethylphenyl)cyclopropanamine (490 mg) as a white solid. M + H ⁺ = 162.1 (LCMS).

Step 3: tert-Butyl (l-(2-ethylphenyl)cyclopropyl)carbamate (182A-4)

To a solution of l-(2-ethylphenyl)cyclopropanamine (490 mg, 3.04 mmol, 1.0 eq) in DCM (50 mL) were added TEA (615 mg, 6.08 mmol, 846 pL, 2.0 eq) and BOC2O (663 mg, 3.04 mmol, 698 pL, 1.0 eq). The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl (l-(2-ethylphenyl)cyclopropyl)carbamate (70.0 mg, 268 pmol, 9% yield) was obtained as a white solid. M + H ⁺ = 262.2 (LCMS).

Step 4: l-(2-Ethylphenyl)cyclopropanamine (182A-5)

To a stirred solution of tert-butyl (l-(2-ethylphenyl)cyclopropyl)carbamate (70.0 mg, 268 pmol, 1.0 eq) in EtOAc (1.5 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product l-(2-ethylphenyl)cyclopropanamine (70 mg, HC1 salt) as a white solid. M + H ⁺ = 162.1 (LCMS). Step 5: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-ethylphenyl)cyclopropyl )-2- methylbenzamide (Compound 364)

To a solution of l-(2-ethylphenyl)cyclopropanamine (60.0 mg, 372 pmol, 1.0 eq) and 5-(2-

(dimethylamino)ethoxy)-2-methylbenzoic acid (83.1 mg, 372 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (113 mg, 1.12 mmol, 155 pL, 3.0 eq), EDCI (107 mg, 558 pmol, 1.5 eq) and

HOBt (75.4 mg, 558 pmol, 1.5 eq). The mixture was stirred at 25 °C for 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex luna Cl 8 column (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 0.2% aqueous TFA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l-(2- ethylphenyl)cyclopropyl)-2-methylbenzamide (4.5 mg, 10.7 pmol, 3% yield, FA salt) was obtained as a white solid. M + H ⁺ = 367.1 (LCMS); 'H NMR (400 MHz, CDCh) 88.43 - 8.23 (m, 1H), 7.76 (d, J= 7.6 Hz, 1H), 7.25 (s, 1H), 7.21 (br d, J= 8.2 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.84 - 6.77 (m, 2H), 6.56 - 6.54 (m, 1H), 6.50 (s, 1H), 4.25 (br t, J= 4.8 Hz, 2H), 3.15 (br t, J= 4.7 Hz, 2H), 3.03 - 2.90 (m, 2H), 2.66 (s, 6H), 2.21 (s, 3H), 1.41 - 1.34 (m, 2H), 1.31 (t, J= 7.6 Hz, 3H), 1.28 - 1.23 (m, 2H).

Example 183: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-isopropylphenyl)cyclopr opyl)-2- methylbenzamide (Compound 344)

183A-1

Step 1: 2-Isopropylbenzonitrile (183 A-2)

A mixture of K4[Fe(CN)e] (370 mg, 1.00 mmol, 0.2 eq), Cui (95.6 mg, 502 pmol, 0.1 eq) and l-bromo-2-isopropyl-benzene (1.00 g, 5.02 mmol, 1.0 eq) in toluene (5.0 mL) was degassed and purged with N2 three times. To the mixture were added tetradecane (381 mg, 1.92 mmol, 500 pL, 0.38 eq) and 1 -butyl- UT-imidazole (624 mg, 5.02 mmol, 5.00 mL, 1.0 eq). The mixture was stirred at 160 °C for 16 h under a N2 atmosphere. TLC indicated that some of the starting material still remained and a new main spot was detected. The reaction mixture was poured into saturated aqueous NH4CI (2.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 2-Isopropylbenzonitrile (330 mg, 2.27 mmol, 45% yield) was obtained as a white solid. M + H ⁺ = 146.1 (LCMS).

Step 2: l-(2-Isopropylphenyl)cyclopropanamine (183A-3)

A mixture of 2-isopropylbenzonitrile (330 mg, 2.27 mmol, 1.0 eq) in anhydrous Et2O (23 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (710 mg, 2.50 mmol, 738 pL, 1.1 eq) slowly at -78 °C, and then EtMgBr (3 M in Et2O, 1.67 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (645 mg, 4.55 mmol, 561 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product l-(2-isopropylphenyl)cyclopropanamine (390 mg) as a white solid. M + H ⁺ = 176.2 (LCMS).

Step 3: /cr/- Butyl (l-(2-isopropylphenyl)cyclopropyl)carbamate (183A-4)

To a solution of l-(2-isopropylphenyl)cyclopropanamine (390 mg, 2.23 mmol, 1.0 eq) in DCM (50 mL) were added TEA (450 mg, 4.45 mmol, 619 pL, 2.0 eq) and BOC2O (583 mg, 2.67 mmol, 613 pL, 1.2 eq). The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. /c/V-Butyl (l-(2- isopropylphenyl)cyclopropyl)carbamate (100 mg, 363 pmol, 16% yield) was obtained as a white solid. M - 56+ H ⁺ = 220.1 (LCMS).

Step 4: l-(2-Isopropylphenyl)cyclopropanamine (183A-5)

To a stirred solution of /c/7-butyl (l-(2-isopropylphenyl)cyclopropyl)carbamate (100 mg, 363 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 4.1 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude product l-(2-isopropylphenyl)cyclopropanamine (100 mg, HC1 salt) as a white solid. M + H ⁺ = 176.2 (LCMS).

Step 5: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-isopropylphenyl)cyclopr opyl)-2-methyl benzamide (Compound 344)

To a solution of l-(2-isopropylphenyl)cyclopropanamine (90.0 mg, 513 pmol, 1.0 eq) and 5- (2-(dimethylamino)ethoxy)-2-methylbenzoic acid (91.7 mg, 411 pmol, 0.8 eq) in DCM (3.0 mL) were added TEA (156 mg, 1.54 mmol, 214 pL, 3.0 eq), EDCI (148 mg, 770 pmol, 1.5 eq) and HOBt (104 mg, 770 pmol, 1.5 eq). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-7V-(l- (2-isopropylphenyl)cyclopropyl)-2-methylbenzamide (15.6 mg, 36.6 pmol, 7% yield, FA salt) was obtained as a white solid. M + H ⁺ = 381.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.46 (br s, 1H), 7.74 (d, J= 7.7 Hz, 1H), 7.29 (d, J = 4.0 Hz, 2H), 7.18 (dd, J = 4.0, 7.6 Hz, 1H), 7.05 (d, J= 8.3 Hz, 1H), 6.89 - 6.69 (m, 2H), 6.32 (s, 1H), 4.04 (t, J= 5.5 Hz, 2H), 3.82 - 3.49 (m, 1H), 2.78 (t, J= 5.4 Hz, 2H), 2.38 (s, 6H), 2.22 (s, 3H), 1.44 - 1.33 (m, 2H), 1.28 (d, J =

7.0 Hz, 6H), 1.25 (br s, 2H).

Example 184: /V-(l-([l,l'-Biphenyl]-2-yl)cyclopropyl)-5-(2-(dimethylamino )ethoxy)-2- methylbenzamide (Compound 267)

Compound 267

Step 1: tc/7- Butyl (l-(2-bromophenyl)cyclopropyl)carbamate (184A-2)

To a solution of l-(2-bromophenyl)cyclopropanamine (500 mg, 2.36 mmol, 1.0 eq) in DCM (13 mL) were added di-/c/7-butyl dicarbonate (515 mg, 2.36 mmol, 542 pL, 1.0 eq) and TEA (262 mg, 2.59 mmol, 361 pL, 1.1 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. te/7-Butyl (l-(2- bromophenyl)cyclopropyl)carbamate (660 mg, 2.11 mmol, 90% yield) was obtained as a yellow gum. flT NMR (400 MHz, CDCh) 8 7.56 - 7.51 (m, 1H), 7.30 - 7.27 (m, 1H), 7.24 (s, 1H), 7.16 - 7.10 (m, 1H), 1.44 - 1.33 (m, 9H), 1.27 - 1.21 (m, 2H), 1.17 - 1.12 (m, 2H).

Step 2: tert-Butyl (l-([l,l'-biphenyl]-2-yl)cyclopropyl)carbamate (184A-3)

A mixture of phenylboronic acid (195 mg, 1.60 mmol, 2.5 eq), tert-butyl (l-(2- bromophenyl)cyclopropyl)carbamate (200 mg, 641 pmol, 1.0 eq), K2CO3 (221 mg, 1.60 mmol, 2.5 eq), Pd(dppf)C12 (46.9 mg, 64.1 pmol, 0.1 eq) in a mixture of dioxane (8.0 mL) and H2O (2.0 mL) was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. tert-Butyl (l-([l,l'-biphenyl]-2- yl)cyclopropyl)carbamate (150 mg, 485 pmol, 76% yield) was obtained as a white solid.

Step 3: l-([l,l'-Biphenyl]-2-yl)cyclopropanamine (184A-4)

To a solution of tert-butyl (l-([l,l'-biphenyl]-2-yl)cyclopropyl)carbamate (100 mg, 323 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude product l-([l,l'-biphenyl]-2-yl)cyclopropanamine (75.0 mg, HC1 salt) as a white solid. M + H ⁺ = 210.1 (LCMS).

Step 4: A-(l-([l,l'-Biphenyl]-2-yl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methyl benzamide (Compound 267)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (68.1 mg, 305 pmol, 1.0 eq) and l-([l,l'-biphenyl]-2-yl)cyclopropanamine (75.0 mg, 305 pmol, 1.0 eq, HC1 salt) in DMF (5.0 mL) were added TEA (92.7 mg, 916 pmol, 127 pL, 3.0 eq), EDCI (70.2 mg, 366 pmol, 1.2 eq) and HOBt (49.5 mg, 366 pmol, 1.2 eq). The mixture was stirred at 25 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over ISfeSCL, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). A-(l-([l,l'-Biphenyl]-2- yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamid e (31.6 mg, 68.4 pmol, 22% yield, FA salt) was obtained as a yellow solid. M + H ⁺ = 415.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.20 (br s, 1H), 8.05 (s, 1H), 7.94 - 7.87 (m, 1H), 7.51 - 7.47 (m, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.38 - 7.27 (m, 3H), 7.14 (dd, J= 1.9, 7.0 Hz, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6.82 (dd, J= 2.6, 8.4 Hz, 1H), 6.48 (d, J= 2.6 Hz, 1H), 3.98 (t, J= 5.7 Hz, 2H), 2.64 (br t, J= 5.6 Hz, 2H), 2.24 (s, 6H), 2.09 (s, 3H), 1.03 - 0.91 (m, 4H).

Example 185: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(4-hydroxyphenyl)cycloprop yl)-2- methylbenzamide (Compound 294)

Step 1

Compound 271 Compound 294

Step 1 : 5-(2-(Dimethylamino)ethoxy)-/V-(l-(4-hydroxyphenyl)cycloprop yl)-2-methyl benzamide (Compound 294)

A mixture of 5-(2-(dimethylamino)ethoxy)-7V-(l-(4-methoxyphenyl)cycloprop yl)-2- methylbenzamide (100 mg, 265 pmol, 1.0 eq) in DCM (1.0 mL) was degassed and purged with N2 three times. The mixture was added a solution of BBr, (1.22 g, 4.89 mmol, 471 pL, 20 eq) in DCM (1.0 mL) at -78 °C and stirred at the same temperature for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-7V-(l-(4-hydroxyphenyl)cycloprop yl)-2-methylbenzamide (5.50 mg, 15.4 pmol, 6% yield, HC1 salt) was obtained as a yellow oil. M + H ⁺ = 355.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 7.15 (d, J= 8.6 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.94 (dd, J= 2.8, 8.4 Hz, 1H), 6.87 (d, J = 2.7 Hz, 1H), 6.70 - 6.62 (m, 2H), 4.28 - 4.19 (m, 2H), 3.48 - 3.43 (m, 2H), 2.81 (s, 6H), 2.17 (s, 3H), 1.15 - 1.07 (m, 4H). Example 186: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(4-methoxyphenyl)cycloprop yl)-2- m ethylbenzamide (Compound 271)

Step 2

Compound 271

Step 1: l-(4-Methoxyphenyl)cyclopropanamine (186A-2)

A mixture of 4-methoxybenzonitrile (2.00 g, 15.0 mmol, 1.0 eq) in anhydrous Et20 (100 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (4.27 g, 15.0 mmol, 4.43 mL, 1.0 eq) slowly at -78 °C, and then EtMgBr (3 M in Et20, 11.0 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 30 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (4.26 g, 30.0 mmol, 3.71 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL x 3). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/1. l-(4- Methoxyphenyl)cyclopropanamine (1.30 g, 7.96 mmol, 53% yield) was obtained as a yellow oil. M + H ⁺ = 164.1 (LCMS). Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(4-methoxyphenyl)cycloprop yl)-2-methyl benzamide (Compound 271)

To a solution of l-(4-methoxyphenyl)cyclopropanamine (100 mg, 447 pmol, 1.2 eq), 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (83.2 mg, 373 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (113 mg, 1.12 mmol, 156 pL, 3.0 eq), EDCI (107 mg, 559 mmol, 1.5 eq) and HOBt (75.5 mg, 559 mmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l-(4- m ethoxyphenyl) cyclopropyl)-2-methylbenzamide (100 mg, 265 pmol, 71% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 369.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 12.80 (br s, 1H), 7.43 - 7.36 (m, 2H), 7.07 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 2.6 Hz, 1H), 6.90 - 6.77 (m, 4H), 4.54 - 4.47 (m, 2H), 3.80 (s, 3H), 3.46 - 3.39 (m, 2H), 2.93 (d, J= 4.9 Hz, 6H), 2.31 (s, 3H), 1.38 - 1.32 (m, 2H), 1.31 - 1.26 (m, 2H).

Example 187: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2- phenoxyphenyl)cyclopropyl)benzamide (Compound 298)

Compound 298 Step 1: l-(2-Phenoxyphenyl)cyclopropanamine (187A-2)

A mixture of 2-phenoxybenzonitrile (300 mg, 1.54 mmol, 1.0 eq) in anhydrous Et20 (20 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (480 mg, 1.69 mmol, 499 pL, 1.1 eq) slowly at -78 °C, and then EtMgBr (3 M in Et20, 1.13 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (436 mg, 3.07 mmol, 379 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (15 mL) and MTBE (15 mL), and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. l-(2-Phenoxyphenyl)cyclopropanamine (90.0 mg, 399 pmol, 26% yield) was obtained as a yellow oil. M + H ⁺ = 226.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.41 - 7.33 (m, 3H), 7.21 (dt, J= 1.6, 7.8 Hz, 1H), 7.15 - 6.98 (m, 4H), 6.87 (dd, J= 0.9, 8.1 Hz, 1H), 1.00 (s, 2H), 0.91 - 0.86 (m, 2H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-phenoxyphenyl) cyclopropyl) benzamide (Compound 298)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (178 mg, 799 pmol, 2.0 eq) and l-(2-phenoxyphenyl)cyclopropanamine (90.0 mg, 399 pmol, 1.0 eq) in DMF (5.0 mL) were added TEA (121 mg, 1.20 mmol, 167 pL, 3.0 eq), EDCI (91.9 mg, 479 pmol, 1.2 eq) and HOBt (64.8 mg, 479 pmol, 1.2 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-7V- (l-(2-phenoxyphenyl)cyclopropyl)benzamide (51.3 mg, 108 pmol, 27% yield, FA) was obtained as a yellow gum. M + H ⁺ = 431.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.74 (s, 1H), 8.17 (s, 1H), 7.64 (br d, J= 7.6 Hz, 1H), 7.37 (br t, J= 7.9 Hz, 2H), 7.25 - 7.20 (m, 1H), 7.13 - 6.99 (m, 5H), 6.82 (br dd, J= 2.1, 8.3 Hz, 1H), 6.75 (br d, J= 8.0 Hz, 1H), 6.67 (d, J= 2.0 Hz, 1H), 3.93 (br t, J= 5.5 Hz, 2H), 2.60 (br s, 2H), 2.22 (s, 6H), 2.14 (s, 3H), 1.11 (br d, J = 9.9 Hz, 4H).

Example 188: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3- phenoxyphenyl)cyclopropyl)benzamide (Compound 270)

123A-1 188A-1

Boc

EtOAc/HCI

2-(dimethylamino)acetic acid EtOAc -dioxane Step 3

Step 1: / f/- Butyl (l-(3-bromophenyl)cyclopropyl)carbamate (188A-1)

To a stirred solution of l-(3-bromophenyl)cyclopropanamine (250 mg, 1.18 mmol, 1.0 eq) in DCM (5.0 mL) were added TEA (131 mg, 1.30 mmol, 180 pL, 1.1 eq) and BOC2O (257 mg, 1.18 mmol, 271 pL, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.5). ter/-Butyl(l -(3 -bromophenyl) cyclopropyl) carbamate (300 mg, 961 pmol, 82% yield) was obtained as a white solid. M - 56 + H ⁺ = 255.9 (LCMS).

Step 2: tert-Butyl (l-(3-phenoxyphenyl)cyclopropyl)carbamate (188A-2)

A mixture of tert-butyl (2-hydroxyethyl)carbamate (50.0 mg, 160 pmol, 1.0 eq), phenol (21.1 mg, 224 pmol, 1.4 eq), Cs2CO3(104 mg, 320 pmol, 2.0 eq) and Cui (3.05 mg, 16.0 pmol, 0.1 eq) in 1, 4-di oxane (3.0 mL) was degassed and purged with N2 three times. To the mixture was added 2-(dimethylamino)acetic acid (4.95 mg, 48.1 pmol, 0.3 eq). The resulting mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.6). tert-Butyl (l-(3-phenoxyphenyl)cyclopropyl) carbamate (45.0 mg, 138 pmol, 86% yield) was obtained as a white solid. M + H ⁺ = 326.1 (LCMS).

Step 3: l-(3-Phenoxyphenyl)cyclopropanamine (188A-3)

To a stirred solution of tert-butyl (l-(3-phenoxyphenyl)cyclopropyl)carbamate (90.0 mg, 277 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to givethe crude product l-(3-phenoxyphenyl)cyclopropanamine (50.0 mg, 168 pmol, 60% yield, HC1 salt) as a white solid. M + H ⁺ = 226.0 (LCMS).

Step 4: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-phenoxyphenyl) cyclopropyl) benzamide (Compound 270)

To a solution of l-(3-phenoxyphenyl)cyclopropanamine (100 mg, 382 pmol, 1.0 eq, HC1 salt) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (85.3 mg, 382 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (77.3 mg, 764 pmol, 106 pL, 2.0 eq), EDCI (110 mg, 573 pmol, 1.5 eq) and HOBt (77.4 mg, 573 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 45% - 80% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2- (Dimethylamino)ethoxy)-2-methyl-7V-(l-(3-phenoxyphenyl)cyclo propyl)benzamide (24.4 mg, 52.1 pmol, 14% yield) was obtained as a yellow gum. M + H ⁺ = 431.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.90 (s, 1H), 7.43 - 7.26 (m, 3H), 7.17 - 7.07 (m, 2H), 7.04 - 6.96 (m, 2H), 6.95 - 6.86 (m, 3H), 6.84 - 6.77 (m, 2H), 4.01 (t, J= 5.8 Hz, 2H), 2.61 (t, J= 5.8 Hz, 2H), 2.21 (s, 6H), 2.15 (s, 3H), 1.25 (br d, J= 1.4 Hz, 4H).

Example 189: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3- phenoxyphenyl)cyclopropyl)benzamide (Compound 279)

Step 1: tert-butyl (l-(4-phenoxyphenyl)cyclopropyl)carbamate (189A-1)

A mixture of tert-butyl (l-(4-bromophenyl)cyclopropyl)carbamate (100 mg, 320 pmol, 1.0 eq), phenol (42.2 mg, 448 pmol, 1.4 eq), Cs2CO3(209 mg, 640 pmol, 2.0 eq) and Cui (6.10 mg, 32.0 pmol, 0.1 eq) in 1, 4-dioxane (5.0 mL) was degassed and purged with N2 three times. To the mixture was added 2-(dimethylamino)acetic acid (9.91 mg, 96.1 pmol, 0.3 eq) and the resulting mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.7). te/7-Butyl(l-(4-phenoxy phenyl)cyclopropyl) carbamate (100 mg, 307 pmol, 96% yield) was obtained as a yellow oil. M + H ⁺ = 326.1 (LCMS). Step 2: l-(4-Phenoxyphenyl)cyclopropanamine (189A-2)

To a stirred solution of tert-butyl (l-(4-phenoxyphenyl)cyclopropyl)carbamate (100 mg, 307 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product l-(4-phenoxyphenyl)cyclopropanamine (100 mg, HC1 salt) as a white solid. M + H ⁺ = 226.0 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(4-phenoxyphenyl) cyclopropyl) benzamide (Compound 279)

To a solution of l-(4-phenoxyphenyl)cyclopropanamine (100 mg, 382 pmol, 1.0 eq, HC1 salt) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (85.3 mg, 382 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (77.3 mg, 764 pmol, 106 pL, 2.0 eq), EDCI (110 mg, 573 pmol, 1.5 eq) and HOBt (77.4 mg, 573 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 50% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2- (Dimethylamino)ethoxy)-2-methyl-7V-(l-(4-phenoxyphenyl)cyclo propyl)benzamide (15.0 mg, 34.8 pmol, 9% yield) was obtained as a white solid. M + H ⁺ = 431.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.93 (s, 1H), 7.42 - 7.33 (m, 2H), 7.25 (d, J= 8.8 Hz, 2H), 7.12 (d, J= 7.5 Hz, 2H), 7.02 - 6.87 (m, 6H), 4.04 (t, J= 5.8 Hz, 2H), 2.60 (br t, J= 5.8 Hz, 2H), 2.27 - 2.15 (m, 9H), 1.23 (br d, J= 7.3 Hz, 4H).

Example 190: /V-(l-(2-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2- methylbenzamide (Compound 327)

Step 1 Step 2

190A-1 190A-2 190A-3 Compound 327

Step 1: 2-(Benzyloxy)benzonitrile (190A-2)

To a solution of 2-hydroxybenzonitrile (2.00 g, 16.8 mmol, 1.0 eq) and K2CO3 (4.64 g, 33.6 mmol, 2.0 eq) in DMF (20 mL) was added (bromomethyl)benzene (3.45 g, 20.2 mmol, 2.39 mL, 1.2 eq). The mixture was stirred at 50 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/10. 2-(Benzyloxy)benzonitrile (3.20 g, 15.3 mmol, 91% yield) was obtained as a white solid. M + H ⁺ = 210.1 (LCMS); ¹ HNMR (400 MHz, CDCL) 87.59 (dd, J= 1.6, 7.9 Hz, 1H), 7.55 - 7.44 (m, 3H), 7.44 - 7.38 (m, 2H), 7.38 - 7.33 (m, 1H), 7.08 - 6.96 (m, 2H), 5.23 (s, 2H).

Step 2: l-(2-(Benzyloxy)phenyl)cyclopropanamine (190A-3)

A mixture of 2-(benzyloxy)benzonitrile (500 mg, 2.39 mmol, 1.0 eq) in anhydrous Et2O (50 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (747 mg, 2.63 mmol, 776 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et2O, 1.75 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (679 mg, 4.78 mmol, 590 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product l-(2-(benzyloxy)phenyl)cyclopropanamine (580 mg) as a brown oil. M + H ⁺ = 240.1 (LCMS).

Step 3: tert-Butyl (l-(2-(benzyloxy)phenyl)cyclopropyl)carbamate (190A-4)

To a solution of l-(2-(benzyloxy)phenyl)cyclopropanamine (570 mg, 2.38 mmol, 1.0 eq) in DCM (30 mL) were added TEA (482 mg, 4.76 mmol, 663 pL, 2.0 eq) and BOC2O (624 mg, 2.86 mmol, 657 pL, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/7. /crt-Butyl (l-(2- (benzyloxy)phenyl)cyclopropyl)carbamate (110 mg, 324 pmol, 14% yield) was obtained as a white solid.

Step 4: l-(2-(Benzyloxy)phenyl)cyclopropanamine (190A-5)

To a stirred solution of tert-butyl (l-(2-(benzyloxy)phenyl)cyclopropyl)carbamate (100 mg, 295 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.2 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude product l-(2-(benzyloxy)phenyl)cyclopropanamine (100 mg, HC1 salt) as a white solid. M + H ⁺ = 240.1 (LCMS).

Step 5: N-( l-(2-( Benzyloxy )phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methyl benzamide (Compound 327)

To a solution of l-(2-(benzyloxy)phenyl)cyclopropanamine (100 mg, 418 pmol, 1.0 eq) and 5- (2-(dimethylamino)ethoxy)-2-methylbenzoic acid (187 mg, 836 pmol, 2.0 eq) in DMF (4.0 mL) were added TEA (127 mg, 1.25 mmol, 174 pL, 3.0 eq), EDCI (96.1 mg, 501 pmol, 1.2 eq) and HOBt (67.8 mg, 501 pmol, 1.2 eq). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (100 x 40 mm, 3 pm); flow rate: 50 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 7V-(l-(2- (Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-m ethylbenzamide (60.3 mg, 123 pmol, 30% yield, FA salt) was obtained as a white solid. M + H ⁺ = 445.1 (LCMS); ^T H NMR (400 MHz, CDCh) 8 8.42 (s, 1H), 7.62 (dd, J= 1.4, 7.4 Hz, 1H), 7.38 (br d, J= 1.0 Hz, 2H), 7.33 (br d, J= 7.0 Hz, 3H), 7.25 (br d, J= 1.1 Hz, 1H), 7.08 - 6.89 (m, 3H), 6.85 - 6.76 (m, 2H), 6.68 (s, 1H), 5.15 (s, 2H), 4.07 (t, J = 5.3 Hz, 2H), 2.93 (t, J = 5.3 Hz, 2H), 2.48 (s, 6H), 2.15 (s, 3H), 1.25 (br d, J= 4.9 Hz, 4H).

Example 191: N-( l-(3-( Benzyloxy )phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2- methylbenzamide (Compound 308)

Compound 308

Step 1: l-(3-(Benzyloxy)phenyl)cyclopropanamine (191 A-2)

To a mixture of 3 -(benzyloxy )benzonitrile (300 mg, 1.43 mmol, 1.0 eq) in anhydrous Et2O (20 mL) was degassed and purged with N2 three times. The mixture was stirred with a stirrer at - 78 °C. To this mixture was added Ti(z-PrO)4 (448 mg, 1.58 mmol, 470 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 1.05 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (407 mg, 2.87 mmol, 350 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (20 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude product l-(3-(benzyloxy)phenyl)cyclopropanamine (150 mg) as a brown solid, which was used in the next step without any further purification. M + H ⁺ = 240.1 (LCMS).

Step 2: /V-(l-(3-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methyl benzamide (Compound 308)

To a solution of l-(3-(benzyloxy)phenyl)cyclopropanamine (57.0 mg, 239 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (53.3 mg, 239 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (48.4 mg, 0.48 mmol, 66.5 pL, 2 eq), EDCI (68.7 mg, 0.36 mmol, 1.5 eq) and HOBt (48.4 mg, 0.36 mmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (2.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 10% - 40% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(3- (Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2 -methylbenzamide (4.00 mg, 8.32 pmol, 4% yield) was obtained as a white gum. M + H ⁺ = 445.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.93 (s, 1H), 7.46 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.36 - 7.31 (m, 1H), 7.24 - 7.16 (m, 2H), 7.03 - 6.92 (m, 2H), 6.90 - 6.75 (m, 3H), 5.08 (s, 2H), 4.47 - 4.23 (m, 2H), 3.49 (br d, J= 1.8 Hz, 2H), 2.85 (d, J= 4.9 Hz, 6H), 2.29 - 2.20 (m, 3H), 1.24 (br d, J= 1.8 Hz, 4H).

Example 192: /V-(l-(4-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2- methylbenzamide (Compound 307)

192A-1 ^Ste P ¹ 192A-2

Step 2

Compound 307

Step 1: l-(4-(Benzyloxy)phenyl)cyclopropanamine (192A-2)

A mixture of 4-(benzyloxy)benzonitrile (1.00 g, 4.78 mmol, 1.0 eq) in anhydrous Et20 (50 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (1.36 g, 4.78 mmol, 1.41 mL, 1.0 eq) slowly at -78 °C and then EtMgBr (3 M in Et20, 3.50 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (1.36 g, 9.59 mmol, 1.18 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(4-(Benzyloxy) phenyl) cyclopropanamine (400 mg, 1.67 mmol, 35% yield) was obtained as a yellow oil. M + H ⁺ = 240.2 (LCMS).

Step 2: N-( l-(4-(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)etho xy)-2-methylb enzamide (Compound 307)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (112 mg, 501 pmol, 1.2 eq) in DMF (2.0 mL) were added l-(4-(benzyloxy) phenyl) cyclopropanamine (100 mg, 418 pmol, 1.0 eq), TEA (127 mg, 1.25 mmol, 174 pL, 3.0 eq), EDCI (120 mg, 627 pmol, 1.5 eq) and HOBt (84.7 mg, 627 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(4-

(Benzyloxy)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2-methylbenzamide (22.2 mg, 50.0 pmol, 12% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 445.2 (LCMS); ^T H

NMR (400 MHz, DMSO-tL) 8 10.73 - 10.55 (m, 1H), 8.96 (s, 1H), 7.45 - 7.30 (m, 5H), 7.21

- 7.14 (m, 3H), 6.99 - 6.90 (m, 4H), 5.08 (s, 2H), 4.36 (br t, J= 4.8 Hz, 2H), 3.53 - 3.44 (m, 2H), 2.82 (d, J= 4.9 Hz, 6H), 2.25 - 2.19 (m, 3H), 1.24 - 1.10 (m, 4H).

Example 193: /V-(l-([l,l'-Biphenyl]-3-yl)cyclopropyl)-5-(2-(dimethylamino )ethoxy)-2- methylbenzamide (Compound 291)

Compound 291

Step 1: tert-Butyl (l-([l,l'-biphenyl]-3-yl)cyclopropyl)carbamate (193A-1) A mixture of tert-butyl 7V-[l-(3-bromophenyl)cyclopropyl]carbamate (150 mg, 480 pmol, 1.0 eq), phenylboronic acid (146 mg, 1.20 mmol, 2.5 eq), Pd(dppf)C12 (35.2 mg, 48.1 pmol, 0.1 eq) and K2CO3 (166 mg, 1.20 mmol, 2.5 eq) in a mixture of dioxane (6.0 mL) and H2O (1.5 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtO Ac/petroleum ether from 1/100 to 1/4. The crude product tert-butyl (l-([l,l'-biphenyl]-3-yl)cyclopropyl)carbamate (180 mg) was obtained as a white solid.

Step 2: l-([l,l'-Biphenyl]-3-yl)cyclopropanamine (193A-2)

To a solution of tert-butyl (1 -([1,1 '-biphenyl] -3 -yl)cyclopropyl)carbamate (100 mg, 323 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product l-([l,l'-biphenyl]-3-yl)cyclopropanamine (120 mg, HC1 salt) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 210.1 (LCMS).

Step 3: A-(l-([l,l'-Biphenyl]-3-yl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methyl benzamide (Compound 291)

To a solution of l-([l,l'-biphenyl]-3-yl)cyclopropanamine (120 mg, 573 pmol, 1.0 eq, HC1 salt) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (154 mg, 688 pmol, 1.2 eq) in DMF (4.0 mL) were added EDCI (165 mg, 860 pmol, 1.5 eq), HOBt (116 mg, 860 pmol, 1.5 eq) and TEA (116 mg, 1.15 mmol, 160 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Cl 8 column (80 x 40 mm, 3 pm); flow rate: 60 mL/min; gradient: 40% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-(l-([l,l'-Biphenyl]-3- yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methylbenzamide (24.5 mg, 55.5 pmol, 10% yield) was obtained as an light yellow gum. M + H ⁺ = 415.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.99 (s, 1H), 7.67 - 7.59 (m, 1H), 7.67 - 7.56 (m, 1H), 7.51 - 7.31 (m, 6H), 7.21 (br d, J= 7.6 Hz, 1H), 7.14 (d, J= 8.3 Hz, 1H), 6.97 - 6.88 (m, 2H), 4.07 - 4.02 (m, 2H), 2.64 - 2.58 (m, 1H), 2.61 (t, J= 5.8 Hz, 1H), 2.27 - 2.18 (m, 9H), 1.37 - 1.25 (m, 4H). Example 194: /V-(l-(3-(Cyclopent-l-en-l-yl)phenyl)cyclopropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (Compound 264) ep

Compound 261 Compound 264

Step 1: /V-(l-(3-(Cyclopent-l-en-l-yl)phenyl)cyclopropyl)-5-(2-(dime thylamino)ethoxy)- 2-methylbenzamide (Compound 264)

To a stirred solution of 7V-(l-(3-(cyclopent-l-en-l-yl)phenyl)cyclopropyl)-5-(2-(dime thyl amino)ethoxy)-2-methylbenzamide (170 mg, 407 pmol, 1.0 eq) and cyclopent- 1-en-l- ylboronic acid (103 mg, 530 pmol, 1.3 eq) in DMSO (5.0 mL) were added Pd(OAc)2 (9.15 mg, 40.7 pmol, 0.1 eq) and KOAc (120 mg, 1.22 mmol, 3.0 eq) under a N2 atmosphere. The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-( 1 -(3 -(Cyclopent- 1-en-l- yl)phenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylb enzamide (120 mg, 297 pmol, 73% yield) was obtained as a yellow solid. M + H ⁺ = 405.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.94 (s, 1H), 7.33 (s, 1H), 7.29 - 7.22 (m, 2H), 7.14 (d, J = 9.3 Hz, 1H), 7.05 (br d, J= 7.0 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.24 (br s, 1H), 4.05 (t, J= 5.8 Hz, 2H), 2.69 - 2.60 (m, 4H), 2.47 (br d, J= 2.1 Hz, 2H), 2.24 (s, 3H), 2.22 (s, 6H), 2.01 - 1.91 (m, 2H), 1.25 (s, 4H). Example 195: /V-(l-(3-Cyclopentylphenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2- methylbenzamide (Compound 276)

Compound 264 Compound 276

Step 1 : /V-(l-(3-Cyclopentylphenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methyl benzamide (Compound 276)

To a solution of 7V-(l-(3-(cyclopent-l-en-l-yl)phenyl)cyclopropyl)-5-(2-(dime thylamino) ethoxy)-2-methylbenzamide (70.0 mg, 173 pmol, 1.0 eq) in EtOAc (7.0 mL) was added 10% palladium on carbon (10.0 mg) at 20 °C for 2 h under a EE atmosphere (15 psi). LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum. 7V-(l-(3-Cyclopentylphenyl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2- methylbenzamide (38.0 mg, 89.1 pmol, 51% yield) was obtained as a yellow solid. M + H ⁺ = 407.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 8.93 (br s, 1H), 7.23 - 7.11 (m, 3H), 7.07 - 7.01 (m, 1H), 6.99 - 6.88 (m, 3H), 4.11 - 3.99 (m, 2H), 3.06 - 2.79 (m, 1H), 2.62 (br d, J= 5.5 Hz, 2H), 2.34 - 2.17 (m, 9H), 1.99 (br d, J= 5.9 Hz, 2H), 1.81 - 1.46 (m, 6H), 1.23 (br s, 4H).

Example 196: 5-(2-(Dimethylamino)ethoxy)-2-methyl-A ^z -(l-(2',3',4',5'-tetrahydro-[l,l'- biphenyl]-3-yl)cyclopropyl)benzamide (Compound 338)

Compound 261 Step 1 Compound 338

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2',3',4',5'-tetr ahydro-[l,l'- biphenyl]-3-yl)cyclopropyl)benzamide (Compound 338)

To a stirred solution of 7V-(l-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy )-2- methylbenzamide (80.0 mg, 192 pmol, 1.0 eq) and cyclohex- 1-en-l-ylboronic acid (29.0 mg, 230 pmol, 1.2 eq) in a mixture of dioxane (1.0 mL) and fbO (1.0 mL) were added K2CO3 (79.5 mg, 575 pmol, 3.0 eq) and Pd(dppf)C12 (14.0 mg, 19.2 pmol, 0.1 eq). The mixture was stirred at 90 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l-(2',3',4',5'-tetra hydro- [l,l'-biphenyl]-3-yl) cyclopropyl)benzamide (44.3 mg, 105 pmol, 55% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 419.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.65 (br s, 1H), 8.99 (br s, 1H), 7.33 - 7.16 (m, 4H), 7.08 (br d, J= 6.4 Hz, 1H), 7.02 - 6.93 (m, 2H), 6.11 (br s, 1H), 4.37 (br s, 2H), 3.54 - 3.48 (m, 2H), 2.83 (br s, 6H), 2.35 (br s, 2H), 2.25 (br s, 3H), 2.17 (br s, 2H), 1.72 (br s, 2H), 1.61 (br d, J= 4.6 Hz, 2H), 1.25 (br s, 4H).

Example 197: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-(pyridin-4- yl)phenyl)cyclopropyl)benzamide (Compound 266)

197A-2 Compound 266

Step 1: tert-Butyl (l-(2-(pyridin-4-yl)phenyl)cyclopropyl)carbamate (197A-1)

A mixture of pyridin-4-ylboronic acid (295 mg, 2.40 mmol, 2.5 eq), tert-butyl (l-(2- bromophenyl)cyclopropyl)carbamate (300 mg, 961 pmol, 1.0 eq), K2CO3 (332 mg, 2.40 mmol, 2.5 eq), Pd(dppf)C12 (70.3 mg, 96.1 pmol, 0.1 eq) in a mixture of dioxane (12 mL) and H2O (3.0 mL) was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. /crt-Butyl (l-(2-(pyridin-4- yl)phenyl)cyclopropyl)carbamate (80.0 mg, 258 pmol, 27% yield) was obtained as a yellow solid. M + H ⁺ = 311.1 (LCMS).

Step 2: l-(2-(Pyridin-4-yl)phenyl)cyclopropanamine (197A-2)

To a solution of tert-butyl (l-(2-(pyridin-4-yl)phenyl)cyclopropyl)carbamate (80.0 mg, 258 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give l-(2-(pyridin-4-yl)phenyl)cyclopropanamine (50.0 mg, 203 pmol, 79% yield, HC1 salt) as a yellow solid. M + H ⁺ = 211.1 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-(pyridin-4-yl) phenyl) cyclopropyl) benzamide (Compound 266)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (54.5 mg, 244 pmol, 1.2 eq), l-(2-(pyridin-4-yl)phenyl)cyclopropanamine (50.0 mg, 203 pmol, 1.0 eq, HC1 salt) in DMF (3.0 mL) were added TEA (61.8 mg, 610 pmol, 84.9 pL, 3.0 eq), EDCI (46.8 mg, 244 pmol, 1.2 eq) and HOBt (33.0 mg, 244 pmol, 1.2 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2- methyl-A-(l-(2-(pyridin-4-yl)phenyl)cyclopropyl)benzamide (49.8 mg, 108 pmol, 53% yield, FA salt) was obtained as a yellow gum. M + H ⁺ = 416.1 (LCMS); ^T H NMR (400 MHz, DMSO- d ₆ ) 6 8.60 (d, J= 5.9 Hz, 2H), 8.25 (s, 1H), 8.17 (s, 1H), 7.90 (dd, J= 1.0, 7.5 Hz, 1H), 7.52 (d, J= 5.9 Hz, 2H), 7.38 (dtd, J = 1.4, 7.4, 18.6 Hz, 2H), 7.18 (dd, J = 1.3, 7.3 Hz, 1H), 7.05 (d, J= 8.4 Hz, 1H), 6.83 (dd, J= 2.6, 8.4 Hz, 1H), 6.48 (d, J= 2.6 Hz, 1H), 4.00 (t, J= 5.6 Hz, 2H), 2.68 (t, J= 5.5 Hz, 2H), 2.27 (s, 6H), 2.08 (s, 3H), 1.02 (s, 4H).

Example 198: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-(thiophen-2- yl)phenyl)cyclopropyl)benzamide (Compound 355)

Compound 261 Compound 355

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-(thiophen-2-yl )phenyl) cyclopro pyl)benzamide (Compound 355)

To a solution of A-(l-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy) -2- methylbenzamide (40.0 mg, 95.9 pmol, 1.0 eq) in toluene (3.0 mL) were added tributyl(thiophen-2-yl)stannane (53.7 mg, 144 pmol, 45.5 pL, 1.5 eq) and Pd(LBu3P)2 (4.90 mg, 9.58 pmol, 0.1 eq). The mixture was stirred at 90 °C for 3 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l -(3-(thi ophen-2 -yl)phenyl) cyclopropyl) benzamide (8.40 mg, 18.0 pmol, 19% yield, FA salt) was obtained as a yellow oil. M + H ⁺ = 421.1 (LCMS); ^X HNMR (400 MHz, DMSO-t/e) 69.01 (s, 1H), 8.19 (s, 1H), 7.56 - 7.51 (m, 2H), 7.51 - 7.46 (m, 2H), 7.35 (t, J= 7.8 Hz, 1H), 7.18 - 7.07 (m, 3H), 6.97 - 6.90 (m, 2H), 4.07 (t, J= 5.8 Hz, 2H), 2.64 (t, J= 5.8 Hz, 2H), 2.30 - 2.20 (m, 9H), 1.30 (br d, J= 3.8 Hz, 4H). Example 199: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-(thiophen-3- yl)phenyl)cyclopropyl)benzamide (Compound 325)

Step 1 : 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-(thiophen-3-yl )phenyl)cyclopro pyl)benzamide (Compound 325)

A mixture of A-(l-(3-bromophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy) -2- methylbenzamide (50.0 mg, 120 pmol, 1.0 eq), thi ophen-3 -ylboronic acid (15.3 mg, 120 pmol, 1.0 eq) and Na2CC>3 (38.1 mg, 359 pmol, 3.0 eq) in dioxane (2.0 mL) was degassed and purged with N2 three times. To the mixture was added Pd(PPh3)2C12 (8.41 mg, 12.0 pmol, 0.1 eq). The mixture was stirred at 100 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with EtOAc (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 X 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A- (l-(3-(thiophen-3-yl)phenyl)cyclopropyl)benzamide (7.50 mg, 16.4 pmol, 14% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 421.1 (LCMS); ^T H NMR (400 MHz, DMSO- d ₆ ) 6 10.09 - 10.38 (m, 1H), 9.02 (s, 1H), 7.83 (d, J= 1.47 Hz, 1H), 7.62 - 7.70 (m, 1H), 7.44 - 7.57 (m, 3H), 7.30 - 7.40 (m, 1H), 7.16 - 7.25 (m, 2H), 6.94 - 7.05 (m, 2H), 4.35 (br t, J = 4.71 Hz, 2H), 3.50 (br d, J= 4.52 Hz, 2H), 2.76 - 2.93 (m, 6H), 2.26 (s, 3H), 1.23 - 1.45 (m, 4H). Example 200: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(3-(thiophen-2- yl)phenyl)cyclopropyl)benzamide (Compound 169)

Step 3

200A-2 Compound 169

Step 1: l-(3-(Thiophen-2-yl)phenyl)cyclopropanamine (200A-1)

To a solution of l-(3-bromophenyl)cyclopropanamine (300 mg, 1.41 mmol, 1.0 eq) in a mixture of THF (10 mL) and H2O (2.5 mL) were added thiophen-2-ylboronic acid (253 mg, 1.98 mmol, 1.4 eq), K3PO4 (901 mg, 4.24 mmol, 3.0 eq) and Pd(dppf)C12 (46.1 mg, 70.7 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times, then stirred at 80 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.2). l-(3-(Thiophen-2-yl)phenyl)cyclopropanamine (100 mg, 464 pmol, 33% yield) was obtained as a yellow oil. M + H ⁺ = 216.2 (LCMS).

Step 2: tert-Butyl 3-((4-methyl-3-((l-(3-(thiophen-2-yl) phenyl) cyclopropyl) carbamoyl) phenyl)amino)azetidine-l-carboxylate (200A-2)

To a solution of 5-((l-(/erLbutoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzo ic acid (71.1 mg, 232 pmol, 1.0 eq) in DCM (5.0 mL) were added l-(3-(thiophen-2-yl) phenyl) cyclopropanamine (50.0 mg, 232 pmol, 1.0 eq), TEA (70.5 mg, 697 pmol, 97.0 pL, 3.0 eq), EDCI (89.0 mg, 464 pmol, 2.0 eq) and HOBt (62.8 mg, 464 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.3). tert-Butyl 3-((4-methyl-3-((l-(3-(thiophen-2-yl) phenyl) cyclopropyl) carbamoyl) phenyl) amino) azetidine- 1 -carboxylate (85.0 mg, 169 pmol, 73% yield) was obtained as a colorless oil. M + H ⁺ = 504.3 (LCMS).

Step 3: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(3-(thiophen-2-yl)phen yl)cyclopropyl)benz amide (Compound 169)

To a stirred solution of tert-butyl 3-((4-methyl-3-((l-(3-(thiophen-2-yl) phenyl) cyclopropyl) carbamoyl) phenyl) amino) azetidine- 1 -carboxylate (85.0 mg, 169 pmol, 1.0 eq) in DCM (8.0 mL) was added TFA (2.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-7V-(l-(3- (thiophen-2-yl)phenyl)cyclopropyl)benzamide (40.2 mg, 99.5 pmol, 59% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 404.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.10 (s, 1H), 7.67 (s, 1H), 7.49 (d, = 7.6 Hz, 1H), 7.41 - 7.31 (m, 3H), 7.21 (d, J= 7.7 Hz, 1H), 7.11 - 7.08 (m, 1H), 7.05 (d, J= 8.1 Hz, 1H), 6.62 - 6.55 (m, 2H), 4.60 - 4.44 (m, 1H), 4.41 - 4.29 (m, 2H), 3.94 (br dd, J= 6.9, 10.8 Hz, 2H), 2.26 (s, 3H), 1.37 (br d, J= 3.5 Hz, 4H).

Example 201: /V-(l-([l,l'-Biphenyl]-3-yl)cyclopropyl)-5-(azetidin-3-ylami no)-2- methylbenzamide (Compound 187)

201A-2 Compound 187

Step 1: l-([l,l'-Biphenyl]-3-yl)cyclopropanamine (201A-1)

A mixture of l-(3-bromophenyl)cyclopropanamine (200 mg, 943 pmol, 1.0 eq), phenylboronic acid (161 mg, 1.32 mmol, 1.4 eq) and potassium phosphate (601 mg, 2.83 mmol, 3.0 eq) in a mixture of H2O (2.0 mL) and THF (8.0 mL) was degassed and purged with N2 three times. To the mixture was added dichloro[l,l'-bis(di-/-butylphosphino)ferrocene]palladium(II ) (30.7 mg, 47.2 pmol, 0.05 eq) at 25 °C. The resulting mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 100/1. l-([l,l'-Biphenyl]-3-yl)cyclopropanamine (30.0 mg, 143 pmol, 15% yield) was obtained as a brown solid. M + H ⁺ = 210.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.60 (d, J = 7.5 Hz, 2H), 7.54 (s, 1H), 7.49 - 7.45 (m, 2H), 7.44 - 7.41 (m, 2H), 7.41 - 7.35 (m, 2H), 1.15 - 1.10 (m, 2H), 1.08 - 1.03 (m, 2H).

Step 2: tert-Butyl 3-((3-((l-([l,l'-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4-met hylphenyl) amino)azetidine-l-carboxylate (201A-2)

To a solution of l-([l,l'-biphenyl]-3-yl)cyclopropanamine (30.0 mg, 143 pmol, 1.0 eq) and 5- (( l -(/c/7-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenzoic acid (43.9 mg, 143 pmol, 1.0 eq) in DCM (10 mL) were added TEA (43.5 mg, 430 pmol, 59.9 pL, 3.0 eq), EDCI (55.0 mg, 287 pmol, 2.0 eq) and HOBt (38.7 mg, 287 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.4). Zc/V-Butyl 3-((3-((l-([l,l'-biphenyl]-3- yl)cyclopropyl)carbamoyl)-4-methylphenyl) amino) azetidine- 1 -carboxylate (10.0 mg, 20.1 pmol, 14% yield) was obtained as a colorless oil. M + H ⁺ = 498.4 (LCMS).

Step 3: /V-(l-([l,r-Biphenyl]-3-yl)cyclopropyl)-5-(azetidin-3-ylamin o)-2-methyl benzamide (Compound 187)

To a stirred solution of tert-butyl 3-((3-((l-([l,l'-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4- methylphenyl)amino)azetidine-l -carboxylate (100 mg, 216 pmol, 1.0 eq) in DCM (8.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10%

- 40% B over 8 min; mobile phase A: 0.10% aqueous TFA, mobile phase B: acetonitrile). N- (l-([l,r-Biphenyl]-3-yl)cyclopropyl)-5-(azetidin-3-ylamino)- 2-methyl benzamide (43.1 mg, 90.3 pmol, 42% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 398.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.91 (s, 1H), 8.77 - 8.70 (m, 1H), 7.63 (d, J= 7.2 Hz, 2H), 7.51

- 7.44 (m, 4H), 7.42 - 7.34 (m, 2H), 7.21 (d, J= 7.7 Hz, 1H), 7.00 (d, J= 7.9 Hz, 1H), 6.53 - 6.49 (m, 2H), 6.35 (br d, J= 6.4 Hz, 1H), 4.41 - 4.31 (m, 1H), 4.24 (br s, 2H), 3.78 (br s, 2H), 2.17 (s, 3H), 1.37 - 1.31 (m, 2H), 1.30 - 1.24 (m, 2H).

Example 202: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(3-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 186)

202A-3

202A-4 Compound 186

Step 1: te/7- Butyl (l-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamate (202A-1)

To a solution of tert-butyl (l-(3-bromophenyl)cyclopropyl)carbamate (200 mg, 640 pmol, 1.0 eq) in DMSO (12 mL) were added (5-formylthiophen-2-yl)boronic acid (100 mg, 640 pmol, 1.0 eq), KOAc (189 mg, 1.92 mmol, 3.0 eq), Pd(OAc)2 (14.4 mg, 64.1 pmol, 0.1 eq), di-(l- adamantyl)-w-butylphosphine (45.9 mg, 128 pmol, 0.2 eq) and di-te/7-butyl dicarbonate (140 mg, 640 pmol, 147 pL, 1.0 eq). The mixture was degassed and purged with N2 three times, then stirred at 90 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.5). tert-Butyl (l-(3-(5- formylthiophen-2-yl) phenyl) cyclopropyl)carbamate (150 mg, 437 pmol, 68% yield) was obtained as a yellow oil. M + H ⁺ = 344.1 (LCMS).

Step 2: 5-(3-(l-Aminocyclopropyl)phenyl)thiophene-2-carbaldehyde (202A-2)

To a solution of tert-butyl (l-(3-(5-formylthiophen-2-yl) phenyl)cyclopropyl)carbamate (120 mg, 349 pmol, 1.0 eq) in EtOAc (6.0 mL) was added HCl/EtOAc (4 M, 18 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude product 5-(3-(l-aminocyclopropyl)phenyl)thiophene-2-carbaldehyde (120 mg, HC1 salt), which was used in the next step without any further purification. M + H ⁺ = 244.1 (LCMS).

Step 3: te/7- Butyl 3-((3-((l-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carba moyl)-4- methylphenyl)amino)azetidine-l-carboxylate (202A-3)

To a solution of 5-(3-(l-aminocyclopropyl)phenyl)thiophene-2-carbaldehyde (120 mg, 429 pmol, 1.0 eq, HC1 salt) and 5-((l-(ter/-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenz oic acid (131 mg, 429 pmol, 1.0 eq) in DCM (15 mL) were added TEA (130 mg, 1.29 mmol, 179 pL, 3.0 eq), EDCI (123 mg, 643 pmol, 1.5 eq) and HOBt (87.0 mg, 643 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/= 0.2). tert-Butyl 3-((3-((l-(3-(5-formylthiophen-2-yl)phenyl)cyclopropyl)carba moyl)- 4-methylphenyl) amino)azetidine-l -carboxylate (250 mg, 409 pmol, 95% yield) was obtained as a yellow oil. M + H ⁺ = 532.3 (LCMS).

Step 4: tert-Butyl 3-((4-methyl-3-((l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-y l) phenyl) cyclopropyl)carbamoyl)phenyl)amino)azetidine-l-carboxylate (202A-4)

To a solution of pyrrolidine (8.03 mg, 113 pmol, 9.42 pL, 2.0 eq) and tert-butyl 3-((3-((l-(3- (5-formylthiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methy lphenyl)amino)azetidine-l- carboxylate (30.0 mg, 56.3 pmol, 1.0 eq) in MeOH (3.0 mL) was added NaBHiCN (7.09 mg, 113 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product tert-butyl 3-((4-methyl-3-((l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-y l) phenyl) cyclopropyl)carbamoyl)phenyl)amino)azetidine-l -carboxylate (40.0 mg), which was used in the next step without any further purification. M + H ⁺ = 587.4 (LCMS).

Step 5: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(3-(5-(pyrrolidin-l-yl methyl)thiophen-2-yl )phenyl)cyclopropyl)benzamide (Compound 186)

To a solution of tert-butyl 3-((4-methyl-3-((l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-y l) phenyl) cyclopropyl)carbamoyl)phenyl)amino)azetidine-l -carboxylate (80.0 mg, 136 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-A-(l-(3-(5-(pyrrolidin- l-ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (30.0 mg, 57.3 pmol, 42% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 487.3 (LCMS); ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 11.21 - 10.87 (m, 1H), 9.31 - 9.08 (m, 2H), 9.04 - 8.87 (m, 1H), 7.53 - 7.45 (m, 3H), 7.42 - 7.34 (m, 2H), 7.17 - 7.11 (m, 1H), 7.03 - 6.95 (m, 1H), 6.60 - 6.55 (m, 1H), 6.53 - 6.48 (m, 1H), 4.76 - 4.49 (m, 2H), 4.46 - 4.32 (m, 1H), 4.28 - 4.16 (m, 2H), 3.87 - 3.83 (m, 2H), 3.46 - 3.37 (m, 2H), 3.18 - 3.01 (m, 2H), 2.21 - 2.15 (m, 3H), 2.05 - 1.82 (m, 4H), 1.35 - 1.22 (m, 4H).

Example 203: 5-(Azetidin-3-ylamino)-/V-(l-(3-(5-((((l»S,3^)-3- hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)cyclopr opyl)-2- methylbenzamide (Compound 196)

Compound 196

Step 1: te/7- Butyl 3-((3-((l-(3-(5-((((15,3^)-3-hydroxy cyclopentyl) amino) methyl) thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)a mino)azetidine-l- carboxylate (203A-1)

To a solution of tert-butyl 3-((3-((l-(3-(5-formylthiophen-2-yl) phenyl) cyclopropyl) carbamoyl)-4-methylphenyl)amino)azetidine-l -carboxylate (130 mg, 245 pmol, 1.0 eq) and (17?,35)-3-aminocyclopentanol (49.6 mg, 489 pmol, 2.0 eq) in MeOH (6.0 mL) was added NaBFLCN (30.7 mg, 489 pmol, 2.0 eq). The mixture was stirred at 20 °C for 20 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). te/7-Butyl 3-((3-((l-(3-(5- ((((LS',3 ^> )-3-hydroxycyclopentyl) amino) methyl) thiophen-2- yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)amino)azetid ine-l -carboxylate (40.0 mg, 59.0 pmol, 24% yield) was obtained as a colorless oil. M + H ⁺ = 617.4 (LCMS).

Step 2: 5-(Azetidin-3-ylamino)-/V-(l-(3-(5-((((l»S,3^)-3-hydroxycyc lopentyl)amino)methy l)thiophen-2-yl)phenyl)cyclopropyl)-2-methylbenzamide (Compound 196)

To a solution of tert-butyl 3-((3-((l-(3-(5-((((15,3A)-3-hydroxycyclopentyl) amino) methyl) thiophen-2-yl)phenyl)cyclopropyl)carbamoyl)-4-methylphenyl)a mino)azetidine-l- carboxylate (30.0 mg, 48.6 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 2.5 mL). The mixture was stirred at 20 °C for 20 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(Azetidin- 3 -ylamino)-A-( 1 -(3 -(5 -(((( 15,3 R)-3 -hy droxy cy clopentyl)amino)methyl)thiophen-2- yl)phenyl)cyclopropyl)-2-methyl benzamide (24.4 mg, 44.1 pmol, 91% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 517.2 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.31 (br d, J= 4.1 Hz, 2H), 9.25 - 9.06 (m, 2H), 8.98 - 8.92 (m, 1H), 7.54 - 7.42 (m, 3H), 7.41 - 7.32 (m, 2H), 7.17 - 7.10 (m, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.60 - 6.48 (m, 2H), 4.42 - 4.32 (m, 3H), 4.23 (br d, J= 13 Hz, 2H), 4.14 - 4.02 (m, 2H), 3.89 - 3.71 (m, 2H), 2.25 - 2.13 (m, 4H), 1.99 - 1.84 (m, 2H), 1.76 - 1.60 (m, 3H), 1.35 - 1.22 (m, 4H).

Example 204: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2,3-dimethylphenyl)cyclop ropyl)-2- methylbenzamide (Compound 318)

Step 1

204A-1 204A-2

Step 2

Compound 318

Step 1: l-(2,3-Dimethylphenyl)cyclopropanamine (204A-2)

A mixture of 2,3 -dimethylbenzonitrile (1.00 g, 7.62 mmol, 1.0 eq) in anhydrous Et20 (50 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (2.17 g, 7.62 mmol, 2.25 mL, 1.0 eq) slowly at -78 °C and then EtMgBr (3 M in Et20, 5.59 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (2.16 g, 15.3 mmol, 1.88 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL) and extracted with MTBE (30 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(2,3-Dimethylphenyl)cyclopropanamine (100 mg, 620 pmol, 8% yield) was obtained as a yellow oil. M + H ⁺ = 162.2 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2,3-dimethylphenyl)cyclop ropyl)-2-methylbe nzamide (Compound 318)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (166 mg, 744 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (188 mg, 1.86 mmol, 259 pL, 3.0 eq), EDCI (178 mg, 930 pmol, 1.5 eq), HOBt (126 mg, 930 pmol, 1.5 eq) and l-(2,3- dimethylphenyl)cyclopropanamine (100 mg, 620 pmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2- (Dimethylamino)ethoxy)-7V-(l-(2,3-dimethylphenyl)cyclopropyl )-2 -methylbenzamide (51.0 mg, 139 pmol, 22% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 367.2 (LCMS); flT NMR (400 MHz, DMSO-tL) 8 10.56 (br s, 1H), 8.85 (s, 1H), 7.49 - 7.44 (m, 1H), 7.11 (d, J= 8.5 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.94 - 6.90 (m, 1H), 6.76 (d, J= 2.6 Hz, 1H), 4.31 (t, J = 5.1 Hz, 2H), 3.49 - 3.40 (m, 2H), 2.80 (d, J= 4.9 Hz, 6H), 2.39 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 1.22 - 1.16 (m, 2H), 1.05 - 0.98 (m, 2H).

Example 205: /V-(l-(2, 3-Dichlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2- methylbenzamide (Compound 335)

Compound 335

Step 1: l-(2, 3-Dichlorophenyl) cyclopropanamine (205A-2)

A mixture of 2, 3 -di chlorobenzonitrile (200 mg, 1.16 mmol, 1.0 eq) in anhydrous Et2O (15 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (363 mg, 1.28 mmol, 377 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 853 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (330 mg, 2.33 mmol, 287 pmL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (2.0 mL) and MTBE (15 mL), and extracted with MTBE (15 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.2). l-(2, 3-Dichlorophenyl)cyclopropanamine (70.0 mg, 346 pmol, 30% yield) was obtained as a yellow oil. M + H ⁺ = 202.0 (LCMS).

Step 2: /V-(l-(2, 3-Dichlorophenyl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2- methyl benzamide (Compound 335)

To a solution of l-(2,3-dichlorophenyl)cyclopropanamine (50.0 mg, 247 pmol, 1.0 eq) and 5- [2-(dimethylamino)ethoxy]-2-methyl-benzoic acid (55.2 mg, 247 pmol, 1.0 eq) in DMF (1.0 mL) were added HATU (141 mg, 371 pmol, 1.5 eq) and DIEA (95.9 mg, 742 pmol, 100 pL, 3.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give A-(l-(2,3-dichlorophenyl)cyclopropyl)-5- (2-(dimethylamino)ethoxy)-2-methylbenzamide (34.4 mg, 71.5 pmol, 29% yield, HC1 salt) as a white solid. M + H ⁺ = 407.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.09 (br s, 1H), 9.02 - 8.92 (m, 1H), 7.70 (dd, J= 1.2, 7.8 Hz, 1H), 7.54 (dd, J= 1.2, 8.0 Hz, 1H), 7.33 (t, J= 8.0 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.97 - 6.91 (m, 1H), 6.80 (d, J= 2.8 Hz, 1H), 4.29 (t, J = 4.8 Hz, 2H), 3.47 (q, J= 4.8 Hz, 2H), 2.82 (d, J= 4.8 Hz, 6H), 2.10 (s, 3H), 1.26 - 1.19 (m, 2H), 1.19 - 1.13 (m, 2H).

Example 206: /V-(l-(2-Bromo-3-methylphenyl)cyclopropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (Compound 317)

Step 1

206A-1 206A-2 ep

Compound 317

Step 1: l-(2-Bromo-3-methylphenyl)cyclopropanamine (206A-2)

A mixture of 2-bromo-3 -methylbenzonitrile (200 mg, 1.02 mmol, 1.0 eq) in anhydrous Et20 (15 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (290 mg, 1.02 mmol, 301 pL, 1.0 eq) slowly at -78 °C and then EtMgBr (3 M in Et20, 748 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (290 mg, 2.04 mmol, 252 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(2-Bromo- 3-methylphenyl)cyclopropanamine (150 mg, 633 pmol, 65% yield) was obtained as a yellow oil. M + H ⁺ = 226.2 (LCMS).

Step 2: N-( l-(2-Bromo-3-methylphenyl)cyclopropyl)-5-(2-(dimethylamino)e thoxy)-2-met hylbenzamide (Compound 317)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (82.9 mg, 372 pmol, 1.2 eq) in DCM (2.0 mL) were added TEA (94.0 mg, 929 pmol, 129 pL, 3.0 eq), EDCI (89.0 mg, 464 pmol, 1.5 eq), HOBt (62.8 mg, 464 pmol, 1.5 eq) and 1 -(2 -bromo-3 -methylphenyl) cyclopropanamine (70.0 mg, 310 pmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l -(2 -Bromo-3 -methylphenyl) cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methylbenzamide (35.7 mg, 82.8 pmol, 27% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 431.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.75 (br s, 1H), 8.79 (s, 1H), 7.59 - 7.52 (m, 1H), 7.27 - 7.18 (m, 2H), 7.11 (d, J= 8.5 Hz, 1H), 6.96 - 6.90 (m, 1H), 6.81 (d, = 2.6 Hz, 1H), 4.32 (br d, J= 5.1 Hz, 2H), 3.53 - 3.40 (m, 2H), 2.80 (d, J= 4.9 Hz, 6H), 2.37 (s, 3H), 2.11 (s, 3H), 1.29 - 1.20 (m, 2H), 1.14 - 1.05 (m, 2H).

Example 207: /V-(l-(3-Bromo-2-methylphenyl)cyclopropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (Compound 336) Compound 336

Step 1: l-(3-Bromo-2-methylphenyl)cyclopropanamine (207A-2)

A mixture of 3 -bromo-2-m ethylbenzonitrile (500 mg, 2.55 mmol, 1.0 eq) in anhydrous Et20 (25 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (725 mg, 2.55 mmol, 753 pL, 1.0 eq) slowly and then EtMgBr (3 M in Et20, 1.87 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (724 mg, 5.10 mmol, 630 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (15 mL) and MTBE (15 mL) and extracted with MTBE (15 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (25 mL x 4). The combined organic layers were dried over ISfeSCL, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(3-Bromo-2- methylphenyl)cyclopropanamine (140 mg, 619 pmol, 24% yield) was obtained as a yellow gum. M + H ⁺ = 226.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.43 (d, J= 7.9 Hz, 1H), 7.27 (d, J= 7.5 Hz, 1H), 7.03 (t, J= 7.8 Hz, 1H), 2.48 (br d, J= 1.6 Hz, 3H), 0.88 - 0.83 (m, 2H), 0.77 - 0.70 (m, 2H).

Step 2: /V-(l-(3-Bromo-2-methylphenyl)cyclopropyl)-5-(2-(dimethylami no)ethoxy)-2-met hylbenzamide (Compound 336)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (166 mg, 743 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (188 mg, 1.86 mmol, 259 pL, 3.0 eq), EDCI (178 mg, 939 pmol, 1.5 eq), HOBt (125 mg, 939 pmol, 1.5 eq) and l-(3-bromo-2- methylphenyl)cyclopropanamine (140 mg, 619 pmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) at 25 °C and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(3-Bromo-2-methylphenyl)cyclopropyl)-5-(2-

(dimethylamino)ethoxy)-2-methylbenzamide (130 mg, 301 pmol, 49% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 433.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.97 - 9.83 (m, 1H), 8.95 (s, 1H), 7.66 (d, J= 7.8 Hz, 1H), 7.50 (d, J= 7.9 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.96 - 6.91 (m, 1H), 6.78 (d, J = 2.6 Hz, 1H), 4.29 (t, J = 5.0 Hz, 2H), 3.49 - 3.45 (m, 2H), 2.83 (d, J= 4.9 Hz, 6H), 2.56 (s, 3H), 2.10 (s, 3H), 1.23 - 1.18 (m, 2H), 1.14 - 1.07 (m, 2H). Example 208: 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l-(2-methyl-[l,l'-bi phenyl]-3- yl)cyclopropyl)benzamide (Compound 340)

Compound 336 Compound 340

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-methyl-[l,l'-b iphenyl]-3-yl) cyclopropyl)benzamide (Compound 340)

To a solution of A-(l-(3-bromo-2-methylphenyl)cyclopropyl)-5-(2-(dimethylamin o)ethoxy)- 2-methylbenzamide (80.0 mg, 185 pmol, 1.0 eq) in a mixture of dioxane (3.0 mL) and H2O (0.8 mL) were added phenylboronic acid (33.9 mg, 278 pmol, 1.5 eq), K2CO3 (76.9 mg, 556 pmol, 3.0 eq) and Pd(dppf)C12 (13.6 mg, 18.6 pmol, 0.1 eq) at 25 °C. The mixture was heated to 90 °C and stirred for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) at 25 °C and extracted with EtOAc (3.0 mL x 3). The combined organic layers were washed with brine (3.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l-(2-methyl-[l,r-bip henyl]-3-yl) cyclopropyl)benzamide (57.8 mg, 135 pmol, 73% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 429.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.07 (br s, 1H), 8.89 (s, 1H), 7.69 - 7.64 (m, 1H), 7.47 - 7.42 (m, 2H), 7.38 - 7.34 (m, 1H), 7.32 - 7.28 (m, 2H), 7.21 - 7.17 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.09 - 7.06 (m, 1H), 6.95 - 6.91 (m, 1H), 6.80 (d, J = 2.6 Hz, 1H), 4.29 (t, J= 5.0 Hz, 2H), 3.48 - 3.44 (m, 2H), 2.82 (d, J= 4.5 Hz, 6H), 2.37 (s, 3H), 2.12 (s, 3H), 1.24 - 1.19 (m, 2H), 1.15 - 1.10 (m, 2H). Example 209: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(5, 6,7,8- tetrahydronaphthalen-l-yl)cyclopropyl)benzamide (Compound 329)

Compound 329

Step 1: l-(5,6,7,8-Tetrahydronaphthalen-l-yl)cyclopropanamine (209A-2)

A mixture of 5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile (200 mg, 1.27 mmol, 1.0 eq) in anhydrous Et20 (15 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (361 mg, 1.27 mmol, 375 pL, 1.0 eq) slowly and then EtMgBr (3 M in Et20, 933 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (361 mg, 2.54 mmol, 314 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(5,6,7,8-Tetrahydronaphthalen-l- yl)cyclopropanamine (60.0 mg, 320 pmol, 25% yield) was obtained as a yellow gum. M + H ⁺ = 188.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 7.08 - 7.04 (m, 1H), 6.98 (t, J= 7.5 Hz, 1H), 6.92 - 6.87 (m, 1H), 2.94 (t, J = 6.0 Hz, 2H), 2.73 - 2.69 (m, 2H), 1.77 - 1.67 (m, 4H), 0.84 - 0.76 (m, 2H), 0.72 - 0.65 (m, 2H).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(5,6,7,8-tetrahyd ronaphthalen-l-yl) cyclopropyl)benzamide (Compound 329)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (85.8 mg, 384 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (97.3 mg, 961 pmol, 134 pL, 3.0 eq), EDCI (92.1 mg, 481 pmol, 1.5 eq), HOBt (64.9 mg, 481 pmol, 1.5 eq) and l-(5,6,7,8-tetrahydronaphthalen-l- yl)cyclopropanamine (60.0 mg, 320 pmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) at 25 °C and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l -(5,6,7, 8-tetrahydronaphthalen-l- yl)cyclopropyl)benzamide (15.0 mg, 38.2 pmol, 12% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 393.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.48 - 10.27 (m, 1H), 8.78 (s, 1H), 7.41 (br d, J= 7.4 Hz, 1H), 7.11 (br d, J= 8.4 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.96 - 6.89 (m, 2H), 6.76 (s, 1H), 4.30 (br s, 2H), 3.46 (br d, J= 4.3 Hz, 2H), 2.96 (br s, 2H), 2.81 (br d, J= 3.9 Hz, 6H), 2.73 (br s, 2H), 2.09 (s, 3H), 1.74 (br d, J= 4.4 Hz, 4H), 1.14 (br s, 2H), 1.02 (br s, 2H).

Example 210: /V-(l-(Benzofuran-7-yl)cyclopropyl)-5-(2-(dimethylamino)etho xy)-2- methylbenzamide (Compound 370)

Step 1 Step 2

210A-1 210A-2

Compound 370

Step 1: l-(Benzofuran-7-yl)cyclopropanamine (210A-2)

To a mixture of benzofuran-7-carbonitrile (200 mg, 1.40 mmol, 1.0 eq) in anhydrous Et20 (20 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (437 mg, 1.54 mmol, 450 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 1.02 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (397 mg, 2.79 mmol, 350 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (20 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.2). l-(Benzofuran-7-yl)cyclopropanamine (60.0 mg, 0.35 mmol, 25% yield) was obtained as a yellow oil. M + H ⁺ = 174.1 (LCMS).

Step 2: N-( l-(Benzofuran-7-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)- 2-methylbenz amide (Compound 370)

To a solution of l-(benzofuran-7-yl)cyclopropanamine (50.0 mg, 289 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (64.5 mg, 289 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (58.4 mg, 0.58 mmol, 80.3 pL, 2.0 eq), EDCI (83.0 mg, 0.43 mmol, 1.5 eq) and HOBt (58.5 mg, 0.43 mmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (100 x 40 mm, 3 pm); flow rate: 50 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 7V-(l-(Benzofuran-7- yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamid e (50.0 mg, 118 pmol, 41% yield, FA salt) was obtained as a white gum. M + H ⁺ = 379.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.08 (s, 1H), 8.18 (s, 1H), 7.88 - 8.04 (m, 1H), 7.45 - 7.55 (m, 1H), 7.29 - 7.37 (m, 1H), 7.17 - 7.24 (m, 1H), 7.08 - 7.14 (m, 1H), 6.87 - 6.97 (m, 3H), 4.07 (t, J= 5.68 Hz, 2H), 2.62 - 2.79 (m, 2H), 2.27 (s, 6H), 2.16 (s, 3H), 1.50 - 1.67 (m, 2H), 1.27 (br d, J= 1.71 Hz, 2H).

Example 211: /V-(l-(Benzofuran-4-yl)cyclopropyl)-5-(2-(dimethylamino)etho xy)-2- methylbenzamide (Compound 357)

Step 2 Compound 357

Step 1: l-(Benzofuran-4-yl)cyclopropanamine (211A-2)

A suspension of benzofuran-4-carbonitrile (200 mg, 1.40 mmol, 1.0 eq) in anhydrous Et20 (15 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (397 mg, 1.40 mmol, 412 pL, 1.0 eq) slowly at -78 °C and then EtMgBr (3 M in Et20, 1.02 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (397 mg, 2.79 mmol, 345 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HC1 (I M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (15 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude product l-(benzofuran-4-yl)cyclopropanamine (120 mg), which was used in the next step without any further purification. M + H ⁺ = 174.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 6 7.97 (d, J= 2.2 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.22 - 7.16 (m, 3H), 0.93 (t, J = 2.3 Hz, 2H), 0.90 (t, J = 2.3 Hz, 2H).

Step 2: /V-(l-(Benzofuran-4-yl)cyclopropyl)-5-(2-(dimethylamino)etho xy)-2-methyl benzamide (Compound 357)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (170 mg, 762 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (193 mg, 1.91 mmol, 265 pL, 3.0 eq), EDCI (183 mg, 953 pmol, 1.5 eq), HOBt (129 mg, 953 pmol, 1.5 eq) and l-(benzofuran-4-yl) cyclopropanamine (110 mg, 635 pmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). N- (l-(Benzofuran-4-yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy) -2-methyl benzamide (69.0 mg, 182 pmol, 29% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 379.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 10.63 (br s, 1H), 9.18 (s, 1H), 8.00 (d, J= 2.0 Hz, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.26 - 7.21 (m, 1H), 7.12 (d, J= 8.4 Hz, 1H), 6.96 - 6.92 (m, 1H), 6.82 (d, J= 2.6 Hz, 1H), 4.33 (t, J= 4.9 Hz, 2H), 3.50 - 3.42 (m, 2H), 2.81 (d, J = 4.9 Hz, 6H), 2.07 (s, 3H), 1.25 (s, 4H).

Example 212: /V-(l-(Benzo[/>]thiophen-7-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2- methylbenzamide (Compound 368)

212A-1 ^{Step 1} 212A-2 Step 2 212A-3

Step 3

Compound 368

Step 1: Benzo[/>]thiophene-7-carbonitrile (212A-2)

To a solution of 7-bromobenzo[Z>]thiophene (200 mg, 939 pmol, 1.0 eq) in DMF (4.0 mL) were added Zn(CN)2 (77.2 mg, 657 pmol, 41.7 pL, 0.7 eq) and Pd(PPh3)4 (108 mg, 93.9 pmol, 0.1 eq) at 25 °C under a N2 atmosphere. The mixture was stirred at 120 °C for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/5, R/= 0.4). Benzo[Z>]thiophene-7-carbonitrile (140 mg, 879 pmol, 94% yield) was obtained as a white solid. M + H ⁺ = 160.0 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.25 (d, J= 8.1 Hz, 1H), 8.06 - 7.91 (m, 2H), 7.69 - 7.53 (m, 2H).

Step 2: l-(Benzo[/>]thiophen-7-yl)cyclopropanamine (212A-3)

A mixture of benzo[Z>]thiophene-7-carbonitrile (140 mg, 879 pmol, 1.0 eq) in anhydrous Et2O (15 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (250 mg, 879 pmol, 260 pL, 1.0 eq) slowly at -78 °C and then EtMgBr (3 M in Et2O, 645 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (250 mg, 1.76 mmol, 217 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (8.0 mL) and MTBE (8.0 mL) and extracted with MTBE (8.0 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 4). The combined organic layers were dried overNa2SO4, filtered, and concentrated under vacuum. l-(Benzo[Z>]thiophen- 7-yl)cyclopropane amine (80 mg, 423 pmol, 48% yield) was obtained as a yellow gum, which was used in the next step without any further purification. M + H ⁺ = 190.0 (LCMS); 'H NMR (400 MHz, DMSO ) 6 7.79 - 7.67 (m, 2H), 7.47 (d, J = 5.5 Hz, 1H), 7.34 - 7.25 (m, 2H), 0.96 (t, J= 2.3 Hz, 2H), 0.92 (t, J= 2.3 Hz, 2H).

Step 3: /V-(l-(Benzo[/>]thiophen-7-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methyl benzamide (Compound 368)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (113 mg, 507 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (128 mg, 1.27 mmol, 176 pL, 3.0 eq), EDCI (122 mg, 634 pmol, 1.5 eq), HOBt (85.7 mg, 634 pmol, 1.5 eq) and l-(benzo[Z>]thiophen-7- yl)cyclopropanamine (80.0 mg, 423 pmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over ISfeSCU, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l- (Benzo[Z>]thiophen-7-yl)cyclopropyl)-5-(2-(dimethylamino) ethoxy)-2-methylbenzamide (93.0 mg, 236 pmol, 56% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 395.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 10.65 (br s, 1H), 9.13 (s, 1H), 7.82 - 7.73 (m, 2H), 7.53 - 7.44 (m, 2H), 7.35 (t, J= 7.6 Hz, 1H), 7.12 (d, J= 8.5 Hz, 1H), 6.99 - 6.91 (m, 1H), 6.89 (d, J = 2.6 Hz, 1H), 4.48 - 4.27 (m, 2H), 3.62 - 3.34 (m, 2H), 2.81 (d, J= 4.9 Hz, 6H), 2.08 (s, 3H), 1.34 - 1.23 (m, 4H).

Example 213: /V-(l-(Benzo[/>]thiophen-4-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2- methylbenzamide (Compound 356)

Step 1

213A-1 213A-2

Step 2

Compound 356

Step 1: l-(Benzo[/>]thiophen-4-yl)cyclopropanamine (213A-2)

A mixture of benzo[Z>]thiophene-4-carbonitrile (200 mg, 1.26 mmol, 1.0 eq) in anhydrous Et20 (15 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (357 mg, 1.26 mmol, 371 pL, 1.0 eq) slowly and then EtMgBr (3 M in Et20, 921 pL, 2.2 eq) was added dropwise over 1 h to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (357 mg, 2.51 mmol, 310 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (8.0 mL) and MTBE (8.0 mL) and extracted with MTBE (8.0 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product, l-(benzo[Z>]thiophen-4-yl)cyclopropanamine (100 mg), which was used in the next step without any further purification. M + H ⁺ = 173.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.89 - 7.83 (m, 1H), 7.79 (s, 2H), 7.32 - 7.25 (m, 2H), 0.99 - 0.93 (m, 2H), 0.86 - 0.79 (m, 2H).

Step 2: N-( l-(Benzo[/>]thiophen-4-yl)cyclopropyl)-5-(2-(dimethylamin o)ethoxy)-2-methyl benzamide (Compound 356)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (142 mg, 634 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (160 mg, 1.58 mmol, 221 pL, 3.0 eq), EDCI (152 mg, 792 pmol, 1.5 eq), HOBt (107 mg, 792 pmol, 1.5 eq) and l-(benzo[Z>]thiophen-4- yl)cyclopropanamine (100 mg, 528 pmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into water (5.0 mL) at 25 °C and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(Benzo[Z>]thiophen-4-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2- methylbenzamide (8.90 mg, 22.6 pmol, 4% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 395.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.15 - 9.99 (m, 1H), 9.15 (s, 1H), 8.03 (d, J= 5.5 Hz, 1H), 7.90 (d, J= 8.1 Hz, 1H), 7.82 (d, J= 5.5 Hz, 1H), 7.56 (d, J= 13 Hz, 1H), 7.31 (t, J= 7.7 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.93 - 6.90 (m, 1H), 6.72 (d, J= 2.3 Hz, 1H), 4.26 (br t, J = 4.9 Hz, 2H), 3.48 - 3.42 (m, 2H), 2.80 (d, J = 4.8 Hz, 6H), 2.01 (s, 3H), 1.30 - 1.25 (m, 2H), 1.19 - 1.14 (m, 2H).

Example 214: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-methylbenzo[J| thiazol-7- yl)cyclopropyl)benzamide (Compound 403) p

Compound 403

Step 1: 2-Methylbenzo[ |thiazole-7-carbonitrile (214A-2)

To a mixture of 7-bromo-2-methylbenzo[J]thiazole (500 mg, 2.20 mmol, 1.0 eq) in DMF (6.0 mL) was degassed and purged with N2 three times. To the mixture were added Zn(CN)2 (386 mg, 3.28 mmol, 1.5 eq), Zn (14.3 mg, 0.22 mmol, 0.1 eq), Pd2(dba)3 (100 mg, 0.11 mmol, 0.05 eq) and DPPF (122 mg, 0.22 mmol, 0.1 eq). The resulting mixture was stirred at 140 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (6.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. 2-Methylbenzo[d]thiazole-7-carbonitrile (300 mg, 1.72 mmol, 79% yield) was obtained as a white solid. M + H ⁺ = 175.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.17 (dd, J= 0.9, 8.2 Hz, 1H), 7.71 (dd, J= 0.9, 7.6 Hz, 1H), 7.49 - 7.59 (m, 1H), 2.91 (s, 3H)

Step 2: l-(2-Methylbenzo[ |thiazol-7-yl)cyclopropanamine (214A-3)

To a mixture of 2-methylbenzo[d]thiazole-7-carbonitrile (200 mg, 1.15 mmol, 1.0 eq) in anhydrous Et2O (10 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (489 mg, 1.72 mmol, 510 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 840 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (326 mg, 2.30 mmol, 280 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product l -(2-methylbenzo[t/]thiazol-7- yl)cyclopropanamine (80.0 mg) as a yellow oil. M + H ⁺ = 205.0 (LCMS);

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(2-methylbenzo[J| thiazol-7- yl)cyclopropyl)benzamide (Compound 403)

To a solution of l-(2-methylbenzo[d]thiazol-7-yl)cyclopropanamine (50.0 mg, 245 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (54.6 mg, 245 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (49.5 mg, 0.49 mmol, 68.1 pL, 2.0 eq), EDCI (70.4 mg, 370 pmol, 1.5 eq) and HOBt (49.6 mg, 370 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2- (Dimethylamino)ethoxy)-2-methyl-7V-(l-(2-methylbenzo[J]thiaz ol-7-yl)cyclopropyl) benzamide (10.0 mg, 22.2 pmol, 9% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 410.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.71 - 7.86 (m, 1H), 7.37 - 7.48 (m, 2H), 7.08 - 7.23 (m, 1H), 6.80 - 7.02 (m, 2H), 4.33 (br d, J= 4.25 Hz, 2H), 3.49 (br t, J = 4.9 Hz, 2H), 2.71 - 2.92 (m, 9H), 2.01 - 2.18 (m, 3H), 1.29 (br d, J= 5.9 Hz, 4H).

Example 215: /V-(l-(Benzo[/>]thiophen-3-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2- methylbenzamide (Compound 346)

Compound 346

Step 1: l-(Benzo[/>]thiophen-3-yl)cyclopropanamine (215A-2)

To a mixture of benzo[Z>]thiophene-3 -carbonitrile (300 mg, 1.88 mmol, 1.0 eq) in anhydrous Et2O (30 mL) was degassed and purged with N2 three times. The mixture was stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (589 mg, 2.07 mmol, 610 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 1.38 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (535 mg, 3.77 mmol, 470 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.3). l-(Benzo[Z>]thiophen-3-yl)cyclopropanamine (120 mg, 0.63 mmol, 34% yield) was obtained as a white solid. M + H ⁺ = 190.0 (LCMS); 'H NMR (400 MHz, DMSO4) 8 8.07 - 8.16 (m, 1H), 7.96 (d, J= 7.50 Hz, 1H), 7.52 (s, 1H), 7.33 - 7.46 (m, 2H), 3.06 (br s, 2H), 0.91 - 0.99 (m, 2H), 0.84 - 0.91 (m, 2H).

Step 2: /V-(l-(Benzo[/>]thiophen-3-yl)cyclopropyl)-5-(2-(dimethyl amino)ethoxy)-2-methyl benzamide (Compound 346)

To a solution of l-(benzo[Z>]thi ophen-3 -yl)cy cl opropanamine (90.0 mg, 476 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (106 mg, 476 pmol, 1.0 eq) in DCM (3 mL) were added TEA (96.2 mg, 950 pmol, 132 pL, 2.0 eq), EDCI (137 mg, 710 pmol, 1.5 eq) and HOBt (96.4 mg, 710 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 10% - 50% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(Benzo[Z>]thiophen-3- yl)cyclopropyl)-5-(2-(dimethylamino)ethoxy)-2-methylbenzamid e (40.0 mg, 92.6 pmol, 20% yield, HC1 salt) was obtained as a yellow oil. M + H ⁺ = 395.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.73 (br s, 1H), 9.16 (s, 1H), 8.32 (d, J = 7.88 Hz, 1H), 7.95 (d, J= 7.88 Hz, 1H), 7.67 (s, 1H), 7.31 - 7.50 (m, 2H), 7.04 - 7.16 (m, 1H), 6.87 - 6.97 (m, 1H), 6.72 - 6.81 (m, 1H), 4.31 (t, J = 5.07 Hz, 2H), 3.45 (q, J = 5.04 Hz, 2H), 2.79 (d, J = 4.88 Hz, 6H), 2.03 (s, 3H), 1.13 - 1.28 (m, 4H).

Example 216: 5-(2-( Dime! hylam ino)etlioxy)-2-niethyl-\-(l-(l -met hyl-l//-indol-3- yl)cyclopropyl)benzamide (Compound 354)

216A-1 216A-2 216A-3

Step 3

Compound 354

Step 1: 1 -Methyl- 1 //-indole-3-carbonit rile (216A-2)

To a solution of UT-indole-3 -carbonitrile (2.00 g, 14.7 mmol, 1.0 eq) in DMF (20 mL) were added DABCO (316 mg, 2.81 mmol, 309 pL, 0.2 eq) and dimethyl carbonate (21.4 g, 238 mmol, 20.0 mL, 16.9 eq). The mixture was stirred at 95 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/1. 1 -Methyl- U/-indole-3 -carbonitrile (2.00 g) was obtained as a brown oil. M + H ⁺ = 157.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.24 (s, 1H), 7.74 - 7.58 (m, 2H), 7.47 - 7.20 (m, 2H), 3.87 (s, 3H).

Step 2: l-( 1 -Methyl- l//-indol-3-yl)cyclopropanainine (216A-3)

A mixture of 1 -methyl- U/-indole-3 -carbonitrile (500 mg, 3.20 mmol, 1.0 eq) in anhydrous Et2O (35 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z- PrO)4 (1.00 g, 3.52 mmol, 1.04 mL, 1.1 eq) slowly at -78 °C, and then EtMgBr (3 M in Et2O, 2.35 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (909 mg, 6.40 mmol, 790 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (30 mL) and MTBE (30 mL), and extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (30 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. l-(l-Methyl-177-indol-3-yl)cyclopropanamine (80.0 mg) was obtained as a brown oil. M - 17 + H ⁺ = 170.1 (LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(l-methyl-lH-indo l-3- yl)cyclopropyl)benzamide (Compound 354)

To a solution of 1-(1 -methyl- 17/-indol-3-yl)cy cl opropanamine (50.0 mg, 268 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (59.9 mg, 268 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (81.5 mg, 805 pmol, 112 pL, 3.0 eq), EDCI (129 mg, 671 pmol, 2.5 eq) and HOBt (90.7 mg, 671 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2- methyl-A-(l-(l -methyl- 17/-indol-3-yl)cy cl opropyl)benzamide (13.8 mg, 30.7 pmol, 11% yield, FA salt) was obtained as a white solid. M + H ⁺ = 392.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.93 (s, 1H), 8.17 (s, 1H), 7.88 (d, J= 7.9 Hz, 1H), 7.36 (d, J= 8.3 Hz, 1H), 7.23 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.85 (dd, J = 2.8, 8.4 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 4.00 (t, J= 5.8 Hz, 2H), 3.73 (s, 3H), 2.63 (t, J= 5.8 Hz, 2H), 2.26 - 2.20 (m, 6H), 2.11 (s, 3H), 1.19 - 1.08 (m, 4H).

Example 217: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(l-phenyl-lH-indo l-3- yl)cyclopropyl)benzamide (Compound 395) p

Compound 395

Step 1: 1 -Phenyl- 1 //-indole-3-carbonit rile (217A-2)

To a solution of UT-indole-3 -carbonitrile (150 mg, 1.06 mmol, 1.0 eq) in toluene (3.0 mL) were added Cui (20.1 mg, 105 pmol, 0.1 eq), K3PO4 (470 mg, 2.22 mmol, 2.1 eq), bromobenzene (198 mg, 1.27 mmol, 133 pL, 1.2 eq) and 7V,7V-dimethylethane-l,2-diamine (18.6 mg, 211 pmol, 22.7 pL, 0.2 eq) at 25 °C under a N2 atmosphere. The mixture was stirred at 110 °C for 24 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mL x 3) and dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. I -Phenyl- 17/- indole-3 -carbonitrile (200 mg, 916 pmol, 87% yield) was obtained as a white solid. M + H ⁺ = 219.1 (LCMS).

Step 2: l-( l-Phenyl-l//-indol-3-yl)cyclopropanainine (217A-3)

A mixture of 1 -phenyl- UT-indole-3 -carbonitrile (500 mg, 2.29 mmol, 1.0 eq) in anhydrous Et2O (25 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (977 mg, 3.44 mmol, 1.01 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 1.68 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (650 mg, 4.58 mmol, 565 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (8.0 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 1 -(1 -Phenyl-1 //-indol-3- yl)cyclopropanamine (130 mg, 523 pmol, 23% yield) was obtained as a white solid. M + H ⁺ = 249.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 7.78 (br d, J= 13 Hz, 1H), 7.64 - 7.42 (m, 7H), 7.21 - 7.07 (m, 2H), 0.98 (br s, 2H), 0.87 (br s, 2H).

Step 3: 5-(2-(l)iinetliyl:iiniiio)ethoxy)-2-niethyl- \-( l-( 1 -phenyl- l//-indol-3-yl)cyclo propyl)benzamide (Compound 395)

To a solution of l-(l-phenyl-U/-indol-3-yl)cyclopropanamine (70.0 mg, 282 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (75.5 mg, 338 pmol, 1.2 eq) in DCM (3.0 mL) were added TEA (85.6 mg, 846 mmol, 118 pL, 3.0 eq), EDCI (81.1 mg, 423 pmol, 1.5 eq) and HOBt (57.1 mg, 423 mmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2- methyl-A-(l-(l-phenyl-lH-indol-3-yl)cyclopropyl)benzamide (41.2 mg, 82.5 pmol, 29% yield, FA salt) was obtained as a white solid. M + H ⁺ = 454.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.05 (s, 1H), 8.21 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.62 - 7.52 (m, 6H), 7.44 - 7.32 (m, 1H), 7.24 - 7.17 (m, 1H), 7.16 - 7.11 (m, 1H), 7.08 (d, J= 8.4 Hz, 1H), 6.86 (dd, J= 2.7, 8.4 Hz, 1H), 6.77 (d, J= 2.7 Hz, 1H), 4.00 (t, J = 5.8 Hz, 2H), 2.59 (t, J = 5.8 Hz, 2H), 2.20 (s, 6H), 2.13 (s, 3H), 1.24 (br d, J= 3.5 Hz, 2H), 1.20 (br d, J= 3.8 Hz, 2H).

Example 218: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(quinolin-5- yl)cyclopropyl)benzamide (Compound 301)

218A-1 218A-2

Compound 301

Step 1: l-(Quinolin-5-yl)cyclopropanamine (218A-2)

A mixture of quinoline-5-carbonitrile (500 mg, 3.24 mmol, 1.0 eq) in anhydrous Et20 (40 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (1.38 g, 4.86 mmol, 1.44 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et20, 2.38 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (921 mg, 6.49 mmol, 801 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (40 mL) and MTBE (40 mL), and extracted with MTBE (40 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (40 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. l-(Quinolin-5-yl)cyclopropanamine (225 mg) was obtained as a brown solid. M + H ⁺ = 185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(quinolin-5-yl)cy clopropyl) benzamide (Compound 301)

To a solution of l-(quinolin-5-yl)cyclopropanamine (80.0 mg, 434 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (97.0 mg, 434 pmol, 1.0 eq) in DCM (3 mL) was added TEA (87.9 mg, 868 pmol, 121 pL, 2.0 eq), EDCI (125 mg, 651 pmol, 1.5 eq) and HOBt (88.0 mg, 651 pmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (75 x 30 mm, 3 m); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2(Dimethylamino)ethoxy)-2- methyl-7V-(l-(quinolin-5-yl)cyclopropyl)benzamide (13.3 mg, 29.0 pmol, 7% yield) as a yellow gum. M + H ⁺ = 390.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.13 (s, 1H), 9.10 - 9.05 (m, 1H), 8.95 - 8.86 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.75 - 7.67 (m, 1H), 7.63 - 7.52 (m, 1H), 7.07 - 7.00 (m, 1H), 6.88 - 6.80 (m, 1H), 6.65 - 6.58 (m, 1H), 3.94 (t, J= 5.8 Hz, 2H), 2.56 - 2.53 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.43 - 1.30 (m, 2H), 1.20 (s, 2H).

Example 219: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 374)

Compound 374

Step 1: /cr/- Butyl (2-(4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)phen oxy) ethyl)carbamate (219A-1)

To a solution of 5-(2-((/ert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (192 mg, 651 pmol, 1.2 eq) and l-(quinolin-5-yl)cyclopropanamine (100 mg, 543 pmol, 1.0 eq) in DCM (1.0 mL) were added TEA (165 mg, 1.63 mmol, 227 pL, 3.0 eq), EDCI (156 mg, 814 pmol, 1.5 eq) and HOBt (110 mg, 814 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product /c/7-butyl (2-(4-methyl-3-((l-(quinolin-5- yl)cyclopropyl)carbamoyl) phenoxy) ethyl)carbamate (150 mg, 325 pmol, 60% yield) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 462.2 (LCMS).

Step 2: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(quinolin-5-yl)cyclopropyl) benzamide (Compound 374)

To a stirred solution of tert-butyl (2-(4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl) phenoxy) ethyl)carbamate (150 mg, 325 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-Aminoethoxy)-2-methyl-7V-(l-(quinolin-5-yl)cyclopropyl) benzamide (120 mg, 318 pmol, 96% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 362.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.88 (d, J= 8.6 Hz, 1H), 9.43 (s, 1H), 9.35 - 9.29 (m, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.34 (br s, 3H), 8.21 - 8.15 (m, 2H), 8.15 - 8.08 (m, 1H), 7.07 (d, J= 8.5 Hz, 1H), 6.89 (dd, J= 2.6, 8.4 Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 4.13 (t, J= 5.1 Hz, 2H), 3.17 - 3.06 (m, 2H), 1.96 (s, 3H), 1.51 - 1.41 (m, 2H), 1.34 - 1.27 (m, 2H).

Example 220: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(quinolin-5- yl)cyclopropyl)benzamide (Compound 385)

Compound 385 Step 1: tert-Butyl methyl(2-(4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoy l) phenoxy)ethyl)carbamate (220A-1)

To a solution of l-(quinolin-5-yl)cyclopropanamine (100 mg, 543 pmol, 1.0 eq) and 5-(2- ((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2 -methylbenzoic acid (168 mg, 543 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (165 mg, 1.63 mmol, 227 pL, 3.0 eq), EDCI (260 mg, 1.36 mmol, 2.5 eq) and HOBt (183 mg, 1.36 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product tert-butyl methyl(2-(4-methyl-3-((l-(quinolin- 5-yl)cyclopropyl)carbamoyl) phen oxy)ethyl)carbamate (250 mg) as a brown oil which was used into the next step without further purification. M + H ⁺ = 476.2 (LCMS).

Step 2: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(quinolin-5-yl)cycl opropyl)benzamide (Compound 385)

To a solution of tert-butyl methyl(2-(4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoy l) phenoxy)ethyl)carbamate (250 mg, 526 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-N-(l-(quinolin-5-yl)cyclo propyl) benzamide (44.4 mg, 107 pmol, 20% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 376.1 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 8 10.06 (d, J= 8.5 Hz, 1H), 9.27 (dd, J= 1.3, 5.4 Hz, 1H), 8.36 (dd, J= 1.3, 6.9 Hz, 1H), 8.27 - 8.15 (m, 3H), 7.11 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 2.7, 8.4 Hz, 1H), 6.82 (d, J= 2.6 Hz, 1H), 4.26 - 4.15 (m, 2H), 3.44 - 3.37 (m, 2H), 2.76 (s, 3H), 2.02 (s, 3H), 1.65 - 1.59 (m, 2H), 1.48 - 1.42 (m, 2H). Example 221: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(quinolin-5- yl)cyclopropyl)benzamide (Compound 381)

221A-3 Compound 381

Step 1: (. )-/c/7-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-l- carboxylate (221A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) and (5)- /c/7-butyl 2-(hydroxymethyl)azetidine-l -carboxylate (508 mg, 2.72 mmol, 1.5 eq) in toluene (15 mL) were added TMAD (935 mg, 5.43 mmol, 3.0 eq) and PPhi (1.42 g, 5.43 mmol, 3.0 eq). The resulting mixture was degassed and purged with N2 three times and then stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. (A')-/c77-Butyl 2-((3-(m ethoxy carbonyl)-4- methylphenoxy)methyl)azetidine-l -carboxylate (500 mg, 1.49 mmol, 82% yield) was obtained as a white solid. M - 100+ H ⁺ = 236.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.49 (br d, J= 1.5 Hz, 1H), 7.15 (br d, J= 8.3 Hz, 1H), 7.00 (br dd, J= 1.6, 8.3 Hz, 1H), 4.51 (br d, J= 4.3 Hz, 1H), 4.28 (br s, 1H), 4.22 - 4.03 (m, 2H), 3.89 (s, 3H), 3.87 (br s, 1H), 2.52 (s, 3H), 2.42 - 2.13 (m, 2H), 1.42 (s, 9H).

Step 2: (5)-5-((l-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth ylbenzoic acid (221A-2)

To a solution of fS')-/c77-butyl 2-((3 -(methoxy carbonyl)-4-methylphenoxy)methyl)azeti dine- 1- carboxylate (500 mg, 1.49 mmol, 1.0 eq) in a mixture of MeOH (20 mL) and THF (10 mL) was added NaOH (2 M aqueous, 3.0 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and washed with petroleum ether (10 mL x 3). The aqueous layer was acidified to pH 5 with HC1 (I M aqueous). The product was extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product CS')-5-(( l -(/c77-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (100 mg) as a white solid. M + H ⁺ = 318.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.62 (d, J= 2.7 Hz, 1H), 7.17 (s, 1H), 7.08 (br d, J= 2.7 Hz, 1H), 4.53 (br d, J= 2.0 Hz, 1H), 4.31 (br s, 1H), 4.12 (dd, J= 2.9, 10.1 Hz, 1H), 4.01 - 3.83 (m, 2H), 2.58 (s, 3H), 2.44 - 2.19 (m, 2H), 1.43 (s, 9H).

Step 3: (S)-/c/7-Butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cycloprop yl)carbamoyl) phenoxy)methyl)azetidine-l-carboxylate (221A-3)

To a solution of CS')-5-(( l -(/c77-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (100 mg, 311 pmol, 1.0 eq) and l-(quinolin-5-yl)cyclopropanamine (68.8 mg, 373 pmol, 1.2 eq) in DMF (3.0 mL) were added TEA (94.5 mg, 933 pmol, 130 pL, 3.0 eq), EDCI (89.5 mg, 467 pmol, 1.5 eq) and HOBt (63.1 mg, 466 pmol, 1.5 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R/= 0.6). fS')-/c/7-Butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)phen oxy) methyl) azetidine- 1 -carboxylate (120 mg, 246 pmol, 79% yield) was obtained as a white solid. M + H ⁺ = 488.3 (LCMS). Step 4: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(quinolin-5-yl)c yclopropyl) benzamide (Compound 381)

To a stirred solution of CS')-/c/7-butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cycloprop yl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (110 mg, 226 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.9 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (C18 column (150* 30 mm, 3 pm); flow rate: 60 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-5- (Azetidin-2-ylmethoxy)-2-methyl-7V-(l-(quinolin-5-yl)cyclopr opyl) benzamide (43.4 mg, 86.5 prnol, 39% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 388.1 (LCMS); ^T H NMR (400 MHz, DMSO ) 8 9.27 (br d, J= 8.3 Hz, 1H), 9.17 (s, 1H), 9.03 (dd, J= 1.3, 4.3 Hz, 1H), 8.99 - 8.72 (m, 2H), 8.13 - 7.89 (m, 2H), 7.87 - 7.67 (m, 2H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.80 - 4.51 (m, 1H), 4.34 - 4.07 (m, 2H), 4.03 - 3.69 (m, 2H), 2.47 - 2.18 (m, 2H), 1.95 (s, 3H), 1.39 (s, 2H), 1.29 - 1.20 (m, 2H).

Example 222: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 383)

Step 3

222A-2 222A-3

Compound 383

Step 1: (l?)-tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)azetidine-l- carboxylate (222 A- 1)

A mixture of methyl 5 -hydroxy -2-methylbenzoate (500 mg, 3.01 mmol, 1.0 eq), methyl 5- hydroxy-2-methylbenzoate (845 mg, 4.51 mmol, 1.5 eq) and PPI13 (2.37 g, 9.03 mmol, 3.0 eq) in toluene (15 mL) was degassed and purged with N2 three times. To the mixture was added TMAD (1.55 g, 9.03 mmol, 3.0 eq) in portions at 20 °C. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. (/?)-/c/7-Butyl 2-((3-(m ethoxy carbonyl)-4- methylphenoxy)methyl)azetidine-l -carboxylate (900 mg, 2.68 mmol, 89% yield) was obtained as a yellow oil. M + Na ⁺ = 358.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.37 (d, J= 2.8 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.11 (dd, J= 2.8, 8.4 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.26 (dd, J= 4.6, 10.4 Hz, 1H), 4.07 (dd, J= 2.9, 10.4 Hz, 1H), 3.82 (s, 3H), 3.76 (br t, J= 7.4 Hz, 2H), 2.42 (s, 3H), 2.34 - 2.25 (m, 1H), 2.19 - 2.09 (m, 1H), 1.33 (s, 9H).

Step 2: (l?)-5-((l-(terCButoxycarbonyl)azetidin-2-yl)methoxy)-2-meth ylbenzoic acid (222A-2)

To a solution of (/?)-/c77-butyl 2-((3 -(methoxy carbonyl)-4-methylphenoxy)methyl)azeti dine- 1- carboxylate (900 mg, 2.68 mmol, 1.0 eq) in a mixture of MeOH (2.0 mL) and THF (8.0 mL) was added NaOH (2 M aqueous, 3.00 mL, 5.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. H2O (10 mL) was added, and the mixture was washed with MTBE (10 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (I M aqueous). The product was extracted with 2, 5 -dimethyltetrahydrofuran (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (7?)-5-((l-(terC butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (200 mg, 622 pmol, 52% yield) as a yellow gum, which was used in the next step without any further purification. M + Na ⁺ = 344.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 12.50 - 12.40 (m, 1H), 7.36 (d, J= 2.9 Hz, 1H), 7.20 (d, J= 8.5 Hz, 1H), 7.07 (dd, J= 2.8, 8.4 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.24 (dd, J = 4.6, 10.3 Hz, 1H), 4.06 (dd, J = 2.8, 10.3 Hz, 1H), 3.75 (br t, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.34 - 2.24 (m, 1H), 2.19 - 2.08 (m, 1H), 1.32 (s, 9H).

Step 3: Butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)phen oxy) methyl)azetidine-l-carboxylate (222A-3)

To a solution of l-(quinolin-5-yl)cyclopropanamine (86.0 mg, 467 pmol, 1.0 eq) and (R)-5- (( l -(/c/7-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenzoic acid (150 mg, 467 pmol, 1.0 eq) in DMF (2.0 mL) were added TEA (142 mg, 1.40 mmol, 195 pL, 3.0 eq), EDCI (134 mg, 700 pmol, 1.5 eq) and HOBt (94.6 mg, 700 mmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product (/ )-/c/7-butyl 2-((4-methyl-3-((l-(quinolin- 5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (200 mg, 410 pmol, 88% yield), which was used in the next step without any further purification. M + H ⁺ = 488.2 (LCMS).

Step 4: (l?)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(quinolin-5-yl) cyclopropyl) benzamide (Compound 383)

To a stirred solution of R)-terLbutyl 2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (200 mg, 410 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (3.0 mL). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-5-(Azetidin-2-ylmethoxy)-2-methyl-7V-(l -(quinolin-5-yl)cyclopropyl)benzamide (120 mg, 310 pmol, 76% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 388.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.23 (d, J= 8.5 Hz, 1H), 9.16 (s, 1H), 9.04 - 8.98 (m, 1H), 8.94 - 8.74 (m, 2H), 8.00 (d, J= 8.4 Hz, 1H), 7.95 (d, J= 7.1 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.72 (dd, J= 4.4, 8.5 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 4.65 (br d, J = 4.9 Hz, 1H), 4.23 (dd, J= 7.2, 11.2 Hz, 1H), 4.18 - 4.10 (m, 1H), 3.98 - 3.89 (m, 1H), 3.83 (br dd, J= 6.0, 10.3 Hz, 1H), 2.48 - 2.43 (m, 1H), 2.39 - 2.30 (m, 1H), 1.95 (s, 3H), 1.44 - 1.33 (m, 2H), 1.28 - 1.19 (m, 2H).

Example 223: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(quinoli n-5- yl)cyclopropyl)benzamide (Compound 391)

223A-3 Compound 391

Step 1: (S)-M ethyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (223 A-l)

To a solution of CS')-/c/7-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine- 1-carboxylate (250 mg, 745 pmol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL, 18 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude product (^-methyl 5-(azetidin-2- ylmethoxy)-2-methylbenzoate (250 mg, TFA salt) as a yellow oil. M + H ⁺ = 236.2 (LCMS). Step 2: (S)-M ethyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (223 A-2)

To a solution of fS')-m ethyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (250 mg, 1.06 mmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (172 mg, 2.10 mmol, 158 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (134 mg, 2.13 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 100/1 to 10/1. (A')-M ethyl 2-methyl-5- ((1-methyl azetidin-2-yl)methoxy) benzoate (160 mg, 642 pmol, 60% yield) was obtained as a colorless oil. M + H ⁺ = 250.1 (LCMS).

Step 3: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (223A-3)

A solution of (S)-methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (260 mg, 1.04 mmol, 1.0 eq) in HC1 (2 M aqueous, 10 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then treated with NaOH (2 M aqueous) to adjust the pH to 6. The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with MeOH/DCM (V/V = 10/1, 10 mL) then filtered. The filter cake was washed with MeOH/DCM (V/V = 5.0 mL x 2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (160 mg, crude) as a hydrophilic, colorless oil. M + H ⁺ = 236.1 (LCMS).

Step 4: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(quinoli n-5- yl)cyclopropyl) benzamide (Compound 391)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (80.0 mg, 340 pmol, 1.0 eq) and l-(quinolin-5-yl)cyclopropanamine (43.9 mg, 238 mmol, 0.7 eq) in ACN (5.0 mL) were added TCFH (95.4 mg, 340 pmol, 1.0 eq) and NMI (27.9 mg, 340 pmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 * 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 5% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l- (quinolin-5-yl)cyclo propyl)benzamide (16.6 mg, 34.6 pmol, 10% yield, HC1 salt) was obtained as a brown solid. M + H ⁺ = 402.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 5 11.03 (br s, 1H), 9.83 (br d, J= 8.5 Hz, 1H), 9.41 - 9.36 (m, 1H), 9.31 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.21 - 8.06 (m, 3H), 7.09 (d, J = 8.3 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 4.70 - 4.57 (m, 1H), 4.42 (dd, J = 8.3, 11.0 Hz, 1H), 4.22 (dd, J= 3.2, 10.9 Hz, 1H), 4.06 - 3.92 (m, 1H), 3.84 (br dd, J= 6.8, 9.4 Hz, 1H), 2.80 (d, J= 5.0 Hz, 3H), 2.41 - 2.20 (m, 2H), 1.95 (s, 3H), 1.46 (br s, 2H), 1.34 - 1.27 (m, 2H).

Example 224: (l?)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(quin olin-5- yl)cyclopropyl)benzamide (Compound 390)

Compound 390

Step 1: (1?)-Methyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (224A-1)

To a stirred solution of (/?)-/c77-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine- 1 -carboxylate (250 mg, 745 pmol, 1.0 eq) in DCM (6.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product (/^-methyl 5-(azetidin-2-ylmethoxy)-2- methylbenzoate (250 mg, TFA salt) as a colorless oil. M + H ⁺ = 236.2 (LCMS). Step 2: (1?)-Methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (224A-2)

To a solution of (//j-methyl 5-(azeti din-2 -ylmethoxy)-2-methylbenzoate (250 mg, 716 pmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (99.6 pL), followed by the addition of formaldehyde (116 mg, 1.43 mmol, 107 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (90.0 mg, 1.43 mmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.5). (//j-Methyl 2-methyl-5-((l-methylazetidin-2- yl)methoxy)benzoate (100 mg, 401 pmol, 56% yield) was obtained as a colorless oil. M + H ⁺ = 250.2 (LCMS).

Step 3: (l?)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (224A-3)

A solution of (//j-methyl 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoate (90.0 mg, 361 pmol, 1.0 eq) in HC1 (2 M aqueous, 3.0 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then treated with NaOH (2 M aqueous) to adjust the pH to 6. The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with DCM/MeOH (V/V = 10/1, 10 mL) then filtered. The filter cake was washed with DCM/MeOH (5.0 mL x 2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give the crude product (7?)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (40.0 mg) as a hydrophilic, colorless oil. M + H ⁺ = 236.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.12 (d, J= 2.8 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.76 (dd, J= 2.8, 8.3 Hz, 1H), 3.90 (d, J= 5.5 Hz, 2H), 3.39 - 3.22 (m, 3H), 2.78 - 2.65 (m, 1H), 2.36 (s, 3H), 2.25 (s, 3H), 2.03 - 1.92 (m, 1H).

Step 4: (l?)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(quin olin-5-yl) cyclo propyl)benzamide (Compound 390)

To a solution of (7?)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (40.0 mg, 170 pmol, 1.0 eq) and l-(quinolin-5-yl)cyclopropanamine (31.3 mg, 170 mmol, 1.0 eq) in ACN (4.0 mL) were added TCFH (57.2 mg, 204 pmol, 1.2 eq) and NMI (48.9 mg, 595 pmol, 47.4 pL, 3.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate:

25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-2-Methyl-5-((l-methylazeti din-2 -yl)methoxy)-A-(l-(quinolin-5-yl) cyclo propyl)benzamide (19.8 mg, 45.2 pmol, 27% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 402.1 (LCMS); ^X H NMR (400 MHz, DMSO-tZ ₆ ) 5 11.07 (br s, 1H), 9.84 - 9.74 (m, 1H), 9.42 - 9.34 (m, 1H), 9.28 (d, J = 4.1 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.18 - 8.14

(m, 1H), 8.14 - 8.05 (m, 2H), 7.08 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 4.69 - 4.57 (m, 1H), 4.42 (dd, J = 8.2, 11.2 Hz, 1H), 4.22 (dd, J = 3.3, 11.3 Hz, 1H), 4.03 - 3.93 (m, 1H), 3.84 (br dd, J= 6.7, 9.6 Hz, 1H), 2.80 (d, J= 5.0 Hz, 3H), 2.41 - 2.23 (m, 2H), 1.95 (s, 3H), 1.50 - 1.41 (m, 2H), 1.35 - 1.26 (m, 2H). Example 225: ( )-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-/V-(l-(quinolin-5- yl)cyclopropyl)benzamide (Compound 380)

Step 2 Step 3

225A-2

225A-3 Compound 380

Step 1: (S)-/c/7-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-l - carboxylate (225 A- 1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq), (S)-tert- butyl 2-(hydroxymethyl)pyrrolidine-l -carboxylate (363 mg, 1.81 mmol, 1.0 eq) in toluene (15 mL) were added TMAD (933 mg, 5.42 mmol, 3.0 eq) and PPhi (1.42 g, 5.42 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/5. CS')-/c77-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-l - carboxylate (600 mg, 1.72 mmol, 95% yield) was obtained as a yellow oil. M + H ⁺ = 350.1 (LCMS).

Step 2: (5)-5-((l-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-me thylbenzoic acid (225A-2)

To a solution of CS')-/c/7-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine- 1-carboxylate (1.20 g, 3.43 mmol, 1.0 eq) in a mixture of MeOH (5.0 mL) and THF (15 mL) was added NaOH (2 M aqueous, 7.0 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with MTBE (15 mL x 2). The aqueous layer was acidified to pH 5 using HC1 (1 M aqueous). The product was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product GS')-5-(( l -(/c77-butoxycarbonyl)pyrrolidin-2-yl)rnethoxy)-2-rnethylben zoic acid (1.10 g, 96% yield), which was used in the next step without any further purification. M - 56 + H ⁺ = 280.1 (LCMS). Step 3: (S)-/c/7- Butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)phen oxy) methyl)pyrrolidine-l-carboxylate (225A-3)

To a solution of (5)-5-((l-(ter/-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-me thylbenzoic acid (200 mg, 596 pmol, 1.0 eq) and l-(quinolin-5-yl)cyclopropanamine (110 mg, 596 pmol, 1.0 eq) in DMF (10 mL) were added TEA (181 mg, 1.79 mmol, 249 pL, 3.0 eq), EDCI (286 mg, 1.49 mmol, 2.5 eq) and HOBt (201 mg, 1.49 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. CS')-/c/7-Butyl 2- ((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)phenox y)methyl)pyrrolidine-l- carboxylate (180 mg, 359 pmol, 60% yield) was obtained as a yellow oil. M + H ⁺ = 502.2 (LCMS).

Step 4: (5)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-/V-(l-(quinolin-5-yl )cyclopropyl)benza mide (Compound 380)

To a stirred solution of (A')-/c/7-butyl 2-((4-methyl-3-((l-(quinolin-5- yl)cy cl opropyl)carbamoyl) phenoxy)methyl)pyrrolidine-l -carboxylate (180 mg, 359 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-7V-(l-(quinolin-5- yl)cyclopropyl)benza mide (27.2 mg, 62.1 pmol, 17% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 402.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.58 - 9.41 (m, 2H), 9.27 (s, 1H), 9.17 (br d, J= 4.3 Hz, 1H), 8.98 - 8.84 (m, 1H), 8.16 (br d, J= 8.5 Hz, 1H), 8.06 (br d, J= 6.9 Hz, 1H), 8.00 - 7.89 (m, 2H), 7.09 (d, J= 8.6 Hz, 1H), 6.90 (dd, J= 2.6, 8.3 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 4.16 (dd, J= 3.9, 10.6 Hz, 1H), 4.09 - 4.01 (m, 1H), 3.88 - 3.75 (m, 1H), 3.23 - 3.12 (m, 2H), 2.12 - 2.02 (m, 1H), 1.95 (s, 4H), 1.92 - 1.82 (m, 1H), 1.73 - 1.63 (m, 1H), 1.42 (br s, 2H), 1.31 - 1.22 (m, 2H). Example 226: ( )-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(quino lin-5- yl)cyclopropyl)benzamide (Compound 379)

Step 1

Compound 380 Compound 379

Step 1: (5)-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(qui nolin-5-yl) cyclo propyl)benzamide (Compound 379)

To a solution of (5)-2-methyl-5-(pyrrolidin-2-ylmethoxy)-7V-(l-(quinolin-5-yl )cyclopropyl) benzamide (130 mg, 324 pmol, 1.0 eq) in MeOH (10 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (52.6 mg, 648 pmol, 48.2 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (40.7 mg, 648 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-A-(l-(quin olin-5-yl) cyclopropyl)benzamide (26.2 mg, 57.7 pmol, 18% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 416.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.76 - 10.57 (m, 1H), 9.73 - 9.57 (m, 1H), 9.33 (s, 1H), 9.23 (br s, 1H), 8.23 (br d, J= 8.2 Hz, 1H), 8.16 - 7.95 (m, 3H), 7.09 (d, J= 8.3 Hz, 1H), 6.92 (dd, J = 2.6, 8.4 Hz, 1H), 6.75 (br s, 1H), 4.31 - 4.20 (m, 2H), 3.73 (dt, J= 3.0, 6.8 Hz, 1H), 3.59 - 3.48 (m, 1H), 3.15 - 2.99 (m, 1H), 2.88 (br d, J= 4.8 Hz, 3H), 2.29 - 2.14 (m, 1H), 2.09 - 1.98 (m, 1H), 1.97 - 1.86 (m, 4H), 1.83 - 1.70 (m, 1H), 1.43 (br s, 2H), 1.29 (br s, 2H). Example 227 : (l?)-2-methyl-5-(pyrrolidin-2-ylmethoxy)-/V-(l-(quinolin-5- yl)cyclopropyl)benzamide (Compound 371)

227A-3 Compound 371

Step 1: Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-l - carboxylate (227 A- 1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) and (R)- /c/V-butyl 2-(hydroxymethyl)pyrrolidine-l -carboxylate (363 mg, 1.81 mmol, 1.0 eq) in toluene (15 mL) were added TMAD (933 mg, 5.42 mmol, 3.0 eq) and PPhi (1.42 g, 5.42 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times, and then stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (8.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. (/?)-/c/7-Butyl 2-((3 -(methoxy carbonyl)-4- methylphenoxy )methyl) pyrrolidine- 1 -carboxylate (590 mg, 94% yield) was obtained as a white solid. M + H ⁺ = 350.1 (LCMS).

Step 2: (l?)-5-((l-(tert-Butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-m ethylbenzoic acid (227A-2)

To a solution of (/?)-/c77-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-

1-carboxylate (1.18 g, 3.38 mmol, 1.0 eq) in a mixture of MeOH (47 mL) and THF (24 mL) was added NaOH (2 M aqueous, 7.0 mL, 4.0 eq). The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The aqueous layer was acidified to pH 7 using HC1 (1 M aqueous). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product ( ^> )-5-(( l -(/c77-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzo ic acid (1.00 g, 88% yield) as a white solid, which was used in the next step without any further purification.

Step 3: (l?)-tert-Butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)phen oxy) methyl)pyrrolidine-l-carboxylate (227A-3)

To a solution of (/?)-5-(( l -(/c77-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzo ic acid (200 mg, 596 pmol, 1.0 eq) and l-(quinolin-5-yl)cyclopropanamine (109 mg, 596 pmol, 1.0 eq) in DMF (10 mL) were added TEA (121 mg, 1.19 mmol, 166 pL, 2.0 eq), EDCI (171 mg, 894 pmol, 1.5 eq) and HOBt (121 mg, 894 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. (/?)-/c/7-Butyl

2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl)carbamoyl)p henoxy)methyl)pyrrolidine-l- carboxylate (200 mg, 399 pmol, 67% yield) was obtained as a yellow gum. M + H ⁺ = 502.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 9.13 - 9.10 (m, 1H), 9.10 - 9.06 (m, 1H), 8.92 - 8.89 (m, 1H), 7.95 (s, 1H), 7.89 - 7.85 (m, 1H), 7.74 - 7.67 (m, 1H), 7.60 - 7.55 (m, 1H), 7.05 - 7.00 (m, 1H), 6.89 - 6.84 (m, 1H), 6.69 - 6.57 (m, 1H), 3.99 - 3.91 (m, 2H), 3.82 - 3.73 (m, 1H), 3.27 - 3.21 (m, 2H), 1.95 - 1.78 (m, 7H), 1.45 - 1.31 (m, 9H), 1.30 (br s, 2H), 1.22 - 1.19 (m, 2H). Step 4: (l?)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-/V-(l-(quinolin-5-y l)cyclopropyl) benzamide (Compound 371)

To a stirred solution of (A)-tert-butyl 2-((4-methyl-3-((l-(quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-l -carboxylate (200 mg, 399 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-A-(l-(quinolin-5-yl) cyclopropyl) benzamide (34.4 mg, 78.6 pmol, 20% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 402.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.92 - 9.72 (m, 2H), 9.40 (s, 1H), 9.30 (d, J = 4.1 Hz, 1H), 9.24 - 9.12 (m, 1H), 8.35 (s, 1H), 8.16 (s, 3H), 7.07 (s, 1H), 6.95 - 6.86 (m, 1H), 6.75 (d, J= 2.6 Hz, 1H), 4.20 - 4.08 (m, 2H), 3.86 - 3.72 (m, 1H), 3.26 - 3.09 (m, 2H), 2.16 - 2.02 (m, 1H), 2.00 - 1.93 (m, 4H), 1.91 - 1.83 (m, 1H), 1.73 - 1.62 (m, 1H), 1.46 (s, 2H), 1.34 - 1.27 (m, 2H).

Example 228: (l?)-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(qu inolin-5- yl)cyclopropyl)benzamide (Compound 382)

Compound 371 Compound 382

Step 1 : (l?)-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(qu inolin-5- yl)cyclopropyl)benzamide (Compound 382)

To a solution of (A)-2-methyl-5-(pyrrolidin-2-ylmethoxy)-7V-(l-(quinolin-5-yl )cyclopropyl) benzamide (140 mg, 349 pmol, 1.0 eq) in MeOH (2.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (20.9 mg, 697 pmol, 19.2 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The reaction mixture was stirred at 20 °C for 30 min, then NaBHiCN (43.8 mg, 697 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-A-(l-(quin olin-5-yl) cyclopropyl)benzamide (52.5 mg, 116 pmol, 33% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 416.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 6 11.06 - 10.82 (m, 1H), 9.89

- 9.66 (m, 1H), 9.37 (s, 1H), 9.31 - 9.23 (m, 1H), 8.37 - 8.27 (m, 1H), 8.21 - 7.99 (m, 3H), 7.07 (s, 1H), 6.98 - 6.85 (m, 1H), 6.76 (s, 1H), 4.38 - 4.21 (m, 2H), 3.82 - 3.65 (m, 1H), 3.63

- 3.45 (m, 1H), 3.16 - 3.00 (m, 1H), 2.87 (d, J= 4.8 Hz, 3H), 2.29 - 2.15 (m, 1H), 1.95 (m, 5H), 1.83 - 1.66 (m, 1H), 1.45 (br s, 2H), 1.30 (br s, 2H).

Example 229: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(isoquinolin-5-yl)cyclopro pyl)-2- methylbenzamide (Compound 299)

Step 2

Compound 299

Step 1: l-(Isoquinolin-5-yl)cyclopropanamine (229A-2)

A mixture of isoquinoline-5-carbonitrile (300 mg, 1.95 mmol, 1.0 eq) in anhydrous Et2O (30 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (608 mg, 2.14 mmol, 632 pL, 1.1 eq) slowly and then EtMgBr (3 M in Et2O, 1.42 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (552 mg, 3.89 mmol, 480 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (I M aqueous) (20 mL) and MTBE (20 mL) and extracted with MTBE (20 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. l-(Isoquinolin-5-yl)cyclopropanamine (100 mg, 543 pmol, 28% yield) was obtained as a yellow oil. M + H ⁺ = 185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(isoquinolin-5-yl)cyclopro pyl)-2-methylbenza mide (Compound 299)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (145 mg, 651 pmol, 1.2 eq) in DCM (5.0 mL) were added TEA (165 mg, 1.63 mmol, 227 pL, 3.0 eq), EDCI (156 mg, 814 pmol, 1.5 eq), HOBt (110 mg, 814 pmol, 1.5 eq) and l-(isoquinolin-5-yl) cyclopropanamine (100 mg, 543 pmol, 1.0 eq). The mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) at 25 °C and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2- (Dimethylamino)ethoxy)-7V-(l-(isoquinolin-5-yl)cyclopropyl)- 2-methylbenzamide (41.6 mg, 100 pmol, 18% yield) was obtained as a yellow solid. M + H ⁺ = 390.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.31 (s, 1H), 9.15 (s, 1H), 8.56 (d, J= 6.0 Hz, 1H), 8.47 (d, J= 6.0 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.89 - 6.79 (m, 1H), 6.61 (d, J= 2.7 Hz, 1H), 3.94 (t, J= 5.8 Hz, 2H), 2.56 - 2.52 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.38 - 1.32 (m, 2H), 1.22 - 1.14 (m, 2H). Example 230: /V-(l-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-

(methylamino)ethoxy)benzamide (Compound 375)

230A-1

Compound 375

Step 1: tert- Butyl (2-(3-((l-(isoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylp heno xy)ethyl)(methyl)carbamate (230A-1)

To a solution of l-(isoquinolin-5-yl)cyclopropanamine (50.0 mg, 231 pmol, 1.0 eq) and 5-(2- ((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2 -methylbenzoic acid (71.4 mg, 231 pmol, 1.0 eq) in acetonitrile (3.0 mL) were added TCFH (77.7 mg, 277 pmol, 1.2 eq) and 1- methylimidazole (66.3 mg, 807 pmol, 64.4 pL, 3.5 eq). The mixture was stirred at 20 °C for 18 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R/ = 0.3). ter/-Butyl (2-(3-((l-(isoquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)ethyl)(methyl)carbamate (30.0 mg, 63.1 pmol, 27% yield) was obtained as a white solid. M + H ⁺ = 476.2 (LCMS).

Step 2: N-( l-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino) ethoxy) benzamide (Compound 375)

To a solution of tert-butyl (2-(3-((l-(isoquinolin-5-yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)(methyl)carbamate (30.0 mg, 631 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCI/EtOAc (4 M, 189 pL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l- (Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylam ino)ethoxy)benzamide (19.6 mg, 47.3 pmol, 75% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 376.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.83 (s, 1H), 9.22 (d, J = 6.8 Hz, 1H), 8.69 (d, J = 6.9 Hz, 1H), 8.63 (dd, J= 0.9, 7.3 Hz, 1H), 8.49 (d, J= 8.3 Hz, 1H), 8.10 - 8.03 (m, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.95 (dd, J = 2.8, 8.5 Hz, 1H), 6.82 (d, J = 2.6 Hz, 1H), 4.24 - 4.18 (m, 2H), 3.44 - 3.38 (m, 2H), 2.76 (s, 3H), 2.00 (s, 3H), 1.63 - 1.57 (m, 2H), 1.46 - 1.39 (m, 2H).

Example 231: /V-(l-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methylaz etidin-2- yl)methoxy)benzamide (Compound 402)

229A-2 Compound 402

Step 1: /V-(l-(Isoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methylaz etidin-2-yl)methoxy) benzamide (Compound 402)

To a solution of l-(isoquinolin-5-yl)cyclopropanamine (40 mg, 217 pmol, 1.0 eq) and 2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (91.9 mg, 391 pmol, 1.8 eq) in DCM (2.0 mL) were added TEA (65.9 mg, 651 mmol, 90.6 pL, 3.0 eq), EDCI (104 mg, 543 pmol, 2.5 eq) and HOBt (73.3 mg, 543 mmol, 2.5 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). A-(l-(Isoquinolin-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (15.1 mg, 33.1 pmol, 15% yield, FA salt) was obtained as a white solid. M + H ⁺ = 402.1 (LCMS); ^T H NMR (400 MHz, DMSO-t/e) 69.32 (s, 1H), 9.16 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 8.19 (s, 1H), 8.03 (d, J= 7.6 Hz, 2H), 7.65 (t, J= 7.7 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.84 (dd, J= 2.7, 8.3 Hz, 1H), 6.62 (d, J= 2.6 Hz, 1H), 3.90 (d, J= 4.9 Hz, 2H), 3.49 - 3.13 (m, 2H), 2.83 (q, J= 8.2 Hz, 1H), 2.27 (s, 3H), 2.06 - 1.95 (m, 1H), 1.94 (s, 3H), 1.92 - 1.81 (m, 1H), 1.36 (s, 2H), 1.25 - 1.13 (m, 2H).

Example 232: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 333)

Compound 333

Step 1: l-(Isoquinolin-8-yl)cyclopropanamine (232A-2)

A mixture of isoquinoline-8-carbonitrile (100 mg, 649 pmol, 1.0 eq) in anhydrous Et20 (7.0 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (203 mg, 714 pmol, 211 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 476 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (185 mg, 1.30 mmol, 160 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that 40% starting material still remained and 13% desired compound was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Cl 8 column (250 x 50 mm, 10 pm); flow rate: 60 mL/min; gradient: 20% - 40% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). l-(Isoquinolin-8-yl)cyclopropanamine (15 mg, 81.4 pmol, 12% yield) was obtained as a white solid. M + H ⁺ = 185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(isoquinolin-8-yl)cyclopro pyl)-2-methylbenz amide (Compound 333)

To a solution of l-(isoquinolin-8-yl)cyclopropanamine (30.0 mg, 163 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (72.7 mg, 326 pmol, 2.0 eq) in DCM (1.0 mL) were added TEA (49.4 mg, 488 pmol, 67.9 pL, 3.0 eq), EDCI (37.5 mg, 195 pmol, 1.2 eq) and HOBt (26.4 mg, 195 pmol, 1.2 eq). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: l 0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-7V-(l- (isoquinolin-8-yl)cyclo propyl)-2-methylbenzamide (3.20 mg, 8.22 pmol, 5% yield) was obtained as a white solid. M + H ⁺ = 390.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.04 (s, 1H), 9.24 (s, 1H), 8.53 (d, J= 5.5 Hz, 1H), 8.04 - 7.79 (m, 3H), 7.77 - 7.59 (m, 1H), 7.03 (d, J= 8.3 Hz, 1H), 6.84 (dd, J= 2.6, 8.7 Hz, 1H), 6.63 (d, J= 2.6 Hz, 1H), 3.95 (s, 2H), 2.60 - 2.54 (m, 2H), 2.16 (s, 6H), 1.93 (s, 3H), 1.39 (br s, 2H), 1.26 (br s, 2H).

Example 233: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(quinolin-8- yl)cyclopropyl)benzamide (Compound 388)

Compound 388 Step 1: l-(Quinolin-8-yl) cyclopropanamine (233 A-2)

To a mixture of quinoline-8-carbonitrile (300 mg, 1.95 mmol, 1.0 eq) in anhydrous Et20 (20 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (608 mg, 2.14 mmol, 630 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et20, 1.43 mL, 2.2 eq) was added dropwise to maintain the temperature between - 78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (552 mg, 3.89 mmol, 480 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (20 mL) and MTBE (20 mL), and extracted with MTBE (20 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(Quinolin-8-yl) cyclopropanamine (60.0 mg, 330 pmol, 17% yield) was obtained as a yellow oil. M + H ⁺ = 185.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(quinolin-8-yl)cy clopropyl)benz amide (Compound 388)

To a solution of l-(quinolin-8-yl) cyclopropanamine (40.0 mg, 217 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (48.5 mg, 217 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (44.0 mg, 430 pmol, 60.4 pL, 2.0 eq), EDCI (62.4 mg, 330 pmol, 1.5 eq) and HOBt (44.0 mg, 330 pmol, 1.5 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (2.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (75 X 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 45% B over 8 min; mobile phase A: 10 mM NH4HCO3, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-7V- (l-(quinolin-8-yl)cyclopropyl)benzamide (15.0 mg, 38.1 pmol, 18% yield) was obtained as a white solid. M + H ⁺ = 390.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.90 - 9.03 (m, 1H), 8.68 (s, 1H), 8.27 - 8.44 (m, 1H), 7.81 - 7.99 (m, 2H), 7.47 - 7.64 (m, 2H), 7.00 (br d, J= 8.38 Hz, 1H), 6.75 - 6.86 (m, 1H), 6.61 - 6.71 (m, 1H), 3.95 (br t, J= 5.50 Hz, 2H), 2.54 - 2.63 (m, 2H), 2.19 (br s, 6H), 1.97 (s, 3H), 1.33 (br d, J= 8.63 Hz, 4H).

Example 234: 5-(2-Aminoethoxy)-/V-(l-(3-methoxynaphthalen-l-yl)cyclopropy l)-2- methylbenzamide (Compound 363)

Compound 363

Step 1: tert-Butyl (2-(3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)carbamoyl)-4 -methyl phenoxy)ethyl)carbamate (234A-1)

To a solution of 5-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylbenzoic acid (166 mg, 563 pmol, 1.2 eq) and 1 -(3 -methoxynaphthal en-l-yl)cy cl opropanamine (100 mg, 469 pmol, 1.0 eq) in DCM (1.0 mL) were added TEA (142 mg, 1.41 mmol, 196 pL, 3.0 eq), EDCI (135 mg, 703 pmol, 1.5 eq) and HOBt (95.0 mg, 703 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 2/1, R/= 0.4) to give tert-butyl (2-(3-((l -(3 -m ethoxynaphthal en-1- yl)cyclopropyl)carbamoyl)-4-methyl phenoxy)ethyl)carbamate (200 mg, 408 pmol, 87% yield) as a yellow oil. M + H ⁺ = 491.2 (LCMS). Step 2: 5-(2-Aminoethoxy)-/V-(l-(3-methoxynaphthalen-l-yl)cyclopropy l)-2-methyl benzamide (Compound 363)

To a stirred solution of tert-butyl (2-(3-((l -(3 -methoxynaphthal en-l-yl)cyclopropyl) carbamoyl)-4-methyl phenoxy)ethyl)carbamate (200 mg, 408 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-(2-aminoethoxy)-7V-(l-(3-methoxynaphthalen-l-yl)cyclopropy l)-2- methylbenzamide (150 mg, 383 pmol, 94% yield, HC1 salt) as a white solid. M + H ⁺ = 391.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.12 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.04 (br s, 3H), 7.83 (d, J = 7.9 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.24 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.88 (dd, J= 2.6, 8.4 Hz, 1H), 6.66 (d, J= 2.6 Hz, 1H), 4.08 (t, J= 5.1 Hz, 2H), 3.87 (s, 3H), 3.19 - 3.08 (m, 2H), 1.98 (s, 3H), 1.33 (br s, 2H), 1.20 - 1.11 (m, 2H).

Example 235: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-methoxynaphthalen-l- yl)cyclopropyl)-2-methylbenzamide (Compound 320)

Step 3

235A-3 Compound 320

Step 1: 3-Methoxy-l-naphthonitrile (235A-2)

To a solution of l-bromo-3-methoxynaphthalene (2.00 g, 8.44 mmol, 1.0 eq) in DMF (40 mL) were added Zn(CN)2 (1.98 g, 16.9 mmol, 1.07 mL, 2.0 eq) and Pd(PPh3)4 (975 mg, 844 pmol, 0.1 eq). The mixture was stirred at 120 °C for 6 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. 3-Methoxy-l- naphthonitrile (1.50 g, 97% yield) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 8.03 - 7.97 (m, 2H), 7.88 (d, J= 2.6 Hz, 1H), 7.76 (d, J= 2.5 Hz, 1H), 7.68 - 7.58 (m, 2H), 3.93 (s, 3H).

Step 2: l-(3-Methoxynaphthalen-l-yl)cyclopropanamine (235A-3)

A mixture of 3 -methoxynaphthalene- 1 -carbonitrile (1.40 g, 7.64 mmol, 1.0 eq) in anhydrous Et2O (100 mL) was degassed and purged with N2 three times. The mixture was stirred at - 78 °C. To this mixture was added Ti(z -PrO)4 (2.39 g, 8.41 mmol, 2.48 mL, 1.1 eq) slowly, and then EtMgBr (3 M, in Et2O, 5.60 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (2.17 g, 15.3 mmol, 1.89 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (50 mL) and MTBE (50 mL), and extracted with MTBE (50 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 3 -Methoxy- 1 -naphthonitrile (500 mg, 2.34 mmol, 31% yield) was obtained as a brown solid. M + H ⁺ = 214.2 (LCMS); 'H NMR (400 MHz, CDCL) 8 8.35 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.52 - 7.39 (m, 2H), 7.20 (d, J= 2.3 Hz, 1H), 7.06 (d, J= 1.9 Hz, 1H), 3.93 (s, 3H), 2.04 (br s, 2H), 1.23 - 1.16 (m, 2H), 1.06 - 0.99 (m, 2H).

Step 3: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-methoxynaphthalen-l-yl) cyclopropyl)-2- methylbenzamide (Compound 320)

To a solution of 1 -(3 -methoxynaphthal en-l-yl)cy cl opropanamine (100 mg, 469 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (105 mg, 469 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (142 mg, 1.41 mmol, 196 pL, 3.0 eq), EDCI (225 mg, 1.17 mmol, 2.5 eq) and HOBt (158 mg, 1.17 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 5-(2- (dimethylamino)ethoxy)-7V-(l -(3 -methoxynaphthal en-l-yl)cy cl opropyl)-2-methylbenzamide (57.5 mg, 124 pmol, 26% yield, FA salt) as a white solid. M + H ⁺ = 419.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.06 (s, 1H), 8.54 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.49 - 7.35 (m, 3H), 7.23 (d, J= 2.5 Hz, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.83 (dd, J = 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.95 (t, J= 5.8 Hz, 2H), 3.87 (s, 3H), 2.58 (t, J= 5.8 Hz, 2H), 2.19 (s, 6H), 1.97 (s, 3H), 1.33 (br s, 2H), 1.19 - 1.12 (m, 2H).

Example 236: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-hydroxynaphthalen-l- yl)cyclopropyl)-2-methylbenzamide (Compound 345)

Compound 320 Compound 345

Step 1: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-hydroxynaphthalen-l-yl) cyclopro pyl)-2- methylbenzamide (Compound 345)

To a solution of EtSH (1.05 g, 16.9 mmol, 1.25 mL, 141 eq) in DCM (5.0 mL) was added AlCh (95.6 mg, 717 pmol, 39.2 pL, 6.0 eq) at 0 °C. To the resulting mixture was added 5-[2- (dimethylamino)ethoxy]-A-[l-(3-methoxy-l-naphthyl)cyclopropy l]-2-methyl-benzamide (50.0 mg, 119 pmol, 1.0 eq) in DCM (0.5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min, then warmed to 20 °C and stirred at the same temperature for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l- (3-hydroxynaphthalen-l-yl)cy clopropyl)-2-methylben zamide (8.70 mg, 19.2 pmol, 16% yield, FA salt) was obtained as a white solid. M + H ⁺ = 405.1 (LCMS); ^T H NMR (400 MHz, DMSO-t/e) 6 9.04 (s, 1H), 8.49 (d, J= 8.4 Hz, 1H), 8.18 (s, 1H), 7.68 (d, = 8.0 Hz, 1H), 7.42 (d, J= 2.4 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.08 - 7.00 (m, 2H), 6.83 (dd, J= 2.6, 8.3 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 3.95 (br t, J= 5.5 Hz, 2H), 2.58 (br t, J = 5.5 Hz, 2H), 2.19 (s, 6H), 1.98 (s, 3H), 1.32 (br s, 2H), 1.13 (br s, 2H).

Example 237 : /V-(l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-(2- (methylamino)ethoxy)benzamide (Compound 347) Step 2

Compound 347

Step 1: / f/- Butyl (2-(3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)ethyl)(methyl)carbamate (237A-1)

To a solution of 5-(2-((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (100 mg, 323 pmol, 1.0 eq) and 1 -(3 -methoxynaphthal en-l-yl)cy cl opropanamine (68.9 mg, 323 pmol, 1.0 eq) in DCM (10 mL) were added TEA (98.1 mg, 970 pmol, 135 pL, 3.0 eq), EDCI (155 mg, 808 pmol, 2.5 eq) and HOBt (109 mg, 808 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.5). ZerLButyl (2-(3-((l-(3- methoxynaphthalen-l-yl)cyclopropyl)carbamoyl)-4-methylphenox y)ethyl)(methyl)carbamate (100 mg, 198 pmol, 61% yield) was obtained as a yellow oil. M + H ⁺ = 505.3 (LCMS).

Step 2: /V-(l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-(2-( methylamino) ethoxy)benzamide (Compound 347)

To a stirred solution of /c/7-butyl (2-(3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)car bamoyl)-4-methylphenoxy)ethyl)(methyl)carbamate (100 mg, 198 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 70% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-(2-

(methylamino)ethoxy) benzamide (48.3 mg, 109 pmol, 55% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 405.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 89.14 (br d, J= 1.5 Hz, 1H), 8.87 (br d, J= 1.0 Hz, 2H), 8.53 (br d, J= 5.4 Hz, 1H), 7.91 - 7.77 (m, 1H), 7.53 - 7.33 (m, 3H), 7.24 (br s, 1H), 7.08 (br d, J= 5.6 Hz, 1H), 6.97 - 6.84 (m, 1H), 6.67 (br s, 1H), 4.15 (br s, 2H), 3.87 (br s, 3H), 3.25 (br s, 2H), 2.57 (br s, 3H), 1.98 (br s, 3H), 1.33 (br s, 2H), 1.16 (br s, 2H).

Example 238: /V-(l-(3-methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 384)

Step 1

235A-3 Compound 384

Step 1: /V-(l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2- yl)methoxy)benzamide (Compound 384)

To a solution of 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (80.0 mg, 340 pmol, 1.0 eq) and 1 -(3 -methoxynaphthal en-l-yl)cy cl opropanamine (72.5 mg, 340 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (103 mg, 1.02 mmol, 142 pL, 3.0 eq), EDCI (163 mg, 850 pmol, 2.5 eq) and HOBt (115 mg, 850 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (200 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 7V-(1- (3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-methyl azetidin-2-yl)methoxy) benzamide (38.2 mg, 80.2 pmol, 24% yield, FA salt) was obtained as a white solid. M + H ⁺ = 431.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.06 (s, 1H), 8.54 (d, J= 8.3 Hz, 1H), 8.20 (s, 1H), 7.83 (d, J= 8.0 Hz, 1H), 7.49 - 7.35 (m, 3H), 7.23 (d, J= 2.4 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.83 (dd, J = 2.8, 8.4 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 3.91 - 3.86 (m, 5H), 3.36 - 3.25 (m, 2H), 2.84 - 2.76 (m, 1H), 2.25 (s, 3H), 2.02 - 1.81 (m, 5H), 1.33 (br s, 2H), 1.18 - 1.13 (m, 2H).

Example 239: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-methylnaphthal en-l- yl)cyclopropyl)benzamide (Compound 401)

Step 2

Compound 401

Step 1 : 4-(l-(5-(2-(Dimethylamino)ethoxy)-2-methylbenzamido)cyclopro pyl)naphthalen- 2-yl trifluoromethanesulfonate (239A-1)

To a solution of 5-(2-(dimethylamino)ethoxy)-7V-(l-(3-hydroxynaphthalen-l-yl) cyclopropyl)- 2-methylbenzamide (110 mg, 272 pmol, 1.0 eq) in DCM (5.0 mL) were added DIEA (105 mg, 816 pmol, 142 pL, 3.0 eq) and Tf20 (115 mg, 408 pmol, 67.3 pL, 1.5 eq) at -78 °C. Then the mixture was stirred at -78 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to warm to room temperature, poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 1/10, R/= 0.4). 4-(l- (5-(2-(Dimethylamino)ethoxy)-2-methylbenzamido) cyclopropyl)naphthalen-2-yl trifluoromethanesulfonate (130 mg, 242 pmol, 89% yield) was obtained as a brown solid. M + H ⁺ = 537.2 (LCMS).

Step 2: 5-(2-(dimethylamino)ethoxy)-2-methyl-N-(l-(3-methylnaphthale n-l- yl)cyclopropyl)benzamide (Compound 401)

To a solution of 4-(l-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopro pyl) naphthaen-2-yl trifluoromethanesulfonate (80.0 mg, 149 pmol, 1.0 eq) in DMF (4.0 mL) were added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (37.4 mg, 149 pmol, 41.7 pL, 50% purity, 1.0 eq), CS2CO3 (160 mg, 492 pmol, 3.3 eq) and Pd(dppf)C12.DCM (12.2 mg, 14.9 pmol, 0.1 eq). The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l-(3-methylnaphthale n-l-yl)cyclopropyl) benzamide (20.8 mg, 49.3 pmol, 33% yield, FA salt) was obtained as a gray solid. M + H ⁺ = 403.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.05 (s, 1H), 8.63 - 8.56 (m, 1H), 7.85 - 7.79 (m, 1H), 7.64 (d, J= 1.6 Hz, 1H), 7.59 (s, 1H), 7.52 - 7.43 (m, 2H), 7.03 (d, J= 8.5 Hz, 1H), 6.83 (dd, J= 2.8, 8.4 Hz, 1H), 6.59 (d, J= 2.8 Hz, 1H), 3.94 (t, J= 5.8 Hz, 2H), 2.55 (t, J = 5.8 Hz, 2H), 2.47 (s, 3H), 2.17 (s, 6H), 1.98 (s, 3H), 1.37 - 1.30 (m, 2H), 1.19 - 1.13 (m, 2H).

Example 240: 5-(2-Dimethylamino)ethoxy)-/V-(l-(6-fluoronaphthalen-l-yl)cy clopropyl)- 2-methylbenzamide (Compound 319)

240A-1 240A-2 240A-3

Compound 319

Step 1: 6-Fluoronaphthalen-l-yl trifluoromethanesulfonate (240A-2)

To a solution of 6-fluoronaphthalen-l-ol (420 mg, 2.59 mmol, 1.0 eq) in DCM (12 mL) were added DIEA (669 mg, 5.18 mmol, 902 pL, 2.0 eq) and Tf20 (730 mg, 2.59 mmol, 427 pL, 1.0 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to warm to room temperature, poured into H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 6-Fluoronaphthalen-l-yl trifluoromethanesulfonate (750 mg, 2.55 mmol, 90% purity) was obtained as a white solid. ^T H NMR (400 MHz, CDCL) 8 8.10 (br dd, J = 5.3, 8.9 Hz, 1H), 7.83 (br d, J= 8.2 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.49 - 7.36 (m, 2H).

Step 2: 6-Fluoro-l-naphthonitrile (240A-3)

To a solution of 6-fluoronaphthalen-l-yl trifluoromethanesulfonate (750 mg, 2.55 mmol, 1.0 eq) in DMF (8.0 mL) were added Zn(CN)2 (598 mg, 5.10 mmol, 323 pL, 2.0 eq) and Pd (PPh3)4 (117 mg, 101 pmol, 0.04 eq) under a N2 atmosphere. The mixture was stirred at 120 °C for 30 min. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NH4CI (16 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 6-Fluoro-l- naphthonitrile (390 mg, 2.28 mmol, 83% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCh) 6 8.26 (dd, J = 5.3, 9.2 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 7.1 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.49 (dt, J= 2.5, 8.7 Hz, 1H).

Step 3: l-(6-Fluoronaphthalen-l-yl)cyclopropanamine (240A-4)

A mixture of 6-fluoro-l -naphthonitrile (200 mg, 1.17 mmol, 1.0 eq) in anhydrous Et20 (35 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (365 mg, 1.29 mmol, 379 pL, 1.1 eq) slowly at -78 °C, and then EtMgBr (3 M in Et20, 856 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (331 mg, 2.34 mmol, 288 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HC1 (1 M aqueous) (20 mL) and MTBE (20 mL). The mixture was washed with MTBE (25 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (25 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 1/10, R/ = 0.5). 1 - (6-Fluoro-l -naphthyl) cyclopropanamine (110 mg, 546 pmol, 46% yield) was obtained as a white solid. M + H ⁺ = 202.1 (LCMS); 'H NMR (400 MHz, CDCh) 88.47 (dd, J= 5.6, 9.3 Hz, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.44 (d, J= 7.7 Hz, 1H), 7.40 - 7.32 (m, 1H), 1.24 - 1.17 (m, 2H), 1.07 - 1.00 (m, 2H).

Step 4: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(6-fluoronaphthalen-l-yl)c yclopropyl)-2- methylbenzamide (Compound 319)

To a solution of 1 -(6-fluoro-l -naphthyl) cyclopropanamine (80.0 mg, 397 pmol, 1.0 eq) in DMF (4.0 mL) were added 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (133 mg, 596 pmol, 1.5 eq), TEA (120 mg, 1.19 mmol, 166 pL, 3.0 eq), EDCI (91.4 mg, 477 pmol, 1.2 eq) and HOBt (64.4 mg, 477 pmol, 1.2 eq). The mixture was stirred at 25 °C for 6 h. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-7V-(l-(6- fluoronaphthalen-l -yl)cy cl opropyl)-2-m ethylbenzamide (67.9 mg, 167 pmol, 42% yield, FA salt) was obtained as a white solid. M + H ⁺ = 407.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.59 (dd, J= 5.6, 9.1 Hz, 1H), 8.43 (br s, 1H), 7.88 (d, J = 7.0 Hz, 1H), 7.73 (d, J= 8.3 Hz, 1H), 7.59 - 7.43 (m, 2H), 7.34 (dt, J= 2.6, 8.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 - 6.57 (m, 3H), 4.08 (t, J = 5.3 Hz, 2H), 2.89 (t, J = 5.3 Hz, 2H), 2.46 (s, 6H), 2.12 (s, 3H), 1.70 - 1.49 (m, 2H), 1.48 - 1.32 (m, 2H).

Example 241: (5)-5-(Azetidin-2-ylmethoxy)-A-(l-(6-fluoronaphthalen-l-yl)c yclopropyl)- 2-methylbenzamide (Compound 392)

Compound 392

Step 1: (. )-/c/7-butyl 2-((3-((l-(6-Fluoronaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)azetidine-l-carboxylate (241A-1)

To a solution of l-(6-fluoronaphthalen-l-yl)cyclopropanamine (31.3 mg, 156 pmol, 1.0 eq) and (5)-5-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth ylbenzoic acid (50.0 mg, 155 pmol, 1.0 eq) in DCM (2.0 mL) were added TEA (47.2 mg, 466 pmol, 64.9 pL, 3.0 eq), EDCI (44.7 mg, 233 pmol, 1.5 eq) and HOBt (31.5 mg, 233 pmol, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R/ = 0.6). CS')-/c/7-Butyl 2-((3-((l-(6-fluoronaphthalen-l-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl) azetidine- 1 -carboxylate (70.0 mg, 139 pmol, 89% yield) was obtained as a white solid. M - 56 + H ⁺ = 449.1 (LCMS).

Step 2: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(6-fluoronaphthalen-l-yl) cyclopropyl)-2- methylbenzamide (Compound 392)

To a solution of CS')-/c/7-butyl 2-((3-((l-(6-fluoronaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)azetidine-l -carboxylate (70.0 mg, 139 pmol, 1.0 eq) in DCM (3.0 mL) was added TFA (2.16 g, 18.9 mmol, 1.40 mL, 136 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Cl 8-1 column (150 * 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 15% - 60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). GS)-5-( Azeti din-2 -ylmethoxy)-7V-(l-(6-fluoronaphthalen-l-yl)cy cl opropyl)-2- methylbenzamide (10.7 mg, 20.6 pmol, 15% yield, TFA salt) as a white solid. M + H ⁺ = 405.1 (LCMS); 'H NMR (400 MHz, DMSO ) 59.11 (s, 1H), 8.95 - 8.67 (m, 3H), 7.84 (d, J= 8.3 Hz, 1H), 7.79 (d, J= 7.0 Hz, 1H), 7.73 (dd, J= 2.6, 10.3 Hz, 1H), 7.59 - 7.39 (m, 2H), 7.09 (d, J= 8.5 Hz, 1H), 6.90 (dd, J = 2.8, 8.4 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H), 4.83 - 4.54 (m, 1H), 4.32 - 4.03 (m, 2H), 3.99 - 3.77 (m, 2H), 2.48 - 2.40 (m, 1H), 2.39 - 2.27 (m, 1H), 1.97 (s, 3H), 1.36 (s, 2H), 1.20 (br s, 2H).

Example 242: /V-(l-(6-Fluoronaphthalen-l-yl)cyclopropyl)-2-methyl-5-(2- (methylamino)ethoxy)benzamide (Compound 377)

Compound 377 Step 1: tert-Butyl (2-(3-((l-(6-fluoronaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methyl phenoxy)ethyl)(methyl)carbamate (242A-1)

To a solution of 5-(2-((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (100 mg, 323 pmol, 1.0 eq) and l-(6-fluoronaphthalen-l-yl)cyclopropanamine (65.1 mg, 323 pmol, 1.0 eq) in DMF (5.0 mL) were added TEA (98.1 mg, 970 pmol, 135 pL, 3.0 eq), EDCI (155 mg, 808 pmol, 2.5 eq) and HOBt (109 mg, 808 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.4). tert-Butyl (2-(3-((l-(6-fluoronaphthalen-l- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl) (methyl)carbamate (100 mg, 203 pmol, 63% yield) was obtained as a colorless oil. M + H ⁺ = 493.2 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.10 (s, 1H), 8.73 (dd, J= 5.4, 9.2 Hz, 1H), 7.83 (d, J= 8.1 Hz, 1H), 7.77 (d, J= 7.0 Hz, 1H), 7.72 (dd, J= 2.4, 10.3 Hz, 1H), 7.50 (t, J= 7.8 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.04 (br d, J= 8.0 Hz, 1H), 6.84 (dd, J= 2.5, 8.5 Hz, 1H), 6.60 (br s, 1H), 4.00 - 3.94 (m, 2H), 3.46 (t, J= 5.6 Hz, 2H), 2.82 (br d, J= 11.0 Hz, 3H), 1.95 (s, 3H), 1.42 - 1.23 (m, 13H).

Step 2: N-( l-(6-Fluoronaphthalen-l-yl)cyclopropyl)-2-methyl-5-(2- (methylamino)ethoxy) benzamide (Compound 377)

To a stirred solution of /c/7-butyl (2-(3-((l-(6-fluoronaphthalen-l-yl)cyclopropyl)carbamoyl)- 4-methyl phenoxy)ethyl) (methyl)carbamate (100 mg, 203 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 10.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(6-Fluoronaphthalen-l-yl)cyclopropyl)-2-methyl-5-(2-(m ethylamino) ethoxy)benzamide (40.7 mg, 94.9 pmol, 47% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 393.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 6 9.13 (s, 1H), 9.01 (br s, 2H), 8.68 (br dd, J= 5.9, 9.1 Hz, 1H), 7.75 (br dd, J = 7.6, 18.0 Hz, 2H), 7.67 (dd, J = 2.1, 10.2 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 2.2, 8.3 Hz, 1H), 6.62 (d, J= 2.0 Hz, 1H), 4.11 (br t, J= 4.3 Hz, 2H), 3.18 (br s, 2H), 2.44 (br s, 3H), 1.89 (s, 3H), 1.30 (br s, 2H), 1.12 (br s, 2H). Example 243: (5)-/V-(l-(6-Fluoronaphthalen-l-yl)cyclopropyl)-2-methyl-5-( (l- methylazetidin-2-yl)methoxy)benzamide (Compound 389)

Compound 392 Compound 389

Step 1: (5)-/V-(l-(6-Fluoronaphthalen-l-yl)cyclopropyl)-2-methyl-5-( (l-methylazetidin- 2-yl)methoxy)benzamide (Compound 389)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-7V-(l-(6-fluoronaphthalen-l-yl) cyclopropyl)-2- methylbenzamide (150 mg, 289 pmol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (40.0 pL), followed by the addition of formaldehyde (47.0 mg, 579 mmol, 43.1 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (36.4 mg, 579 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luma C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)-A-(l-(6-Fluoronaphthalen-l-yl)cyclopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (10.7 mg, 13.0 pmol, 8% yield, FA salt) was obtained as a white solid. M + H ⁺ = 419.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.08 (s, 1H), 8.74 (dd, J= 5.8, 9.3 Hz, 1H), 8.22 (s, 1H), 7.87 - 7.66 (m, 3H), 7.56 - 7.40 (m, 2H), 7.02 (d, J= 8.4 Hz, 1H), 6.83 (dd, J= 2.8, 8.4 Hz, 1H), 6.60 (d, J= 2.6 Hz, 1H), 3.86 (d, J= 5.5 Hz, 2H), 3.27 - 3.18 (m, 3H), 2.71 (td, J = 8.1, 16.0 Hz, 1H), 2.21 (s, 3H), 1.95 (s, 3H), 1.90 - 1.77 (m, 1H), 1.36 (s, 2H), 1.22 - 1.09 (m, 2H). Example 244: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(7-fluoronaphthalen-l- yl)cyclopropyl)-2-methylbenzamide (Compound 365)

Compound 365

Step 1: 7-Fluoronaphthalen-l-ol (244A-2)

To a solution of 7-fluoro-3,4-dihydronaphthalen-l(2J7)-one (1.00 g, 6.09 mmol, 1.0 eq) in DMA (10 mL) was added 10% palladium on carbon (100 mg, 1.83 mmol, 0.3 eq) and K2CO3 (2.53 g, 18.3 mmol, 3.0 eq). The mixture was stirred at 160 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was poured into H2O (50 mL) and extracted with EtOAc (25 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7- Fluoronaphthalen-l-ol (900 mg, 5.55 mmol, 91% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCL) 8 8.23 - 8.15 (m, 1H), 7.87 - 7.78 (m, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.43 (m, 1H), 7.35 - 7.29 (m, 1H), 6.87 - 6.80 (m, 1H), 5.24 - 5.18 (m, 1H).

Step 2: 7-Fluoronaphthalen-l-yl trifluoromethanesulfonate (244A-3)

To a solution of 7-fluoronaphthalen-l-ol (350 mg, 2.16 mmol, 1.0 eq) in DCM (20 mL) were added Tf20 (670 mg, 2.37 mmol, 392 pL, 1.0 eq) and pyridine (588 mg, 7.43 mmol, 0.6 mL, 3.4 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (20 mL x 3). The combined layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7- Fluoronaphthalen-l-yl trifluoromethane sulfonate (600 mg, 2.04 mmol, 94% yield) was obtained as a yellow oil. 'H NMR (400 MHz, CDCh) 8 7.97 - 7.87 (m, 2H), 7.72 - 7.66 (m, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.36 (m, 1H).

Step 3: 7-Fluoro-l-naphthonitrile (244A-4)

To a solution of 7-fluoronaphthalen-l-yl trifluoromethanesulfonate (500 mg, 1.70 mmol, 1.0 eq) in DMF (8.0 mL) were added Zn(CN)2 (399 mg, 3.40 mmol, 216 pL, 2.0 eq) and Pd (PPh3)4 (196 mg, 170 pmol, 0.1 eq). The mixture was stirred at 110 °C for 18 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NH4CI (2.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-Fluoro-l- naphthonitrile (150 mg, 876 pmol, 52% yield) was obtained as a white solid. 'H NMR (400 MHz, CDCh) 68.13 - 8.07 (m, 1H), 7.99 - 7.92 (m, 2H), 7.91 - 7.84 (m, 1H), 7.56 - 7.49 (m, 1H), 7.46 - 7.38 (m, 1H).

Step 4: l-(7-Fluoronaphthalen-l-yl)cyclopropanamine (244A-5)

A mixture of 7-fluoro-l -naphthonitrile (45.0 mg, 263 pmol, 1.0 eq) in anhydrous Et2O (10 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (82.2 mg, 289 pmol, 85.3 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et2O, 193 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (74.6 mg, 526 pmol, 64.9 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HC1 (I M aqueous) (5.0 mL) and MTBE (5.0 mL), and extracted with MTBE (5.0 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (pure EtOAc, R/ = 0.3). l-(7- Fluoronaphthalen-l-yl)cyclopropane mine (30.0 mg, 149 pmol, 57% yield) was obtained as a yellow oil. M + H ⁺ = 202.1 (LCMS).

Step 5: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(7-fluoronaphthalen-l-yl)c yclopropyl)-2- methylbenzamide (Compound 365)

To a solution of l-(7-fluoronaphthalen-l-yl)cyclopropanamine (20.0 mg, 49.7 pmol, 1.0 eq) in DCM (1.0 mL) was added 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (111 mg, 49.7 pmol, 1.0 eq), TEA (15.1 mg, 149 pmol, 20.8 pL, 3.0 eq), EDCI (23.8 mg, 124 pmol, 2.5 eq) and HOBt (16.8 mg, 124 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 5). The combined layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l-(7- fluoronaphthalen-1 -yl)cy cl opropyl)-2-m ethylbenzamide (8.20 mg, 18.0 pmol, 36% yield, FA salt) was obtained as a white solid. M + H ⁺ = 407.1 NMR (400 MHz, CDCh) 8 8.43 - 8.40 (m, 1H), 8.12 - 8.07 (m, 1H), 8.02 - 7.96 (m, 1H), 7.92 - 7.85 (m, 1H), 7.82 - 7.76 (m, 1H), 7.47 - 7.42 (m, 1H), 7.32 - 7.28 (m, 1H), 7.04 - 6.99 (m, 1H), 6.83 - 6.74 (m, 2H), 6.59 - 6.56 (m, 1H), 4.08 - 4.00 (m, 2H), 2.84 - 2.76 (m, 2H), 2.42 - 2.38 (m, 6H), 2.19 - 2.10 (m, 3H), 1.61 - 1.52 (m, 2H), 1.43 - 1.33 (m, 2H).

Example 245: 5-(Azetidin-3-ylamino)-2-methyl-/V-(3-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)benzyl)benzamide (Compound 120)

245A-5 Compound 120

Step 1: te/7- Butyl 3-(5-formylthiophen-2-yl)benzylcarbamate (245A-2)

A mixture of tert-butyl 3-bromobenzylcarbamate (300 mg, 1.05 mmol, 1.0 eq), (5- formylthiophen-2-yl)boronic acid (196 mg, 1.26 mmol, 1.2 eq) and KOAc (308 mg, 3.15 mmol, 3.0 eq) in DMSO (6.0 mL) was degassed and purged with N2 three times. To the mixture were added cataCXium® A (70.6 mg, 210 pmol, 0.2 eq) and Pd(OAc)2 (23.5 mg, 105 pmol, 0.1 eq). The resulting mixture was stirred at 80 °C for 6 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.5). /c Z-Butyl 3-(5-formylthiophen-2- yl)benzylcarbamate (150 mg, 473 pmol, 45% yield) was obtained as a brown oil. M + H ⁺ = 318.3 (LCMS).

Step 2: tert-Butyl 3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)benzylcarbamate (245A-3)

To a solution of tert-butyl 3-(5-formylthiophen-2-yl)benzylcarbamate (150 mg, 473 pmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of pyrrolidine (67.2 mg, 945 pmol, 78.9 pL, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (44.5 mg, 708 pmol, 1.5 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl 3-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)benzylcarbamate (90.0 mg, 242 pmol, 51% yield) was obtained as a yellow oil. M + H ⁺ = 373.1 (LCMS).

Step 3: (3-(5-(Pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)methanamin e (245A-4)

To a stirred solution of tert-butyl 3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)benzylcarbamate (90.0 mg, 242 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give (3-(5-(Pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)methanamin e (40.0 mg, 147 pmol, 61% yield, HC1 salt) as a yellow oil. M + H ⁺ = 273.1 (LCMS).

Step 4: tert-Butyl 3-((4-methyl-3-((3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)b enzyl) carbamoyl)phenyl)amino)azetidine-l-carboxylate (245A-5)

To a solution of (3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)methanamin e (40.0 mg, 147 pmol, 1.0 eq) and 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)amino)-2-methylbenz oic acid (45.0 mg, 147 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (44.6 mg, 441 pmol, 61.3 pL, 3 eq), EDCI (33.7 mg, 176 pmol, 1.2 eq) and HOBt (23.8 mg, 176 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of MeOH/DCM from 0/1 to 1/50. Zc/V-Butyl 3-((4- methyl-3-((3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)benzyl) carbamoyl)phenyl)amino) azetidine- 1 -carboxylate (40.0 mg, 71.3 pmol, 59% yield) was obtained as a yellow solid. M + H ⁺ = 561.2 (LCMS).

Step 5: 5-(Azetidin-3-ylamino)-2-methyl-/V-(3-(5-(pyrrolidin-l-ylmet hyl)thiophen-2- yl)benzyl)benzamide (Compound 120)

To a stirred solution of tert-butyl 3-((4-methyl-3-((3-(5-(pyrrolidin-l-ylmethyl)thiophen-2 yl)benzyl)carbamoyl)phenyl)amino)azeti dine- 1 -carboxylate (40.0 mg, 71.3 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3-ylamino)-2-methyl-7V-(3-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)benzyl)benzamide (9.20 mg, 19.9 pmol, 28% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 461.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 7.69 (s, 1H), 7.58 - 7.47 (m, 1H), 7.41 - 7.37 (m, 3H), 7.31 - 7.30 (m, 1H), 7.03 - 7.01 (m, 1H), 6.60 - 6.58 (m, 2H), 4.90 - 4.62 (m, 4H), 4.57 - 4.52(m, 1H), 4.50 - 4.34(m, 2H), 3.97 - 3.92(m, 2H), 3.58 (s, 2H), 3.31 - 3.22 (m, 2H), 2.27 (s, 3H), 2.23 - 1.85 (m, 4H).

Example 246: (l?)-5-Methyl-/V-(l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)phenyl)ethyl)-lH-benzo[ ]imidazole-6-carboxamide (Compound 126)

246A-1 246A-2 246A-3

Compound 126

Step 1: (/? Her/- Butyl (l-(3-bromophenyl)ethyl)carbamate (246A-2)

To a solution of (7?)-l-(3-bromophenyl)ethanamine (1.00 g, 5.00 mmol, 1.0 eq) and TEA (759 mg, 7.50 mmol, 1.02 mL, 1.5 eq) in DCM (25 mL) was added BOC2O (1.09 g, 5.00 mmol, 1.23 mL, 1.0 eq). The mixture was stirred at 20 °C for 4 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. (/?)-/c/7-Butyl (l-(3-bromophenyl)ethyl)carbamate (1.40 g, 4.66 mmol, 93% yield) was obtained as a white solid. ^T H NMR (400 MHz, CDCh) 8 7.44 (s, 1H), 7.38 (td, J= 1.8, 7.3 Hz, 1H), 7.26 - 7.16 (m, 2H), 4.78 (br s, 2H), 1.51 - 1.33 (m, 12H).

Step 2: (/? Her/- Butyl (l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (246A-3)

To a mixture of (/?)-/er/-butyl (l-(3-bromophenyl)ethyl)carbamate (100 mg, 333 pmol, 1.0 eq), (5-formyl-2-thienyl)boronic acid (52.0 mg, 333 pmol, 1.0 eq), KO Ac (98.1 mg, 999 pmol, 3.0 eq), Pd(OAc)2 (7.48 mg, 33.3 pmol, 0.1 eq) and cataCXium® A (23.9 mg, 66.6 pmol, 0.2 eq) in DMSO (5.0 mL) was degassed and purged with N2 for three times. The mixture was stirred at 80 °C for 6 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.3). (A)-tert-Butyl (l-(3-(5- formylthiophen-2-yl)phenyl)ethyl)carbamate (50.0 mg, 151 pmol, 45% yield) was obtained as a yellow solid.

Step 3: (l?)-tert-Butyl (l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)ethyl) carbamate (246A-4)

To a mixture of (A)-terZ-butyl (l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (50.0 mg, 151 pmol, 1.0 eq) and pyrrolidine (21.5 mg, 302 pmol, 25.2 pL, 2.0 eq) in MeOH (4.0 mL) was added NaBEECN (28.4 mg, 453 pmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude product (/?)-/c/7-butyl (l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)phenyl)ethyl) carbamate (55.0 mg, 80% purity) as a brown oil, which was used in the next step without any further purification. M + H ⁺ = 387.2 (LCMS).

Step 4: (l?)-l-(3-(5-(Pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)eth anamine (246A-5)

To a mixture of (/?)-/c77-butyl (l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)ethyl) carbamate (55.0 mg, 142 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product (A)-l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl) phenyl)ethanamine (50.0 mg, 80% purity) as a brown solid, which was used in the next step without any further purification. M + H ⁺ = 287.3 (LCMS).

Step 5: (/ )-5- I el by l- \-( 1 -( 3-(5-( pyrrol id i n- 1 -yl in et by 1 )t Ii io p hen-2-yl ) p he nyl )et Iiyl )- 1 //- benzo [ |imidazole-6-carboxamide (Compound 126)

To a solution of (A)-l-(3-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)etha namine (50.0 mg, 175 pmol, 1.0 eq) and 5-methyl-17/-benzo[ ]imidazole-6-carboxylic acid (40.8 mg, 192 pmol, 1.1 eq) in DCM (2.0 mL) were added TEA (88.3 mg, 873 pmol, 122 pL, 5.0 eq), EDCI (40.2 mg, 209 pmol, 1.2 eq) and HOBt (28.3 mg, 209 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (R)- 5 -Methyl -7V-(1 -(3 -(5-(pyrrolidin- 1 -ylmethyl)thiophen-2-yl)phenyl)ethyl)- 1 //-benzoft/] imidazole-6-carboxamide (9.10 mg, 20.0 pmol, 12% yield) was obtained as a white solid. M + H ⁺ = 445.2 (LCMS); flT NMR (400 MHz, CD3OD) 6 8.18 (s, 1H), 7.70 (s, 1H), 7.56 - 7.49 (m,

1H), 7.41 - 7.34 (m, 3H), 7.28 (d, J= 3.6 Hz, 1H), 7.01 (d, J = 3.6 Hz, 1H), 5.26 (q, J = 7.0 Hz, 1H), 3.94 (s, 2H), 2.73 (br s, 4H), 2.47 (s, 3H), 1.86 (br s, 4H), 1.58 (d, J= 7.0 Hz, 3H).

Example 247: A-((l?)-l-(3-(5-((((15',3^)-3-hydroxycyclopentyl)amino)methy l)thiophen-2- yl)phenyl)ethyl)-5-methyl-l//-benzo|7|imid:izole-6-c:irboxam ide (Compound 134)

Step 1: (l?)-5-(3-(l-Aminoethyl)phenyl)thiophene-2-carbaldehyde (247A-1)

To a stirred solution of (R) -tert-butyl (l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamate (40.0 mg, 121 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give (A)-5-(3-(l-aminoethyl)phenyl)thiophene-2-carbaldehyde (30 mg, 110 pmol, 91% yield, HC1 salt) as a white solid. M + H ⁺ = 232.1 (LCMS). Step 2: (/?)- X-( 1 -(3-( 5- l or my H h iophen-2-y 1 ) p heny 1 )et hy 1 )-5-ni et hy 1- 1 //- benzo [z/| ini id azole-6-carboxamide (247A-2)

To a solution of (7?)-5-(3-(l-aminoethyl)phenyl)thiophene-2-carbaldehyde (100 mg, 432 pmol,

I.0 eq) and 5-methyl-U/-benzo[J]imidazole-6-carboxylic acid (101 mg, 476 pmol, 1.1 eq) in DCM (5.0 mL) were added TEA (131 mg, 1.30 mmol, 181 pL, 3 eq), EDCI (99.0 mg, 519 pmol, 1.2 eq) and HOBt (70.1 mg, 519 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.5). (7?J-7V-(l-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-5-methyl- UT- benzofd] imidazole-6-carboxamide (100 mg, 257 pmol, 60% yield) was obtained as a yellow solid. M + H ⁺ = 390.1 (LCMS).

Step 3: \-((/?)-l-(3-(5-(((( l.S.3/?)-3-Hydi oxycyclopentyl):iniino)iiietliyl)tliiophen-2- yl)phenyl)ethyl)-5-methyl-lH-benzo[J|imidazole-6-carboxamide (Compound 134)

To a solution of (U?,3X)-3-aminocyclopentanol (27.2 mg, 198 pmol, 25.2 pL, 1.1 eq) in MeOH (3.0 mL) was added TEA (10.0 pL), followed by the addition of (R)-N-(l-(3-(5- formylthiophen-2-yl)phenyl)ethyl)-5-methyl-lJ7-benzo[J]imida zole-6-carboxamide (70.0 mg, 180 pmol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (22.6 mg, 359 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). N-((R)-l-(3-(5-((((lS,3R)-3- Hydroxycyclopentyl)amino) methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-lH- benzo[t/]imidazole-6-carboxamide (3.40 mg, 7.16 pmol, 4% yield) was obtained as a colorless gum. M + H ⁺ = 475.2 (LCMS); ¹ HNMR (400 MHz, CD ₃ OD) 8 8.57 - 8.45 (m, 1H), 8.24 - 8.16 (m, 1H), 7.76 - 7.64 (m, 2H), 7.59 - 7.53 (m, 1H), 7.49 - 7.44 (m, 1H), 7.41 (dd, J= 4.3,

I I.4 Hz, 3H), 7.32 - 7.22 (m, 1H), 5.29 - 5.24 (m, 1H), 4.40 (s, 2H), 4.32 (td, J= 4.1, 8.6 Hz, 1H), 3.68 - 3.58 (m, 1H), 2.54 - 2.42 (m, 3H), 2.30 - 2.09 (m, 2H), 2.01 - 1.76 (m, 4H), 1.66 (br d, J = 6.9 Hz, 3H).

Example 248: \-((/?)-l-(3-(5-(((( l.S.3/?)-3-Hydroxycyclopeiityl):imino)methyl)thiophen- 2-yl)plieiiyl)ethyl)-2-iiiethyl-5-(( 1 -methyl- 1 //-pyr:izol-4-yl):iiiiiiio)beiiz:imide (Compound 137)

248A-2 Compound 137

Step 1: 2-Methyl-5-(( 1 -m ethyl- LH-pyrazol-4-yl)amino)benzoic acid (248A-1)

To a stirred solution of 5-amino-2-methylbenzoate (200 mg, 1.21 mmol, 1.0 eq) and 4-bromo- 1 -methyl- UT-pyrazole (234 mg, 1.45 mmol, 1.2 eq) in dioxane (8.0 mL) was added Z-BuONa

(582 mg, 6.05 mmol, 5.0 eq) and /BuXPhos Pd G3 (96.2 mg, 121 pmol, 0.1 eq) under a N2 atmosphere. The mixture was stirred at 100°C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with petroleum ether (3.0 mL x 5). The aqueous layer was treated with HC1 (1 M aqueous) to adjust pH 4 and extracted with EtOAc (2.0 mL x 5). The combined organic layers dried over Na2SO4, filtered and concentrated under vacuum to give the crude product 2-methyl-5-((l -methyl- UT-pyrazol- 4-yl)amino)benzoic acid (0.25 g) as a brown oil. Step 2: (l?)-/V-(l-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl- 5-(( 1 -methyl- 1//- pyrazol-4-yl)amino)benzamide (248A-2)

To a solution of 2-methyl-5-((l-methyl-U/-pyrazol-4-yl)amino)benzoic acid (198 mg, 856 pmol, 1.1 eq) and (7?)-5-(3-(l-aminoethyl)phenyl)thiophene-2-carbaldehyde (180 mg, 778 pmol, 1.0 eq) in DCM (6.0 mL) were added TEA (236 mg, 2.33 mmol, 325 pL, 3.0 eq), EDCI (179 mg, 934 pmol, 1.2 eq) and HOBt (126 mg, 934 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (5 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.6). (7?)-7V-(l-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl- 5-((l-methyl-lH-pyrazol-4-yl)amino)benzamide (75.0 mg, 169 pmol, 22% yield) was obtained as a yellow solid. M + H ⁺ = 445.1 (LCMS).

Step 3: \-((/?)-l-(3-(5-(((( l.S.3/?)-3-Hydi oxycyclopentyl):iniino)iiiethyl)thiophen-2- yl)plieiiyl)ethyl)-2-niethyl-5-(( 1 -in ethyl- l//-py razol-4-yl ):iiniiio)beiizain ide (Compound 137)

To a solution of ( 1R, 3S)-3 -aminocyclopentanol (25.5 mg, 186 pmol, 25 pL, 1.1 eq) in MeOH (3.0 mL) was added TEA (10.0 pL), followed by the addition of (R)-N-(l-(3-(5- formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5-((l-methyl-U/-p yrazol-4-yl)amino)benzamide (75.0 mg, 169 pmol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBH ₃ CN (21.2 mg, 337 pmol, 2.0 eq) was added. The result mixture was stirred at 20 °C for another 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 X 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 7V-((/?)-l-(3-(5-((((15,3/?)-3- Hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)- 2-methyl-5-((l -methyl- 1H- pyrazol-4-yl)amino)benzamide (7.00 mg, 13.2 pmol, 8% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 530.2 (LCMS); ¹ HNMR (400 MHz, CD ₃ OD) 8 7.69 - 7.65 (m, 1H), 7.58 - 7.51 (m, 2H), 7.45 - 7.35 (m, 4H), 7.29 - 7.25 (m, 1H), 7.05 - 6.98 (m, 1H), 6.85 - 6.74 (m, 2H), 5.26 - 5.13 (m, 1H), 4.55 - 4.39 (m, 2H), 4.35 - 4.33 (m, 1H), 3.88 - 3.72 (m, 3H), 3.71 - 3.68 (m, 1H), 2.27 - 2.18 (m, 5H), 1.97 - 1.84 (m, 4H), 1.61 - 1.41 (m, 3H).

Example 249: 5-((lH-Pyrazol-4-yl)amino)-/V-((l?)-l-(3-(5-((((l»S,3^)-3- hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)- 2-methylbenzamide (Compound 140)

Compound 140

Step 1: 2-\Iethyl-5-(( 1 -(tetr:iliydro-2//-pyr:iii-2-yl)-l//-pyr:izol-4-yl):iinino)b enzoic acid (249A-1)

To a mixture of methyl 5-amino-2-methylbenzoate (200 mg, 1.21 mmol, 1.0 eq) and 4-bromo- l-(tetrahydro-2J/-pyran-2-yl)-U/-pyrazole (336 mg, 1.45 mmol, 1.2 eq) in anhydrous dioxane (8.0 mL) were added Z-BuONa (582 mg, 6.05 mmol, 5.0 eq) and /BuXPhos Pd G3 (96.2 mg, 121 pmol, 0.1 eq) degassed and purged with N2 three times. The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give 2-methyl-5-(( l -(tetrahydro-2//- pyran-2-yl)-lJ/-pyrazol-4-yl)amino)benzoic acid (210 mg, 697 pmol, 58% yield) as a yellow solid. M + H ⁺ = 302.3 (LCMS).

Step 2: /V-((l?)-l-(3-(5-Formylthiophen-2-yl)phenyl)ethyl)-2-methyl- 5-((l-(tetrahydro- 2//-pyran-2-yl)-l //-pyr:izol-4-yl):iiiiino)benz:iinide (249A-2)

To a solution of 2-methyl-5-(( l-(tetrahydro-27/-pyran-2-yl)- IT/-pyrazol-4-yl)amino)benzoic acid (72.6 mg, 241 pmol, 1.1 eq) and (7?)-5-(3-(l-aminoethyl)phenyl)thiophene-2- carbaldehyde (50.7 mg, 219 pmol, 1.0 eq) in DCM (3.0 mL) were added TEA (66.5 mg, 657 pmol, 91.5 pL, 3.0 eq), EDCI (50.4 mg, 263 pmol, 1.2 eq) and HOBt (35.5 mg, 263 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.7). A-((R)-l-(3-(5-Formylthiophen- 2-yl)phenyl)ethyl)-2-methyl-5-(( l -(tetrahydro-27/-pyran-2-yl)- l7/-pyrazol-4-yl)amino) benzamide (85.0 mg, 165 pmol, 75% yield) was obtained as a yellow solid. M + H ⁺ = 515.4 (LCMS).

Step 3: \-((/?)-l-(3-(5-(((( l.S.3/?)-3-Hydroxycyclopeiityl)aniino)iiietliyl)tliioplien-2 - yl)plieiiyl)ethyl)-2-niethyl-5-(( l-(tetr:iliydro-2//-pyr:iii-2-yl)-l//-pyr:izol-4-yl)aniino) benzamide (249A-3)

To a stirred solution of A-((R)-l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-2-methyl-5- ((l- (tetrahydro-2J/-pyran-2-yl)-U/-pyrazol-4-yl)amino)benzamide (85.0 mg, 165 pmol, 1.0 eq) and (17?,35)-3-aminocyclopentanol (25.0 mg, 182 pmol, 1.1 eq) in MeOH (3.0 mL). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then mixture NaBHiCN (20.8 mg, 330 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 40% - 70% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-((A)-l-(3-(5-((((15,3A)-3-hydroxycyclopentyl)amino)methyl) thiophen-2-yl)phenyl)ethyl)-2-methyl-5-((l-(tetrahydro-2J/-p yran-2-yl)-U/-pyrazol-4-yl) amino)benzamide (20.0 mg, 33.4 pmol, 20% yield) was obtained as a yellow solid. M + H ⁺ = 600.3 (LCMS).

Step 4: 5-((l//-I’yr:izol-4-yl)ainino)- \-((/?)-l-(3-(5-(((( l.S.3/?)-3-hydroxycyclopentyl) amino)methyl)thiophen-2-yl)phenyl)ethyl)-2-methylbenzamide (Compound 140)

To a mixture of A-((A)-l-(3-(5-((((l£,3A)-3-hydroxycyclopentyl)amino)methyl )thiophen-2- yl)phenyl)ethyl)-2-methyl-5-((l-(tetrahydro-2J/-pyran-2-yl)- U/-pyrazol-4-yl)amino) benzamide (20.0 mg, 33.4 pmol, 1.0 eq) in MeOH (2.0 mL) was added TsOH.JLO (19.0 mg, 100 pmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5- ((U/-Pyrazol-4-yl)amino)-A-((A)-l-(3-(5-((((15,3A)-3-hydroxy cyclopentyl) amino)methyl)thiophen-2-yl)phenyl)ethyl)-2 -methylbenzamide (4.12 mg, 6.54 pmol, 20% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 516.1 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 8 7.65 (s, 1H), 7.57 - 7.52 (m, 3H), 7.43 - 7.35 (m, 3H), 7.27 (d, J = 3.6 Hz, 1H), 7.02 (d, J= 8.3 Hz, 1H), 6.84 - 6.76 (m, 2H), 5.19 (q, J= 7.0 Hz, 1H), 4.47 (s, 2H), 4.34 (quin, J= 4.1 Hz, 1H), 3.74 - 3.66 (m, 1H), 2.30 - 2.23 (m, 1H), 2.22 (s, 3H), 2.20 - 2.14 (m, 1H), 2.04 -1.79 (m, 4H), 1.53 (d, J= 7.0 Hz, 3H).

Example 250: A-((l?)-l-(3-(5-((((15',3^)-3-Hydroxycyclopentyl)amino)methy l)thiophen- 2-yl)phenyl)ethyl)-5-methyl-l//-ind:izole-6-c:irboxamide (Compound 146)

250A-1

Compound 146

Step 1: (/? - \-(l-(3-(5-I ormylthiophen-2-yl)phenyl)ethyl)-5-methyl-l//-indazole-6- carboxamide (250A-1)

To a solution of 5-methyl-U/-indazole-6-carboxylic acid (70.0 mg, 397 pmol, 1.0 eq) and (R)- 5-(3-(l-aminoethyl)phenyl)thiophene-2-carbaldehyde (91.9 mg, 397 pmol, 20.0 pL, 1.0 eq) in DCM (2.0 mL) were added TEA (80.4 mg, 795 pmol, 111 pL, 2.0 eq), EDCI (91.4 mg, 477 pmol, 1.2 eq) and HOBt (64.4 mg, 477 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (RJ-7V-(l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-5- methyl-U/-indazole-6-carboxamide (130 mg) as a brown oil. M + H ⁺ = 390.2 (LCMS).

Step 2: N-((R)-l-(3-(5-((((lS,3R)-3-Hydroxycyclopentyl)amino)methyl) thiophen-2- yl)phenyl)ethyl)-5-methyl-l H-indazole-6-carboxamide (Compound 146)

To a solution of (U?,35)-3-aminocyclopentanol (50.5 mg, 367 pmol, 1.1 eq, HC1 salt) in MeOH (2.0 mL) was added TEA (30.0 pL), followed by the addition of (R)-N-(l-(3-(5- formylthiophen-2-yl)phenyl)ethyl)-5-methyl-lJ7-indazole-6-ca rboxamide (130 mg, 334 pmol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, and then NaBHiCN (62.9 mg, 1.00 mmol, 3.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-((7?)-l-(3-(5-((((15,37?)-3-Hydroxycyclo pentyl) amino)methyl)thiophen-2-yl)phenyl)ethyl)-5-methyl-l//-indazo le-6-carboxamide (14.1 mg, 29.0 pmol, 9% yield) was obtained as a white solid. M + H ⁺ = 475.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 88.27 (br s, 1H), 7.74 (s, 2H), 7.70 (s, 1H), 7.62 (s, 1H), 7.42 (dd, J= 4.3, 7.8 Hz, 3H), 7.30 3.7 Hz, 1H), 5.28 (q, J= 7.0 Hz, 1H), 4.47 (s, 2H), 4.40 - 4.28 (m, 1H),

3.77 - 3.64 (m, 1H), 2.42 (s, 3H), 2.08 - 1.93 (m, 2H), 1.86 (br dd, J= 3.7, 8.0 Hz, 4H), 1.60 (d, J = 7.0 Hz, 3H).

Example 251: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 151)

28A-6 251 A-1

Compound 151 Step 1: (/?)-ter/-Butyl ((6-((l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamoyl)-5- inethyl- 1 //-benzo |7| ini idazol-2-yl)inethyl)carbainat (251 A-l)

To a solution of 2-(((ter/-butoxycarbonyl)amino)methyl)-5-methyl-lZ7-benzo[t/ ]imidazole-6- carboxylic acid (100 mg, 328 pmol, 1.0 eq) and (7?)-5-(3-(l-aminoethyl)phenyl)thiophene-2- carbaldehyde (75.8 mg, 328 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (66.3 mg, 655 pmol, 91.2 pL, 2.0 eq), EDCI (75.3 mg, 393 pmol, 1.2 eq) and HOBt (23.1 mg, 393 pmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/2. (Z?)-/er/-Butyl ((6-((l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)carbamoyl)-5- m ethyl- l/7-benzo[t/] imidazole-2-yl)methyl)carbamate (70 mg, 135 pmol, 41% yield) was obtained as a white solid. M + H ⁺ = 519.3 (LCMS).

Step 2: tc/7- Butyl ((6-(((l?)-l-(3-(5-((((15',3^)-3-hydroxycyclopentyl)amino)me thyl) thiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-lE/-benzo[J|i midazol-2-yl)methyl) carbamate (251A-2)

To a solution of (U?,35)-3-aminocyclopentanol (47.8 mg, 347 pmol, 3.0 eq) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of (/?)-/c/7-butyl ((6-((l-(3-(5- formylthiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-l/7-ben zo[t/]imidazol-2-yl)methyl) carbamate (60.0 mg, 116 pmol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (21.8 mg, 347 pmol, 3.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product Zc/V-butyl ((6-(((/?)-l-(3-(5-((((15,3/?)-3- hydroxycyclopentyl)amino)methyl)thiophen-2-yl)phenyl)ethyl)c arbamoyl)-5-methyl-l/7- benzo[t/]imidazol-2-yl)methyl)carbamate (70.0 mg).M + H ⁺ = 604.4 (LCMS). Step 3: 2-(Aminomethyl)-/V-((l?)-l-(3-(5-((((l»S,3^)-3-hydroxycyclo pentyl)amino)methyl) thiophen-2-yl)phenyl)ethyl)-5-methyl-l//-benzo|7|imid:izole- 6-carboxamide (Compound 151)

To a stirred solution of tert-butyl ((6-(((A)-l-(3-(5-((((15,3A)-3-hydroxycyclopentyl)amino) methyl)thiophen-2-yl)phenyl)ethyl)carbamoyl)-5-methyl-U/-ben zo[J]imidazol-2-yl)methyl) carbamate (50.0 mg, 82.8 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 82.8 pL, 4.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 2-(aminomethyl)- A-((A)-l-(3-(5-((((15,3A)-3-hydroxycyclopentyl)amino)methyl) thiophen-2-yl)phenyl)ethyl)- 5-methyl-lJ/-benzo[t/]imidazole-6-carboxamide (5.50 mg, 9.96 pmol, 12% yield, HC1 salt) as a white solid. M + H ⁺ = 504.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 7.81 (s, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.58 (dd, J= 2.4, 6.2 Hz, 1H), 7.43 (t, J= 4.8 Hz, 3H), 7.31 3.7 Hz,

1H), 5.27 (d, J= 1A Hz, 1H), 4.69 (s, 2H), 4.48 (s, 2H), 4.37 - 4.31 (m, 1H), 3.71 (br t, J = 6.1 Hz, 1H), 2.50 (s, 3H), 2.34 - 2.13 (m, 2H), 2.07 - 1.94 (m, 1H), 1.91 - 1.82 (m, 3H), 1.60 (d, J = 7.1 Hz, 3H).

Example 252: A-((l?)-l-(3-(5-((((15',3^)-3-Hydroxycyclopentyl)amino)methy l)thiophen- 2-yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (Compound 154)

32A-4 252A-1

Compound 154

Step 1 : (l?)-/V-(l-(3-(5-formylthiophen-2-yl)phenyl)ethyl)-6-methylq uinoline-7- carboxamide (252A-1)

To a solution of 6-methylquinoline-7-carboxylic acid (70.0 mg, 374 pmol, 1.0 eq) in DCM (5 mL) were added (R)-5-(3-(l-aminoethyl)phenyl)thiophene-2-carbaldehyde (110 mg, 411 pmol, 83 pL, 1.1 eq, HC1 salt), TEA (75.7 mg, 748 pmol, 104 pL, 2.0 eq), EDCI (108 mg, 561 pmol, 1.5 eq) and HOBt (75.8 mg, 561 pmol, 1.5 eq). The mixture was stirred at 20°C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. (7?)-7V-(l-(3-(5-Dormylthiophen-2-yl)phenyl)ethyl)-6-methylq uinoline-7- carboxamide (130 mg, 325 pmol, 87% yield) was obtained as a yellow oil. 'H NMR (400 MHz, CD ₃ OD) 8 9.93 - 9.83 (m, 1H), 8.88 - 8.78 (m, 1H), 8.32 (d, J= 8.1 Hz, 1H), 8.05 - 7.99 (m, 1H), 7.93 (d, J= 4.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.83 - 7.80 (m, 1H), 7.75 - 7.68 (m, 1H), 7.64 - 7.61 (m, 1H), 7.59 - 7.48 (m, 3H), 5.33 (q, J= 7.1 Hz, 1H), 2.57 - 2.49 (m, 3H), 1.66 - 1.59 (m, 3H).

Step 2: \-((/?)-l-(3-(5-(((( l.S.3/?)-3-hydroxycyclopeiityl):iniino)niethyl)thiophen-2- yl)phenyl)ethyl)-6-methylquinoline-7-carboxamide (Compound 154)

To a solution of (1R,3S)~3 -aminocyclopentanol (179 mg, 1.30 mmol, 4.0 eq, HC1 salt) in MeOH (5.0 mL) was added TEA (40.0 pL), followed by the addition of (R)-N-(l-(3-(5- dormylthiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7-carbox amide (130 mg, 325 pmol, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBH ₃ CN (134 mg, 2.13 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-((7?)-l-(3-(5-((((15,37?)-3-Hydroxycyclopentyl) amino)methyl)thiophen-2-yl)phenyl)ethyl)-6-methylquinoline-7 -carboxamide (39.0 mg, 80.3 pmol, 25% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 486.1 (LCMS); HNMR^H NMR (400 MHz, CD ₃ OD) 8 9.23 - 9.19 (m, 1H), 9.14 (d, J= 8.4 Hz, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 8.12 (dd, J= 5.4, 8.4 Hz, 1H), 7.76 (s, 1H), 7.60 (dt, J= 1.8, 4.3 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.31 (d, = 3.6 Hz, 1H), 7.30 (m, 1H), 5.38 - 5.28 (m, 1H), 4.50 - 4.44 (m, 2H), 4.38 - 4.30 (m, 1H), 3.76 - 3.64 (m, 1H), 2.59 (s, 3H), 2.32 - 2.13 (m, 2H), 2.07 - 1.95 (m, 1H), 1.92 - 1.81 (m, 3H), 1.64 (d, J= 1A Hz, 3H).

Example 253: 5-(2-Aminoethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 143)

253A-3 Compound 143

Step 1: / f/- Butyl 3-(2-((3-fluorobenzyl)amino)-2-oxoethyl)azetidine-l-carboxyl ate (253A-2)

To a solution of 2-(l-(te/7-butoxy carbonyl)azeti din-3 -yl)acetic acid (500 mg, 2.32 mmol, 1.0 eq) in DCM (15 mL) were added (3-fluorophenyl)methanamine (436 mg, 3.48 mmol, 396 pL, 1.5 eq), TEA (705 mg, 6.97 mmol, 970 pL, 3.0 eq), EDCI (668 mg, 3.48 mmol, 1.5 eq) and HOBt (471 mg, 3.48 mmol, 1.5 eq). The resulting mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over TsfeSC , filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petr oleum ether from 0/1 to 1/1. Zc/V-Butyl 3-(2-((3-fluorobenzyl)amino)-2- oxo ethyl)azetidine-l -carboxylate (700 mg, 2.17 mmol, 93% yield) was obtained as a colorless oil. M + H ⁺ = 323.3 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.36 - 7.28 (m, 1H), 7.07 - 6.92 (m, 3H), 4.43 (br d, J= 5.9 Hz, 2H), 4.21 - 4.01 (m, 2H), 3.72 - 3.49 (m, 2H), 3.07 - 2.87 (m, 1H), 2.55 (br d, J= 7.9 Hz, 2H), 1.47 - 1.40 (m, 9H).

Step 2: 2-(Azetidin-3-yl)-/V-(3-fluorobenzyl)acetamide (253 A-3)

To a solution of Zc/V-butyl 3-(2-((3-fluorobenzyl)amino)-2-oxoethyl)azetidine-l-carboxyl ate (300 mg, 936 pmol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 30.0 mL) at 0 °C. Then the mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product 2-(azetidin-3-yl)-A-(3-fluorobenzyl)acetamide (300 mg, HC1 salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 223.3 (LCMS).

Step 3: /V-(3-Fluorobenzyl)-2-(l-(l-(naphthalen-l-yl)ethyl)azetidin- 3-yl)acetamide (Compound 143)

To a solution of 2-(azeti din-3 -yl)-A-(3-fluorobenzyl)acetamide (300 mg, 1.16 mmol, 2.63 eq, HC1 salt) in MeOH (15 mL) was added TEA (50.0 pL), followed by the addition of 1-(1- naphthyl)ethanone (150 mg, 881 pmol, 134 pL, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (83.1 mg, 1.32 mmol, 3.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3; mobile phase B: acetonitrile). A-(3-Fluorobenzyl)-2-(l-(l-(naphthalen-l-yl)ethyl)azetidin-3 -yl)acetamide (7.82 mg, 20.8 pmol, 5% yield) was obtained as a yellow gum. 'H NMR (400 MHz, CD3OD) 8 8.20 (br d, J = 8.3 Hz, 1H), 7.89 - 7.84 (m, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.58 - 7.41 (m, 4H), 7.29 (dt, J= 6.0, 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.02 - 6.89 (m, 2H), 4.35 - 4.26 (m, 3H), 3.66 - 3.57 (m, 1H), 3.50 - 3.40 (m, 1H), 3.08 (t, J= 7.1 Hz, 1H), 2.90 - 2.78 (m, 2H), 2.52 (d, J= 7.0 Hz, 2H), 1.33 (d, J= 6.6 Hz, 3H).

Example 254: /V-(3-Fluorobenzyl)-l-(l-(naphthalen-l-yl)ethyl)pyrrolidine- 3- carboxamide

Step 3

Compound 144

Step 1: / f/- Butyl 3-((3-fluorobenzyl)carbamoyl)pyrrolidine-l-carboxylate (254A-2)

To a solution of l-(/er/-butoxycarbonyl)pyrrolidine-3 -carboxylic acid (1.00 g, 4.65 mmol, 1.0 eq) and (3-fluorophenyl)methanamine (581 mg, 4.65 mmol, 0.53 mL, 1.0 eq) in DCM (15 mL) were added TEA (940 mg, 9.29 mmol, 1.30 mL, 2.0 eq), EDCI (1.07 g, 5.58 mmol, 1.2 eq) and HOBt (753 mg, 5.58 mmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into FLO (15 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtO Ac/petroleum ether from 1/100 to 1/1. tert- Butyl 3-((3-fluorobenzyl)carbamoyl)pyrrolidine-l-carboxylate (600 mg, 1.86 mmol, 40% yield) was obtained as a white solid. M - 56 + H ⁺ = 267.2 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.52 (br s, 1H), 7.36 (dt, J= 6.4, 7.7 Hz, 1H), 7.14 - 6.94 (m, 3H), 4.29 (d, J = 6.0 Hz, 2H), 3.45 (dd, J= 8.0, 10.5 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.31 - 3.26 (m, 1H), 3.25 - 3.15 (m, 1H), 3.06 - 2.90 (m, 1H), 2.05 - 1.89 (m, 2H), 1.39 (s, 9H). Step 2: \-(3-I liiorobenzyl)pyrrolidine-3-carbox:iinide (254A-3)

To a stirred solution of tert-butyl 3 -((3 -fluorobenzyl)carbamoyl)pyrrolidine-l -carboxylate (200 mg, 434 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product 7V-(3-fluorobenzyl)pyrrolidine-3-carboxami de (200 mg), which was used in the next step without any further purification. M + H ⁺ = 223.1 (LCMS).

Step 3: \-(3-I luorobenzyl)-l-( l-(naphthalen-l-yl)ethyl)pyrrolidine-3-carboxamide (Compound 144)

To a solution of7V-(3-fluorobenzyl)pyrrolidine-3-carboxamide (200 mg, 773 pmol, 1.0 eq, HC1 salt) in MeOH (10 mL) was added TEA (10.0 pL), followed by the addition of 1 -(naphthal en- l-yl)ethanone (132 mg, 773 pmol, 120 pL 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (146 mg, 2.32 mmol, 3.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 45% - 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). N-(3 -Fluorobenzyl)- 1-(1 -(naphthal en-l-yl)ethyl)pyrrolidine-3 -carboxamide (87.4 mg, 232 pmol, 30% yield) was obtained as a colorless gum. M + H ⁺ = 377.3 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.39 (br d, J= 7.2 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.62 (dd, J= 3.8, 6.7 Hz, 1H), 7.50 - 7.38 (m, 3H), 7.34 - 7.22 (m, 1H), 7.11 - 6.84 (m, 3H), 4.39 - 4.30 (m, 1H), 4.27 (d, J = 8.7 Hz, 1H), 4.23 - 4.10 (m, 1H), 3.06 - 2.87 (m, 2H), 2.83 - 2.53 (m, 3H), 2.22 - 1.95 (m, 2H), 1.59 - 1.45 (m, 3H).

Example 255: (H?,55,6r)-A-(3-Fluorobenzyl)-3-(l-(naphthalen-l-yl)ethyl)-3 - azabicyclo[3.1.0]hexane-6-carboxamide (Compound 149)

255A-3 Compound 149

Step 1: ( 1 /?.5.S.6r)-/c/7-Butyl 6-((3-fluorobenzyl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (255A-2)

To a solution of (U?,55,6r)-3-(terLbutoxycarbonyl)-3-azabicyclo[3.1.0]hexane- 6-carboxylic acid (500 mg, 2.20 mmol, 1.0 eq) and (3-fluorophenyl)methanamine (275 mg, 2.20 mmol, 1.0 eq) in DCM (10 mL) were added TEA (445 mg, 4.40 mmol, 612 pL, 2.0 eq) and T3P (1.68 g, 2.64 mmol, 1.57 mL, 50% purity in EtOAc, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. ( l/?,5A',6/')-/c77-Butyl 6-((3- fluorobenzyl)carbamoyl)-3-azabicyclo[3. L0] hexane-3 -carboxylate (400 mg, 1.20 mmol, 54% yield) was obtained as a white solid. M + H ⁺ = 335.2 (LCMS); ^T H NMR (400 MHz, DMSO- d ₆ ) 6 8.56 (br t, J= 5.9 Hz, 1H), 7.47 - 7.27 (m, 1H), 7.15 - 6.96 (m, 3H), 4.28 (br d, J= 5.9 Hz, 2H), 3.48 (br dd, J = 4.1, 10.8 Hz, 2H), 3.34 - 3.24 (m, 2H), 1.87 (br s, 2H), 1.43 (t, J = 3.1 Hz, 1H), 1.37 (s, 9H).

Step 2: ( 1 /?.5.S.6r)-\-(3-I liiorobenzyl)-3-azabicyclo|3.1.()|hex:ine-6-carboxainide (255A- 3)

To a stirred solution of (U?,55,6r)-terLbutyl 6-((3-fluorobenzyl)carbamoyl)-3 -azabicyclo [3.1.0]hexane-3-carboxylate (200 mg, 598 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude product ().R,5S,6r)-N-(3- fluorobenzyl)-3-azabicyclo[3.L0]hexane-6-carboxamide (200 mg, HC1 salt), which was used in the next step without any further purification.. M + H ⁺ = 235.2 (LCMS). Step 3: (ll?,5»S,6r)-/V-(3-Fluorobenzyl)-3-(l-(naphthalen-l-yl)ethy l)-3-azabicyclo[3.1.0] hexane-6-carboxamide (Compound 149)

To a solution of (17?,5£,6r)-7V-(3-fluorobenzyl)-3-azabicyclo[3.1.0]hexane-6 -carboxamide (100 mg, 369 pmol, 1.0 eq, HC1 salt) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of 1 -(naphthal en-l-yl)ethanone (62.9 mg, 369 pmol, 56.1 pL, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (69.6 mg, 1.11 mmol, 3.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 60% - 90% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (lA,55,6r)-A-(3-Fluorobenzyl)-3-(l-(naphthalen-l- yl)ethyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide (27.9 mg, 71.8 pmol, 19% yield) was obtained as a white solid.. M + H ⁺ = 389.3 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.45 (br d, = 8.0 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.54 (d, = 6.9 Hz, 1H), 7.50 - 7.36 (m, 3H), 7.31 (dt, J = 6.0, 7.9 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.04 - 6.92 (m, 2H), 4.35 (s, 2H), 4.07 (q, J= 6.4 Hz, 1H), 3.39 (d, J= 9.0 Hz, 1H), 2.77 (d, J= 9.4 Hz, 1H), 2.63 (dd, J= 3.4, 8.9 Hz, 1H), 2.28 (dd, J = 3.5, 9.4 Hz, 1H), 2.13 (t, J = 2.8 Hz, 1H), 2.01 - 1.95 (m, 1H), 1.84 - 1.79 (m, 1H), 1.45 (d, J= 6.6 Hz, 3H).

Example 256: 2-(l-(Naphthalen-l-yl)ethyl)-l,2,3,4-tetrahydroisoquinolin-7 -amine (Compound 135)

Compound 135 Step 1: 2-(l-(Naphthalen-l-yl)ethyl)-7-nitro-l,2,3,4-tetrahydroisoqu inoline (256A-1)

To a mixture of 1 -(naphthal en-l-yl)ethanone (200 mg, 1.18 mmol, 178 pL, 1.0 eq) and 7-nitro-

1.2.3.4-tetrahydroisoquinoline (230 mg, 1.29 mmol, 1.1 eq) in MeOH (5.0 mL) was added Ti(z-

PrO)4 (668 mg, 2.35 mmol, 694 pL, 2.0 eq). The mixture was stirred at 60 °C for 16 h. The mixture was cooled to 0 °C and NaBHj (88.9 mg, 2.35 mmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into ice water (6.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 75% - 98% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-(l-(Naphthalen-l-yl)ethyl)-7-nitro-l, 2,3,4- tetrahydroisoquinoline (100 mg, 301 pmol, 26% yield) was obtained as a white solid. M + H ⁺ = 333.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.42 (br s, 1H), 8.02 - 7.94 (m, 1H), 7.93 - 7.86 (m, 2H), 7.80 (br d, J= 8.1 Hz, 1H), 7.66 (br d, J= 6.4 Hz, 1H), 7.53 - 7.42 (m, 3H), 7.23 (d, J= 8.4 Hz, 1H), 4.36 (br s, 1H), 4.01 (br d, J= 14.6 Hz, 1H), 3.73 (br d, J= 14.9 Hz, 1H), 3.05 - 2.64 (m, 4H), 1.62 (br d, J= 6.5 Hz, 3H).

Step 2: 2-(l-(Naphthalen-l-yl)ethyl)-l,2,3,4-tetrahydroisoquinolin-7 -amine (Compound 135)

To a solution of 2-(l-(naphthalen-l-yl)ethyl)-7-nitro-l,2,3,4-tetrahydroisoqu inoline (70.0 mg, 211 pmol, 1.0 eq) in a mixture of MeOH (2.5 mL) and H2O (0.5 mL) were added iron powder (58.8 mg, 1.05 mmol, 5.0 eq) and NH4CI (56.3 mg, 1.05 mmol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then poured into H2O (6.0 mL). The product was extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 60% - 95% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-(l -(Naphthal en-l-yl)ethyl)-

1.2.3.4-tetrahydroisoquinolin-7-amine (3.40 mg, 10.3 pmol, 5% yield) was obtained as a white gum. M + H ⁺ = 303.1 (LCMS); ^X H NMR (400 MHz, CDCh) 68.48 (br s, 1H), 7.90 - 7.83 (m, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.69 (br d, J= 7.3 Hz, 1H), 7.52 - 7.42 (m, 3H), 6.89 (d, J= 8.2 Hz, 1H), 6.51 (br d, J= 8.0 Hz, 1H), 6.36 (s, 1H), 4.25 (br d, J= 6.0 Hz, 1H), 3.86 (br d, J = 14.7 Hz, 1H), 3.56 (br d, J= 15.1 Hz, 2H), 2.86 - 2.57 (m, 4H), 1.58 (br s, 3H).

Example 257: /V-(2-(l-(Naphthalen-l-yl)ethyl)-l,2,3,4-tetrahydroisoquinol in-7-yl)-2- phenylacetamide (Compound 139)

Step 1

Compound 135 Compound 139

Step 1: /V-(2-(l-(Naphthalen-l-yl)ethyl)-l,2,3,4-tetrahydroisoquinol in-7-yl)-2- phenylacetamide (Compound 139)

To a solution of 2-(l-(naphthalen-l-yl)ethyl)-l,2,3,4-tetrahydroisoquinolin-7 -amine (40.0 mg, 132 pmol, 1.0 eq) and 2-phenylacetic acid (21.7 mg, 159 pmol, 20.0 pL, 1.2 eq) in DCM (2.0 mL) were added TEA (26.8 mg, 265 pmol, 368 pL, 2.0 eq), EDCI (30.4 mg, 159 pmol, 1.2 eq) and HOBt (21.5 mg, 159 pmol, 1.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 27% - 57% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). A-(2-(l -(Naphthal en-1- yl)ethyl)-l,2,3,4-tetrahydroisoquinolin-7-yl)-2-phenylacetam ide (7.04 mg, 12.9 pmol, 10% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 421.1 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 58.16 - 7.97 (m, 2H), 7.85 (br s, 1H), 7.66 (br t, J= 7.8 Hz, 4H), 7.32 (br s, 8H), 5.58 (br d, J= 6.6 Hz, 1H), 4.77 - 3.94 (m, 2H), 3.86 - 3.38 (m, 4H), 3.29 - 2.66 (m, 2H), 1.95 (d, J= 6.8 Hz, 3H). Example 258: 5-((l,2-Dimethylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(napht halen-l- yl)cyclopropyl)benzamide (Compound 404)

Compound 404

Step 1: te/7- Butyl 2-methyl-2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)car bamoyl) phenoxy)methyl)azetidine-l-carboxylate (258A-1)

To a solution 5-hydroxy-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzam ide (300 mg, 945 pmol, 1.0 eq) and tert-butyl 2-(hydroxymethyl)-2-methylazetidine-l -carboxylate (190 mg, 945 pmol, 1.0 eq) in toluene (18 mL) were added TMAD (488 mg, 2.84 mmol, 3.0 eq) and

PPhi (744 mg, 2.84 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times, then stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NajSCh, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. te/7-Butyl 2-methyl-2-((4-methyl-3-((l- (naphthalen- l-yl)cy cl opropyl)carbamoyl)phenoxy)m ethyl) azetidine- 1 -carboxylate (370 mg, 740 pmol, 79% yield) was obtained as a yellow solid. M + H ⁺ = 501.3 (LCMS). Step 2: 2-Methyl-5-((2-methylazetidin-2-yl)methoxy)-/V-(l-(naphthale n-l-yl)cyclopropyl) benzamide (258A-2)

To a solution of tert-butyl 2-methyl-2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (180 mg, 360 pmol, 1.0 eq) in DCM (10 mL) was added TFA (3.6 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the product 2-methyl-5-((2- methyl azetidin-2-yl)methoxy)-7V-(l -(naphthal en-l-yl)cyclopropyl)benzamide (90.0 mg, TFA salt) as a brown oil, which was used in the next step without any further purification. M + H ⁺ = 401.1 (LCMS).

Step 3: 5-(( 1 ,2-Dimethylazetidin-2-yl)methoxy)-2-methyl-/V-( l-(naphthalen-l-yl) cyclopropyl)benzamide (Compound 404)

To a solution of 2-methyl-5-((2-methylazetidin-2-yl)methoxy)-7V-(l-(naphthale n-l- yl)cyclopropyl)benzamide (80.0 mg, 155 pmol, 1.0 eq, TFA salt) inMeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (9.34 mg, 311 pmol, 8.57 pL, 2.0 eq). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6, then NaBHiCN (19.5 mg, 311 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-((2-methylazetidin-2- yl)methoxy)-/'/-( l -(naphthalen- l -yl)cycl opropyl (benzamide (33.0 mg, 73.2 pmol, 47% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 415.2 (LCMS); 1H NMR (400 MHz, DMSO-tL) 6 11.32 - 10.41 (m, 1H), 9.13 (s, 1H), 8.67 (d, = 8.4 Hz, 1H), 7.93 (d, = 7.6 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.64 - 7.41 (m, 3H), 7.13 - 7.04 (m, 1H), 6.99 - 6.88 (m, 1H), 6.80 - 6.68 (m, 1H), 4.52 - 4.29 (m, 1H), 4.25 - 3.98 (m, 1H), 4.00 - 3.73 (m, 2H), 2.67 - 2.56 (m, 3H), 2.45 - 2.03 (m, 2H), 1.95 (s, 3H), 1.59 (s, 3H), 1.37 (br s, 2H), 1.18 (br s, 2H). Example 259: rac-5-((l»S,21?)-2-Aminocyclobutoxy)-2-methyl-/V-(l-(naphth alen-l- yl)cyclopropyl)benzamide (Compound 406)

Compound 406

Step 1: rac-tert-Butyl ((ll?,25)-2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)phenoxy)cyclobutyl)carbamate (259A-1)

To a solution of rac-tert-butyl ((15,2A)-2-hydroxycyclobutyl)carbamate (118 mg, 630 pmol, 1.0 eq) and 5-hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (200 mg, 630 prnol, 1.0 eq) in toluene (12 mL) was added CMBP (228 mg, 945 pmol, 1.5 eq). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (8.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 45% - 85% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). rac-tert-Butyl((lA,25)-2-(4-methyl-3-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenoxy) cyclobutyl)carbamate (46.0 mg, 94.53 pmol, 5% yield) was obtained as a red solid. M + H ⁺ = 487.3 (LCMS).

Step 2: rac-5-((l»S,21?)-2-Aminocyclobutoxy)-2-methyl-/V-(l-(naphth alen-l-yl) cyclopropyl)benzamide (Compound 406)

To a solution of rac-terLbutyl ((lA,25)-2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)phenoxy)cyclobutyl)carbamate (46.0 mg, 94.5 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80* 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). rac-5-((15,2A)-2-Aminocyclobutoxy)-2-methyl-A-(l-(naphthalen -l-yl)cyclopropyl) benzamide (10.1 mg, 23.7 pmol, 25% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 387.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.18 - 9.08 (m, 1H), 8.71 - 8.61 (m, 1H), 8.30 - 8.15 (m, 3H), 7.98 - 7.91 (m, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.42 (m, 3H), 7.10 - 7.03 (m, 1H), 6.84 - 6.77 (m, 1H), 6.60 - 6.54 (m, 1H), 4.86 - 4.74 (m, 1H), 4.03 - 3.90 (m, 1H),

2.38 - 2.23 (m, 1H), 2.20 - 2.07 (m, 2H), 2.02 - 1.95 (m, 3H), 1.94 - 1.87 (m, 1H), 1.40 - 1.32 (m, 2H), 1.23 - 1.14 (m, 2H).

Example 260: rac-5-(((21?,41?)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl -/V-(l-

(naphthalen-l-yl)cyclopropyl)benzamide (Compound 416)

260A-6

Compound 416

Step 1: l-tc/7- Butyl 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (260A-2)

To a solution of 1 -tert-butyl 2-methyl 4-oxopyrrolidine-l,2-dicarboxylate (5.00 g, 20.6 mmol, 1.0 eq) in EtOH (50.0 mL) was added sodium tetrahydroborate (778 mg, 20.6 mmol, 1.0 eq) in portions at 0 °C. The mixture was stirred at 0 °C for 30 min under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into cold H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by column chromatography using a gradient of EtOAc/petroleum ether from 1/10 to 1/1. l -tert-Butyl 2-methyl 4-hydroxypyrrolidine-l,2- dicarboxylate (1.30 g, 5.30 mmol, 26% yield) was obtained as a white solid. M - 56 + H ⁺ = 190.2 (LCMS); 'H NMR (400 MHz, CDC13) 8 4.38 - 4.35 (m, 1H), 3.79 (s, 3H), 3.75 - 3.57 (m, 3H), 3.52 - 3.46 (m, 1H), 2.11 (br d, J= 7.8 Hz, 1H), 1.43 (s, 9H).

Step 2: l-tert-Butyl2-methyl4-((tert-butyldimethylsilyl)oxy)pyrrolid ine-l,2-dicarboxylate (260A-3)

To a stirred solution of l -tert-butyl 2-methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (300 mg, 1.22 mmol, 1.0 eq) in DMF (3.0 mL) were added imidazole (167 mg, 2.45 mmol, 2.0 eq) and TBSC1 (221 mg, 1.47 mmol, 1.2 eq) at 0 °C in portions. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by column chromatography using a gradient of DCM. l -/crt-Butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylat e (400 mg, 1.11 mmol, 91% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 360.1 (LCMS); 'H NMR (400 MHz, CDCh) 64.40 - 4.25 (m, 2H), 3.71 (s, 3H), 3.67 - 3.56 (m, 1H), 3.39 - 3.24 (m, 1H), 2.37 - 2.22 (m, 1H), 2.15 - 2.06 (m, 1H), 1.43 (s, 9H), 0.92 - 0.86 (m, 9H), 0.07 - 0.03 (m, 6H). Step 3: te/7- Butyl 4-((terCbutyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine -l- carboxylate (260A-4)

To a solution of l-ter/-Butyl 2-methyl 4-((ter/-butyldimethylsilyl)oxy)pyrrolidine-l,2- dicarboxylate (400 mg, 1.11 mmol, 1.0 eq) in THF (5.0 mL) was added lithium borohydride (60.6 mg, 2.78 mmol, 2.5 eq) in portions at 0 °C. The mixture was stirred at 25 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by column chromatography using a gradient of DCM to give tert-butyl 4-((lerl- butyldimethylsilyl)oxy)-2-(methoxymethyl)pyrrolidine-l -carboxylate (200 mg, 603 pmol, 54% yield) as a yellow oil. M + H ⁺ = 332.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 4.45 - 4.25 (m, 1H), 4.15 - 3.96 (m, 1H), 3.88 - 3.76 (m, 1H), 3.74 - 3.65 (m, 1H), 3.55 (br dd, J = 7.4, 11.3 Hz, 1H), 3.36 - 3.20 (m, 1H), 3.17 - 3.04 (m, 1H), 2.34 - 2.14 (m, 1H), 1.65 - 1.56 (m, 1H), 1.48 (s, 9H), 0.90 (s, 9H), 0.09 (br s, 6H).

Step 4: tert-Butyl 4-((/cr/‘-biityldiinethylsilyl)oxy)-2-((4-methyl-3-(( 1 -(naphthalen-l-yl) cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carboxyla te (260A-5)

A mixture of tert-butyl 4-((/c/7-butyldimethyl silyl )oxy)-2-(methoxymethyl)pyrrolidine- l - carboxylate (190 mg, 573 pmol, 1.0 eq), 5-hydroxy-2-methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (182 mg, 573 pmol, 1.0 eq) and PPhs (4.34 g, 16.6 mmol, 1.1 eq) in toluene (2.0 mL) was degassed and purged with N2 three times. To the mixture was added TMAD (296 mg, 1.72 mmol, 3.0 eq) in portions at 20 °C. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. tert-Butyl 4-((te/7-butyldimethylsilyl)oxy)-2-((4- methyl-3-((l -(naphthal en-l-yl)cy clopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l- carboxylate (150 mg, 238 pmol, 41% yield) was obtained as a yellow oil. M + H ⁺ = 631.4 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.10 - 9.02 (m, 1H), 8.65 (br d, J= 8.3 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.88 - 7.75 (m, 2H), 7.59 - 7.39 (m, 3H), 7.02 (d, J= 8.3 Hz, 1H), 6.83 (br dd, = 2.3, 8.3 Hz, 1H), 6.61 (br d, J= 12.0 Hz, 1H), 4.48 - 4.33 (m, 1H), 4.13 - 4.05 (m, 1H), 3.97 - 3.91 (m, 1H), 3.50 (dd, J= 5.1, 11.6 Hz, 1H), 3.31 - 3.22 (m, 1H), 3.15 - 3.00 (m, 1H), 2.15 - 2.02 (m, 1H), 1.95 (s, 3H), 1.91 - 1.80 (m, 1H), 1.45 - 1.29 (m, 11H), 1.17 - 1.13 (m, 2H), 0.74 (br d, J= 8.0 Hz, 9H), 0.06 - 0.08 (m, 6H).

Step 5: rac-(21?,41?)-tert-Butyl-4-hydroxy-2-((4-methyl-3-((l-(napht halen-l-yl)cyclo propyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carboxylate (260A-6)

A solution of tert-butyl 4-((tert-butyldimethylsilyl)oxy)-2-((4-methyl-3-((l-(naphtha len-l- yl)cy cl opropyl)carbamoyl) phenoxy)methyl)pyrrolidine-l -carboxylate (150 mg, 238 pmol, 1.0 eq) in THF (2.0 mL) was degassed and purged with N2 three times. To the mixture was added tetrabutylammonium fluoride (1 M in THF, 713 pmol, 3.0 eq) dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 3 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.6). rac-( RAR)-tert- Butyl 4-hydroxy-2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)ca rbamoyl)phenoxy) methyl)pyrrolidine-l -carboxylate (80.0 mg, 155 pmol, 65% yield) was obtained as a white solid. M + H ⁺ = 517.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.08 (s, 1H), 8.65 (br d, J= 8.5 Hz, 1H), 7.92 (d, J= 7.5 Hz, 1H), 7.82 (t, J= 7.8 Hz, 2H), 7.60 - 7.42 (m, 3H), 7.02 (d, J = 8.5 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.62 (br d, J= 14.5 Hz, 1H), 5.01 (br s, 1H), 4.24 (br s, 1H), 4.10 (br s, 1H), 3.96 (br d, J = 4.9 Hz, 2H), 3.44 (dd, J= 4.8, 11.4 Hz, 1H), 3.19 - 3.07 (m, 1H), 2.09 - 2.01 (m, 1H), 1.94 (s, 3H), 1.87 (br d, J= 13.5 Hz, 1H), 1.48 - 1.30 (m, 9H), 1.30 (br s, 2H), 1.17 - 1.15 (m, 2H).

Step 6: rac-5-(((2R, 41?)-4- Hydroxy py rrolidin-2-yl )met boxy )-2-met hyl-\-( l-(naphthalen- l-yl)cyclopropyl)benzamide (Compound 416)

To a stirred solution of rac-(2R,4R)-tert-butyl 4-hydroxy-2-((4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carbox ylate (80.0 mg, 155 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). rac-5-(((2/?,4/?)-4-Hydroxypyrrolidin-2-yl)methoxy)-2- methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (140 mg, 334 pmol, 77% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.1 (LCMS); 1H NMR (400 MHz, DMSO-tL) 8 9.61 - 9.45 (m, 1H), 9.12 (s, 1H), 9.10 - 8.97 (m, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.87 - 7.77 (m, 2H), 7.61 - 7.42 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.88 (dd, J = 2.6, 8.4 Hz, 1H), 6.66 (d, = 2.5 Hz, 1H), 5.46 (br s, 1H), 4.39 (br s, 1H), 4.21 - 4.13 (m, 1H), 4.07 (t, J = 9.9 Hz, 1H), 3.89 (br d, J= 3.9 Hz, 1H), 3.22 - 3.11 (m, 1H), 3.10 - 3.01 (m, 1H), 2.32 - 2.22 (m, 1H), 1.97 (s, 3H), 1.72 - 1.59 (m, 1H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 261: 5-(((21?,45)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methyl-A-(l -

(naphthalen-l-yl)cyclopropyl)benzamide (Compound 414)

Compound 414

Step 1: rac-(2/?.4.S)-/cr/‘-Butyl4-hydroxy-2-((4-methyl-3-(( 1 -(n:iphthalen-l-yl)cyclo propyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carboxylate (261A-1)

A solution of tert-Butyl 4-((ter/-butyldimethylsilyl)oxy)-2-((4-methyl-3-((l-(naphtha len-l- yl)cyclopropyl)carbamoyl) phenoxy)methyl)pyrrolidine-l -carboxylate (150 mg, 238 pmol, 1.0 eq) in THF (2.0 mL) was degassed and purged with N2 three times. To the mixture was added tetrabutylammonium fluoride (1 M in THF, 713 pmol, 3.0 eq) dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 3 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/2, R/ = 0.6). rac-(2R,4S)-tert- Butyl 4-hydroxy-2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)ca rbamoyl)phenoxy) methyl)pyrrolidine-l -carboxylate (40.0 mg, 77.4 pmol, 33% yield) was obtained as a white solid. M + H ⁺ = 517.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.07 (s, 1H), 8.65 (br d, J= 8.1 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.82 (t, J= 7.6 Hz, 2H), 7.59 - 7.43 (m, 3H), 7.02 (br d, J= 7.8 Hz, 1H), 6.83 (dd, J= 2.4, 8.3 Hz, 1H), 6.61 (br s, 1H), 4.91 (br s, 1H), 4.25 (br s, 1H), 4.00 (br d, J= 3.8 Hz, 1H), 3.96 - 3.81 (m, 1H), 3.31 - 3.19 (m, 2H), 1.94 (br s, 5H), 1.45 - 1.31 (m, 9H), 1.30 (br s, 2H), 1.16 (br s, 2H).

Step 2: rac-5-(((21?,4»y)-4-Hydroxypyrrolidin-2-yl)methoxy)-2-methy l-/V-(l-(naphthalen- l-yl)cyclopropyl)benzamide (Compound 414)

To a stirred solution of rac-(2A,48)-/er/-Butyl 4-hydroxy-2-((4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carbox ylate (40.0 mg, 77.4 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 8.0 mL). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). rac-5-(((2A,48)-4-Hydroxypyrrolidin-2-yl)methoxy)-2- methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (5.70 mg, 13.5 pmol, 17% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.55 - 9.36 (m, 1H), 9.10 (s, 1H), 8.91 - 8.74 (m, 1H), 8.65 (d, J= 7.9 Hz, 1H), 7.94 (d, J= 7.8 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.60 - 7.45 (m, 3H), 7.08 (d, J= 8.4 Hz, 1H), 6.88 (dd, J = 2.7, 8.2 Hz, 1H), 6.66 (d, J= 2.5 Hz, 1H), 5.45 - 5.43 (m, 1H), 4.42 (br s, 1H), 4.18 (br d, J= 13 Hz, 1H), 4.06 - 3.94 (m, 2H), 3.26 - 3.20 (m, 1H), 3.12 - 2.97 (m, 1H), 2.13 - 2.01 (m, 1H), 1.97 (s, 3H), 1.86 - 1.76 (m, 1H), 1.39 - 1.31 (m, 2H), 1.19 (br s, 2H).

Example 262: 5-((2-Aminoethyl)amino)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 412)

Step 1

50A-1 Compound 412 Step 1: 5-((2-Aminoethyl)amino)-2-methyl-/V-(l-(naphthalen-l-yl)cycl opropyl) benzamide (Compound 412)

To a stirred solution of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (100 mg, 263 pmol, 1.0 eq) and ethane- 1,2-diamine (23.7 mg, 394 pmol, 26.4 pL, 1.5 eq) in dioxane (1.0 mL) were added K2CO3 (36.3 mg, 263 pmol, 1.0 eq), Cui (5.01 mg, 26.3 pmol, 0.1 eq) and DMEDA (4.64 mg, 52.6 pmol, 5.66 pL, 0.2 eq) in one portion. The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-((2-Aminoethyl)amino)-2-methyl-7V-(l-(naphthalen-l-yl)cycl opropyl) benzamide (44.0 mg, 122 pmol, 47% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 360.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 8.99 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.87 - 7.71 (m, 5H), 7.61 - 7.42 (m, 3H), 6.87 (d, J = 8.4 Hz, 1H), 6.51 (dd, J= 2.4, 8.2 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 3.18 (t, J = 6.3 Hz, 2H), 2.95 - 2.76 (m, 2H), 1.88 (s, 3H), 1.41 - 1.27 (m, 2H), 1.21 - 1.11 (m, 2H).

Example 263: 5-((2-Aminoethyl)(methyl)amino)-2-methyl-/V-(l-(naphthalen-l - yl)cyclopropyl)benzamide (Compound 421)

Compound 421 Step 1: tert-Butyl (2-(methyl(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carba moyl) phenyl)amino)ethyl)carbamate (263A-1)

A mixture of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (150 mg, 394 pmol, 1.0 eq) and tert-butyl (2-(methylamino)ethyl)carbamate (103 mg, 592 pmol, 1.5 eq) in dioxane (7.5 mL) was degassed and purged with N2 three times. To the mixture were added K2CO3 (54.5 mg, 394 pmol, 1.0 eq), DMEDA (6.96 mg, 78.9 pmol, 8.49 pL, 0.2 eq) and Cui (7.50 mg, 39.5 pmol, 0.1 eq) at 20 °C. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.3). tert-Butyl (2-(methyl(4-methyl-3-((l -(naphthal en-l-yl)cyclopropyl)carbamoyl) phenyl)amino)ethyl) carbamate (150 mg, 317 pmol, 80% yield) was obtained as a colorless oil. M + H ⁺ = 474.2 (LCMS).

Step 2: 5-((2-aminoethyl)(methyl)amino)-2-methyl-/V-(l-(naphthalen-l -yl)cyclopropyl) benzamide (Compound 421)

To a stirred solution of tert-butyl (2-(methyl(4-methyl-3-((l -(naphthal en-l-yl)cyclopropyl) carbamoyl)phenyl)amino)ethyl)carbamate (100 mg, 211 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-((2-Aminoethyl)(methyl)amino)-2-methyl-7V-(l-(naphthalen-l -yl)cyclopropyl) benzamide (25.8 mg, 60.2 pmol, 29% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 374.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 8.99 (s, 1H), 8.60 - 8.71 (m, 3H), 7.93 (d, J = 7.8 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.60 - 7.43 (m, 3H), 6.87 (d, J= 8.3 Hz, 1H), 6.54 (dd, J = 2.5, 8.3 Hz, 1H), 6.32 (d, = 2.5 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.02 - 2.91 (m, 2H), 2.53 (br d, = 3.9 Hz, 3H), 1.88 (s, 3H), 1.40 - 1.30 (m, 2H), 1.20 - 1.12 (m, 2H). Example 264: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(pyrrolidin-3 - yl)benzamide (Compound 413)

Step 2

Compound 413

Step 1: tert-Butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)pyrrolidine-l-carboxylate (264A-1)

To a solution of tert-butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)-2,5-dihydro-17/-pyrrole-l-carboxylate (150 mg, 288 pmol, 1.0 eq) in MeOH (2 mL) was added 10% palladium on carbon (10.0 mg). The mixture was stirred at 20 °C for 2 h under aH2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give the crude product tert-butyl 3 -(4- methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenyl)pyrrolidine-l -carboxylate (70.0 mg, 147 pmol, 51% yield) as a yellow oil, which was used in the next step without any further purification. M - 56 + H ⁺ = 415.2 (LCMS).

Step 2: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(pyrrolidin-3 -yl)benzamide (Compound 413)

To a stirred solution of tert-butyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)pyrrolidine-l -carboxylate (70.0 mg, 134 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-5-(pyrrolidin-3-yl )benzamide (20.2 mg, 54.0 prnol, 40% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 371.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.11 (s, 1H), 9.03 - 8.86 (m, 1H), 8.65 (d, J= 8.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.83 (dd, J= 4.6, 7.4 Hz, 2H), 7.62 - 7.43 (m, 3H), 7.22 (dd, J= 1.5, 7.8 Hz, 1H), 7.12 (d, J= 7.9 Hz, 1H), 7.02 (s, 1H), 3.56 - 3.47 (m, 1H), 3.37 (br s, 2H), 3.22 - 3.11 (m, 1H), 2.96 (br t, J = 10.4 Hz, 1H), 2.30 - 2.20 (m, 1H), 1.99 (s, 3H), 1.90 - 1.77 (m, 1H), 1.36 (s, 2H), 1.24 - 1.14 (m, 2H).

Example 265: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-4- yl)benzamide (Compound 407)

Compound 407

Step 1: te/7- Butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)piperidine-l-carboxylate (265A-1)

To a solution of tert-butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)-5,6-dihydropyridine-l(2J7)-carboxylate (150 mg, 280 pmol, 1.0 eq) in MeOH (2 mL) was added 10% palladium on carbon (10.0 mg). The mixture was stirred at 20 °C for 2 h under aH2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a crude product tert-butyl 4-(4-methyl- 3 -((1 -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenyl)piperi dine- 1 -carboxylate (70.0 mg, 142 prnol, 51% yield) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 485.3 (LCMS). Step 2: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-4- yl)benzamide (Compound 407)

To a stirred solution of /c/7-butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)piperi dine- 1 -carboxylate (70.0 mg, 130 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HClZEtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- Methyl-A-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperidin-4-yl) benzamide (47.7 mg, 122 pmol, 94% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 385.1 (LCMS); ^T H NMR (400 MHz, DMSO- e) 8 9.11 (s, 1H), 8.81 - 8.69 (m, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.53 - 8.35 (m, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.62 - 7.43 (m, 3H), 7.09 (s, 2H), 6.88 (s, 1H), 3.29 (br s, 2H), 2.99 - 2.85 (m, 2H), 2.79 - 2.69 (m, 1H), 1.98 (s, 3H), 1.88 - 1.78 (m, 2H), 1.76 - 1.63 (m, 2H), 1.40 - 1.32 (m, 2H), 1.23 - 1.13 (m, 2H).

Example 266: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperazin-l- yl)benzamide (Compound 410)

50A-1 Compound 410

Step 1: 2-Methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperazin-l- yl)benzamide (Com pound 410)

To a solution of 5-bromo-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)benzamide (200 mg, 526 pmol, 1.0 eq) and piperazine (68.0 mg, 789 pmol, 4.38 pL, 1.5 eq) in THF (10 mL) were added Z-BuONa (151.6 mg, 1.58 mmol, 3.0 eq) and /BuXPhos Pd G3 (41.8 mg, 52.6 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times and then the mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 45% B over 8 min; mobile phase A: 0.05% aqueous NH4HCO3, mobile phase B: acetonitrile). 2 -Methyl -7V-(1- (naphthalen-l-yl)cyclopropyl)-5-(piperazin-l-yl)benzamide was obtained as a white solid. M + H ⁺ = 386.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 89.03 (s, 1H), 8.67 (d, = 7.8 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.81 (dd, J= 7.7, 12.3 Hz, 2H), 7.58 - 7.43 (m, 3H), 6.94 (d, J= 8.6 Hz, 1H), 6.80 (dd, J = 2.5, 8.4 Hz, 1H), 6.55 (d, J = 2.6 Hz, 1H), 2.94 - 2.85 (m, 4H), 2.81 - 2.73 (m, 4H), 1.91 (s, 3H), 1.37 - 1.32 (m, 2H), 1.16 (br s, 2H).

Example 267: 2-Methyl-5-(4-methylpiperazin-l-yl)-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 418)

Compound 410 Compound 418

Step 1: 2-Methyl-5-(4-methylpiperazin-l-yl)-/V-(l-(naphthalen-l-yl)c yclopropyl)benzami de (Compound 418)

To a solution of 2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-5-(piperazin-l- yl)benzamide (60.0 mg, 156 pmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (10.0 pL), followed by the addition of formaldehyde (25.3 mg, 300 pmol, 23.2 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (19.6 mg, 311 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-(4-methylpiperazin-l-yl)-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (17.9 mg, 40.59 pmol, 16% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 400.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.21 (s, 1H), 9.06 (s, 1H), 8.68 - 8.62 (m, 1H), 7.93 (d, J= 8.1 Hz, 1H), 7.82 (t, J = 8.6 Hz, 2H), 7.58 - 7.44 (m, 3H), 7.01 (d, J= 8.2 Hz, 1H), 6.90 (dd, J= 2.5, 8.7 Hz, 1H), 6.65 (d, J= 2.1 Hz, 1H), 3.68 (br d, J = 11.9 Hz, 2H), 3.45 (br d, J= 12.3 Hz, 2H), 3.13 - 3.02 (m, 2H), 2.90 (br t, J= 12.7 Hz, 2H), 2.80 (d, J= 4.8 Hz, 3H), 1.92 (s, 3H), 1.38 - 1.32 (m, 2H), 1.21 - 1.15 (m, 2H).

Example 268: 5-(l,4-Diazepan-l-yl)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 411)

Compound 411

Step 1: tert-Butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe nyl)- 1 ,4-diazepane- 1-carboxylate (268 A- 1 )

To a solution of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (120 mg, 316 pmol, 1.0 eq) and tert-butyl 1,4-diazepane- 1-carboxylate (94.8 mg, 473 pmol, 92.9 pL,

1.5 eq) in THF (10 mL) were added Z-BuONa (91.0 mg, 947 pmol, 3.0 eq), /BuXPhos Pd G3 (25.1 mg, 31.6 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times and then the mixture was stirred at 80 °C for 3 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (4 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 4-(4- methyl-3 -(( 1 -(naphthal en- 1 -yl)cyclopropyl)carbamoyl)phenyl)- 1 ,4-diazepane- 1 -carboxylate (80.0 mg, 160 pmol, 51% yield) was obtained as a yellow oil. M + H ⁺ = 500.3 (LCMS); ^T H NMR (400 MHz, CDCh) 8 8.67 (d, J= 8.6 Hz, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.89 (br d, J =

7.6 Hz, 2H), 7.81 - 7.75 (m, 2H), 6.90 (d, J= 8.4 Hz, 2H), 6.60 (dd, J= 2.8, 8.4 Hz, 1H), 6.33 (d, J= 1.6 Hz, 1H), 3.74 - 3.66 (m, 2H), 3.50 (br t, J= 5.8 Hz, 2H), 3.45 - 3.41 (m, 3H), 1.79 - 1.69 (m, 2H), 1.50 (br d, J= 0.6 Hz, 2H), 1.41 - 1.34 (m, 6H), 1.22 (s, 9H). Step 2: 5-(l,4-Diazepan-l-yl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclop ropyl)benzamide (C ompound 411)

To a solution of tert-butyl 4-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)- 1,4-diazepane-l -carboxylate (80.0 mg, 160 pmol, 51% yield) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-( 1 ,4-Diazepan- 1 -yl)-2-methyl-A-( 1 -(naphthal en- 1 -yl)cyclopropyl)benzamide (13.9 mg, 31.9 pmol, 20% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 400.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.01 (s, 3H), 8.67 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.86 - 7.75 (m, 2H), 7.59 - 7.43 (m, 3H), 6.93 (d, J= 8.6 Hz, 1H), 6.67 (dd, J = 2.6, 8.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 3.64 - 3.55 (m, 2H), 3.39 (t, J= 6.1 Hz, 2H), 3.10 (br s, 2H), 3.00 (br s, 2H), 2.04 - 1.95 (m, 2H), 1.91 (s, 3H), 1.35 (s, 2H), 1.21 - 1.12 (m, 2H).

Example 269: 5-(2-(Dimethylamino)ethoxy)-2,4-dimethyl-/V-(l-(naphthalen-l - yl)cyclopropyl)benzamide (Compound 405)

269A-3 Compound 405 Step 1: Methyl 5-hydroxy-2,4-dimethylbenzoate (269A-1)

To a solution of methyl 5-hydroxy-4-iodo-2-methylbenzoate (600 mg, 2.05 mmol, 1.0 eq) in DMF (20 mL) were added methylboronic acid (738 mg, 12.3 mmol, 6.0 eq), CS2CO3 (2.34 g, 7.19 mmol, 3.5 eq) and Pd2(dba)3 (94.1 mg, 103 pmol, 0.05 eq). The resulting mixture was degassed and purged with N2 three times and then was stirred at 130 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 5-hydroxy-2,4-dimethylbenzoate (200 mg, 333 pmol, 54% yield) was obtained as a yellow oil.

M + H ⁺ = 181.1(LCMS).

Step 2: Methyl 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoate (269A-2)

To a solution of 2-chloro-7V,7V-dimethylethanamine (95.9 mg, 666 pmol, 2.0 eq, HC1 salt) in DMF (10 mL) was added K2CO3 (230 mg, 1.66 mmol, 5.0 eq). The mixture was stirred at 20 °C for 30 min. To the resulting mixture were added methyl 5-hydroxy-2,4-dimethylbenzoate (200 mg, 333 pmol, 1.0 eq), 18-crown-6 (139 mg, 532 pmol, 1.6 eq) and KI (92.9 mg, 566 pmol, 1.7 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. Methyl 5-(2-(dimethylamino)ethoxy)-2,4- dimethyl benzoate (180 mg, 716 pmol, 50% yield) was obtained as a white solid. M + H ⁺ = 252.1(LCMS).

Step 3: 5-(2-(Dimethylamino)ethoxy)-2,4-dimethylbenzoic acid (269A-3)

To a solution of methyl 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoate (90.0 mg, 358 prnol, 1.0 eq) in a mixture of MeOH (7.0 mL) and THF (3.5 mL) was added NaOH (2 M aqueous, 2.26 mL, 12.7 eq). The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and treated with HC1 (I M aqueous) to adjust the pH to 6 and the product was extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuum to give the crude product 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoic acid (70.0 mg, 82% yield) as a yellow solid, which was used in the next step without any further purification. M + H ⁺ = 238.1 (LCMS).

Step 4: 5-(2-( Dimet hylamino jet hoxy)-2.4-dimethyl- \-( l-(naphthalen-l-yl)cyclopropyl) benzamide (Compound 405)

To a solution of 5-(2-(dimethylamino)ethoxy)-2,4-dimethylbenzoic acid (70.0 mg, 295 pmol, 1.0 eq) and 1 -(naphthal en-l-yl)cy cl opropanamine (54.1 mg, 295 pmol, 1.0 eq) in DMF (3.5 mL) were added EDCI (84.8 mg, 442 pmol, 1.5 eq), HOBt (59.8 mg, 442 pmol, 1.5 eq) and TEA (59.7 mg, 590 pmol, 82.1 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)- 2,4-dimethyl-A-(l-(naphthalen-l-yl)cyclopropyl)benzamide (27.1 mg, 60.8 pmol, 21% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 403.1 (LCMS); ¹ H NMR (400 MHz, DMSO- d ₆ ) 6 10.92 - 10.67 (m, 1H), 9.11 - 9.01 (m, 1H), 8.74 - 8.62 (m, 1H), 8.01 - 7.88 (m, 1H), 7.81 (s, 2H), 7.62 - 7.42 (m, 3H), 6.94 - 6.88 (m, 1H), 6.74 - 6.67 (m, 1H), 4.30 - 4.21 (m, 2H), 3.50 - 3.40 (m, 2H), 2.81 (d, J= 4.9 Hz, 6H), 2.12 (s, 3H), 1.99 - 1.88 (m, 3H), 1.44 - 1.34 (m, 2H), 1.21 - 1.11 (m, 2H).

Example 270: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(isoquinolin-4-yl)cyclopro pyl)-2- methylbenzamide (Compound 409)

Step 1 Step 2

270A-1 270A-2

Compound 409

Step 1: l-(Isoquinolin-4-yl)cyclopropanamine (270A-2)

A mixture of isoquinoline-4-carbonitrile (200 mg, 1.30 mmol, 1.2 eq) in anhydrous Et20 (12 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (553 mg, 1.95 mmol, 574 pL, 1.5 eq) slowly, and then EtMgBr (3 M, 951 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and - 75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (368 mg, 2.59 mmol, 320 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.25). 1- (Isoquinolin-4-yl)cyclopropanamine (60.0 mg, 25% yield) was obtained as a yellow oil. M + H ⁺ = 185.0 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(isoquinolin-4-yl)cyclopro pyl)-2-methylbenz amide (Compound 409)

To a solution of l-(isoquinolin-4-yl)cyclopropanamine (70.0 mg, 380 pmol, 1.0 eq) and 5-(2- (dimethylamino)ethoxy)-2-methylbenzoic acid (84.8 mg, 380 pmol, 1.0 eq) in DCM (4 mL) were added TEA (115 mg, 1.14 mmol, 159 pL, 3.0 eq), EDCI (182 mg, 950 pmol, 2.5 eq) and HOBt (128 mg, 950 pmol, 2.5 eq). The mixture was stirred at 20 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-7V-(l-(isoquinolin-4- yl)cyclopropyl)-2-methylbenzamide (38.3 mg, 85.6 pmol, 23% yield, FA salt) was obtained as a pink solid. M + H ⁺ = 390.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.23 (s, 1H), 9.14 (s, 1H), 8.75 (s, 1H), 8.64 (d, J= 8.4 Hz, 1H), 8.19 - 8.09 (m, 2H), 7.85 (ddd, J= 1.3, 7.0, 8.4 Hz, 1H), 7.73 - 7.62 (m, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.63 (d, J= 2.6 Hz, 1H), 3.97 (t, J= 5.8 Hz, 2H), 2.62 (t, J= 5.7 Hz, 2H), 2.22 (s, 6H), 1.94 (s, 3H), 1.40 - 1.33 (m, 2H), 1.26 - 1.19 (m, 2H). Example 271: /V-(l-(9H-Carbazol-4-yl)cyclopropyl)-5-(2-(dimethylamino)eth oxy)-2- methylbenzamide (Compound 415)

Step 5

271A-5 Compound 415 Step 1: 9//-Carb:izole-4-c:irbonitrile (271A-2)

To a solution of 4-bromo-9J/-carbazole (1.00 g, 4.06 mmol, 1.0 eq) in DMF (10 mL) was added CuCN (582 mg, 6.50 mmol, 1.42 mL, 1.6 eq) at 20 °C. The mixture was stirred at 150 °C for 18 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 9H- Carbazole-4-carbonitrile (600 mg, 3.12 mmol, 77% yield) was obtained as a white solid. M - H“ = 191.0 (LCMS).

Step 2: terf-Butyl 4-cy:ino-9//-c:irb:izole-9-carboxylate (271A-3)

To a solution of 9J/-carbazole-4-carbonitrile (400 mg, 2.08 mmol, 1.0 eq) in THF (5.0 mL) were added DMAP (280 mg, 2.29 mmol, 1.1 eq) and BOC2O (500 mg, 2.29 mmol, 526 pL, 1.1 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. te/7-Butyl 4- cyano-9J7-carbazole-9-carboxylate (400 mg, 1.37 mmol, 66% yield) was obtained as a white solid. M + H ⁺ = 293.1 (LCMS).

Step 3: terf-Butyl 4-( l-aminocyclopropyl)-9Z/-carbazole-9-carboxylate (271A-4)

A mixture of tert-butyl 4-cyano-9J/-carbazole-9-carboxylate (100 mg, 342 pmol, 1.0 eq) in anhydrous Et2O (7.5 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (146 mg, 513 pmol, 151 pL, 1.5 eq) slowly and then EtMgBr (3 M in Et2O, 251 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (97.1 mg, 684 pmol, 84.4 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (8.0 mL) and MTBE (8.0 mL) and the mixture was extracted with MTBE (8.0 mL x 4). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. te/7-Butyl 4-(l- aminocyclopropyl)-9rt-carbazole-9-carboxylate (30.0 mg, 93.1 pmol, 27% yield) was obtained as a white solid. M + H ⁺ = 323.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.49 (d, J= 7.7 Hz, 1H), 8.31 (d, J= 8.2 Hz, 1H), 8.21 - 8.17 (m, 1H), 7.57 - 7.52 (m, 1H), 7.48 - 7.42 (m, 2H), 7.40 - 7.35 (m, 1H), 1.71 (s, 9H), 1.11 (br s, 2H), 0.97 (br s, 2H).

Step 4: tert- Butyl 4-(l-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopro pyl)- 9//-ca r bazole-9-ca r boxy la t e (271 A-5)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (49.9 mg, 223 pmol, 1.2 eq) in DCM (2.0 mL) were added TEA (56.5 mg, 558 pmol, 77.7 pL, 3.0 eq), EDCI (53.5 mg, 279 pmol, 1.5 eq), HOBt (37.7 mg, 279 pmol, 1.5 eq) and tert-butyl 4-(l-aminocyclopropyl)- 9J/-carbazole-9-carboxylate (60.0 mg, 186 pmol, 1.0 eq). The mixture was stirred at 20 °C for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.4). tert-Butyl 4-(l-(5-(2- (dimethylamino)ethoxy)-2-methylbenzamido)cyclopropyl)-9J/-ca rbazole-9-carboxylate (30.0 mg, 56.9 pmol, 31% yield) was obtained as a white solid. M + H ⁺ = 528.2 (LCMS).

Step 5: \-( l-(9//-C:irb:izol-4-yl)cyclopropyl)- -(2-(diinetliyl:iiniiio)etlioxy)-2-inethylbenz amide (Compound 415)

To a solution of tert-butyl 4-(l-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido) cyclopropyl)-9J/-carbazole-9-carboxylate (30.0 mg, 56.9 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(9rt-Carbazol-4-yl)cyclopropyl)-5-(2-(dimethylamino)et hoxy)-2- methylbenzamide (6.50 mg, 15.2 pmol, 27% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 428.2 (LCMS); 'H NMR (400 MHz, DMSO-tZ ₆ ) 5 11.32 (s, 1H), 10.14 - 10.03 (m, 1H), 8.96 (s, 1H), 8.62 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.42 - 7.36 (m, 2H), 7.34 - 7.29 (m, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.90 - 6.85 (m, 1H), 6.62 (d, J= 2.6 Hz, 1H), 4.15 (br t, J= 4.8 Hz, 2H), 3.42 - 3.36 (m, 2H), 2.78 - 2.73 (m, 6H), 1.99 (s, 3H), 1.44 (br s, 2H), 1.23 (br s, 2H). Example 272: 5-(2-( Dimet liylamino)etlioxy)-\-(l-(7-hydroxynaphthalen-l- yl)cyclopropyl)-2-methylbenzamide (Compound 417)

Compound 417

Step 1: 7-((/c/7-Butyldiniethylsilyl)oxy)-l -naphthonitrile (272A-2)

To a solution of 7-hydroxy-l -naphthonitrile (500 mg, 2.96 mmol, 1.0 eq) in DMF (5.0 mL) were added TBSCI (535 mg, 3.55 mmol, 435 pL, 1.2 eq) and imidazole (402 mg, 5.91 mmol, 2.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were washed with brine (10 mL x 2), dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 7-((/c/7-Butyldirnethylsilyl)oxy)- l - naphthonitrile (770 mg, 2.72 mmol, 92% yield) was obtained as a yellow gum. M + H ⁺ = 284.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.00 (d, J= 8.3 Hz, 1H), 7.87 (d, J= 7.1 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.21 (dd, J = 2.3, 8.8 Hz, 1H), 1.04 (s, 9H), 0.31 (s, 6H). Step 2: l-(7-((tert-Butyldimethylsilyl)oxy)naphthalen-l-yl)cycloprop anamine (272A-3)

A mixture of 7-((/er/-butyldimethylsilyl)oxy)-l-naphthonitrile (300 mg, 1.06 mmol, 1.0 eq) in Et20 (20 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z- PrO)4 (451 mg, 1.59 mmol, 469 pL, 1.5 eq) slowly at -78 °C and then EtMgBr (3 M in Et20, 776 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. Then BF3.Et2O (300 mg, 2.12 mmol, 261 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (10 mL) and MTBE (10 mL), and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. l -(7-((/c/7-Butyldimethylsilyl)oxy)naphthalen- l -yl)cyclopropanamine (220 mg, 702 pmol, 66% yield) was obtained as a yellow gum. 'H NMR (400 MHz, CDCL) 8 7.75 (br d, J= 8.9 Hz, 2H), 7.68 (br d, J= 7.0 Hz, 1H), 7.60 (s, 1H), 7.32 - 7.28 (m, 1H), 7.10 (dd, J= 1.8, 8.8 Hz, 1H), 1.10 (s, 2H), 1.05 - 0.76 (m, 11H), 0.24 (s, 6H).

Step 3: N-(l-(7-((tert-Butyldimethylsilyl)oxy)naphthalen-l-yl)cyclop ropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (272A-4)

To a solution of l-(7-((tert-butyldimethylsilyl)oxy)naphthalen-l-yl)cycloprop anamine (220 mg, 702 pmol, 1.0 eq) and 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (157 mg, 702 pmol, 1.0 eq) in DMF (10 mL) were added TEA (213 mg, 2.11 mmol, 293 pL, 3.0 eq), EDCI (161 mg, 842 pmol, 1.2 eq) and HOBt (114 mg, 842 pmol, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 7V-(l-(7-((terLButyldimethylsilyl)oxy)naphthalen-l-yl)cyclop ropyl)-5-(2- (dimethylamino) ethoxy)-2-methylbenzamide (140 mg, 270 pmol, 38% yield) was obtained as a yellow gum.

Step 4: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(7-hydroxynaphthalen-l-yl) cyclopropyl)-2-m ethylbenzamide (Compound 417)

To a solution of A-(l-(7-((tert-butyldimethylsilyl)oxy)naphthalen-l-yl)cyclop ropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (130 mg, 251 pmol, 1.0 eq) in THF (10 mL) was added TBAF (1 M in THF, 752 pL, 3.0 eq) at 0°C. The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 5), concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2- (Di methyl ami no)ethoxy )-/'/-( l -(7-hydroxynaphthalen- l -yl)cy cl opropyl )-2-methylbenzami de (17.9 mg, 40.6 pmol, 16% yield, HC1 salt) was obtained as a brown solid. M + H ⁺ = 405.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.08 - 9.89 (m, 1H), 9.77 - 9.51 (m, 1H), 9.05 (s, 1H), 7.84 (d, J= 2.1 Hz, 1H), 7.79 - 7.61 (m, 3H), 7.27 - 7.04 (m, 3H), 6.90 (dd, J = 2.7, 8.3 Hz, 1H), 6.69 (d, J= 2.6 Hz, 1H), 4.25 (br t, J= 4.9 Hz, 2H), 3.44 (q, J= 5.0 Hz, 2H), 2.80 (d, J= 4.9 Hz, 6H), 2.00 (s, 3H), 1.32 (br s, 2H), 1.12 (br s, 2H).

Example 273: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylthio)naphthalen-l - yl)cyclopropyl)-2-methylbenzamide (Compound 408)

Compound 408 Step 1: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylthio)naphthalen-l -yl)cyclopropyl)-2- methylbenzamide (Compound 408)

To a solution of EtSH (5.04 g, 81.1 mmol, 6.0 mL, 67.9 eq) in DCM (25 mL) was added AlCh (956 mg, 7.17 mmol, 392 pL, 6.0 eq) at 0 °C, then 5-(2-(dimethylamino)ethoxy)-7V-(l-(3- methoxynaphthalen- l-yl)cy cl opropyl)-2 -methylbenzamide (500 mg, 1.19 mmol, 1.0 eq) in DCM (5.0 mL) was added at 0 °C dropwise. The resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C. The resulting mixture was stirred at the same temperature for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (200 x 40 mm, 10 pm); flow rate: 50 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l-(3-(ethylthio)naphthalen-l- yl)cyclopropyl)-2-methyl benzamide (250 mg, 535 pmol, 45% yield) was obtained as a brown gum. M + H ⁺ = 449.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.09 (s, 1H), 8.58 (dd, J= 3.4, 6.2 Hz, 1H), 8.19 (s, 1H), 7.94 - 7.79 (m, 1H), 7.75 - 7.66 (m, 2H), 7.56 - 7.39 (m, 2H), 7.03 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 2.6, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.97 (t, J= 5.7 Hz, 2H), 3.10 (q, J= 7.3 Hz, 2H), 2.63 (t, J= 5.7 Hz, 2H), 2.23 (s, 6H), 1.97 (s, 3H), 1.39 - 1.28 (m, 5H), 1.18 (br s, 2H).

Example 274: ( )-/V-(l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-(p yrrolidin- 2-ylmethoxy)benzamide (Compound 419)

Compound 419 Step 1: (S)-/c/7-Butyl 2-((3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)carbamoyl)-4 -me thylphenoxy)methyl)pyrrolidine-l-carboxylate (274A-1)

To a solution of 1 -(3 -m ethoxynaphthal en-l-yl)cy cl opropanamine (63.6 mg, 298 pmol, 1.0 eq) and (5)-5-((l-(ter/-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-me thylbenzoic acid (100 mg, 298 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (90.5 mg, 894 pmol, 125 pL, 3.0 eq), EDCI (143 mg, 745 pmol, 2.5 eq) and HOBt (101 mg, 745 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/10 to 1/2. fS')-/c 7-Butyl 2-((3-((l -(3 -methoxynap hthalen-l-yl)cy cl opropyl)carbamoyl)-4-methylphenoxy)methyl) pyrrolidine- 1 -carboxylate (150 mg, 283 pmol, 95% yield) was obtained as a colorless oil. M + H ⁺ = 531.3 (LCMS).

Step 2: (.S')-\-( l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-(pyrroli din-2-ylme thoxy)benzamide (Compound 419)

To a solution of (S)-terCbutyl 2-((3-((l -(3 -methoxynaphthal en-l-yl)cy clopropyl)carbam oyl)- 4-methylphenoxy)methyl)pyrrolidine-l -carboxylate (150 mg, 283 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-7V-(l-(3-Methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5- (pyrrolidin-2- ylmethoxy) benzamide (80.3 mg, 172 pmol, 61% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 431.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.55 (br d, J= 4.0 Hz, 1H), 9.14 (s, 1H), 8.97 (br d, J = 3.9 Hz, 1H), 8.54 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.51 - 7.35 (m, 3H), 7.24 (d, J= 2.3 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 6.89 (dd, J= 2.6, 8.4 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 4.20 - 4.11 (m, 1H), 4.09 - 4.00 (m, 1H), 3.87 (s, 4H), 3.23 - 3.11 (m, 2H), 2.12 - 2.01 (m, 1H), 1.99 - 1.96 (m, 3H), 1.95 - 1.82 (m, 2H), 1.72 - 1.61 (m, 1H), 1.33 (br s, 2H), 1.16 (br s, 2H). Example 275: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-(thiophen-2- yl)naphthalen-l-yl)cyclopropyl)benzamide (Compound 420)

Compound 420

Step 1: 5-(2-(Dimethylamino)ethoxy)-2-methyl-/V-(l-(3-(thiophen-2-yl )naphthalen-l-yl)c yclopropyl)benzamide (Compound 420)

To a solution of 4-(l-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopro pyl) naphthalen-2-yl trifluoromethanesulfonate (50.0 mg, 93.2 pmol, 1.0 eq) and thiophen-2- ylboronic acid (14.3 mg, 112 pmol, 1.2 eq) in DMSO (5.0 mL) were added Pd(OAc)2 (2.09 mg, 9.32 pmol, 0.1 eq), KOAc (27.4 mg, 280 pmol, 3.0 eq) and bis(l-adamantyl)-butyl- phosphane (6.68 mg, 18.6 pmol, 0.2 eq). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 10 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-2-methyl-A-(l-(3-(thiophen-2- yl)naphthalen-l-yl)cyclopropyl) benzamide (7.10 mg, 14.0 pmol, 15% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 371.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 10.16 - 10.05 (m, 1H), 9.19 (s, 1H), 8.66 - 8.58 (m, 1H), 8.14 - 8.07 (m, 2H), 8.03 - 7.95 (m, 1H), 7.68 - 7.65 (m, 1H), 7.63 (d, J = 5.0 Hz, 1H), 7.60 - 7.50 (m, 2H), 7.21 (dd, J = 3.7, 5.0 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.90 (dd, J= 2.6, 8.3 Hz, 1H), 6.69 (d, J= 2.6 Hz, 1H), 4.24 (t, J= 4.8 Hz, 2H), 3.47 - 3.39 (m, 2H), 2.79 (d, J = 4.9 Hz, 6H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.27 (br s, 2H).

Example 276: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl) prop-2-yn-l-yl)benzamide (Compound 459)

276A-4

Compound 459

Step 1: (/:)-2-Metliyl-\-(n:iplitlialen-l-ylmethylene) propane-2-sulfinamide (276A-1)

To a mixture of naphthalene- 1-carbaldehy de (2.00 g, 12.8 mmol, 1.74 mL, 1.0 eq) and 2- methylpropane-2-sulfmamide (2.33 g, 19.2 mmol, 1.5 eq) in THF (80 mL) was added Ti(0Et)4

(5.26 g, 23.0 mmol, 4.78 mL, 1.8 eq) at 25 °C, the reaction mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (50 ml) and the mixture was filtered. The filtrate was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 3/1. (E)-2-Methyl-7V- (l-naphthylmethylene)propane-2-sulfinamide (3.00 g, 11.6 mmol, 90% yield) was obtained as a yellow oil. M + H ⁺ = 260.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.12 (s, 1H), 9.03 (d, J = 8.4 Hz, 1H), 8.16 - 8.07 (m, 2H), 8.01 (d, J= 7.6 Hz, 1H), 7.74 - 7.56 (m, 3H), 1.33 (s, 9H). Step 2: 2-Methyl-/V-(l-(naphthalen-l-yl) prop-2-yn-l-yl)propane-2-sulfinamide (276A-2)

To a mixture of (£)-2-methyl-7V-(l-naphthylmethylene)propane-2-sulfinamide (3.00 g, 11.6 mmol, 1.0 eq) in THF (60 mL) was added bromo(ethynyl)magnesium (0.5 M in THF, 46.3 mL, 2.0 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/0 to 1/1. 2-Methy !-/'/-[ ! -( I -naphthyl) prop-2-ynyl] propane-2- sulfinamide (1.00 g, 3.50 mmol, 30% yield) was obtained as a brown oil. M + H ⁺ = 286.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.24 (d, J= 8.0 Hz, 1H), 7.99 - 7.84 (m, 4H), 7.65 - 7.47 (m, 4H), 5.92 (dd, J= 2.0, 6.8 Hz, 1H), 2.75 (d, J= 2.4 Hz, 1H), 1.22 (s, 9H).

Step 3: l-(Naphthalen-l-yl) prop-2-yn-l-amine (276A-3)

To a mixture of 2-methyl-7V-[l-(l-naphthyl)prop-2-ynyl]propane-2-sulfinamide (500 mg, 1.75 mmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 4.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacumm to give a crude product l-(l-naphthyl)prop-2-yn-l -amine (250 mg, HC1 salt) as a brown solid. M + H ⁺ = 182.2 (LCMS).

Step 4: 2-Methyl-/V-(l-(naphthalen-l-yl) prop-2-yn-l-yl)-5-nitrobenzamide (276A-4)

To a solution of l-(l-naphthyl)prop-2-yn-l -amine (100 mg, 459 pmol, 1.0 eq, HC1 salt) and 2- methyl-5-nitro-benzoic acid (83.2 mg, 459 pmol, 1.0 eq) in DMF (2.0 mL) were added HATU (262 mg, 689 pmol, 1.5 eq) and DIEA (178 mg, 1.38 mmol, 240 pL, 3.0 eq) at 25 °C, the reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (50 ml) and the mixture was filtered. The filter cake was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.2). 2-Methyl-7V-[l-(l -naphthyl) prop-2-ynyl]-5-nitro- benzamide (60.0 mg, 174 pmol, 38% yield) was obtained as a white solid. M + H ⁺ = 182.2 (LCMS). Step 5: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl) prop-2-yn-l-yl)benzamide (Compound 459)

To a mixture of 2-methyl-7V-[l-(l-naphthyl)prop-2-ynyl]-5-nitro-benzamide (45.0 mg, 130 pmol, 1.0 eq) in a mixture of THF (600 pL), EtOH (600 pL) and H2O (200 pL) were added Fe (36.5 mg, 653 pmol, 5.0 eq) and NH4CI (34.9 mg, 653 pmol, 5.0 eq) at 25 °C. The reaction mixture was stirred at 80 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The mixture was filtered, and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5- Amino-2-methyl-7V-[l-(l -naphthyl) prop-2-ynyl] benzamide (9.80 mg, 31.2 pmol, 24% yield) was obtained as a brown solid. M + H ⁺ = 315.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.12 (d, J= 8.4 Hz, 1H), 7.91 (d, J= 7.2 Hz, 1H), 7.81 (dd, J= 8.4, 12.0 Hz, 2H), 7.55 - 7.37 (m, 3H), 6.88 (d, J= 8.0 Hz, 1H), 6.81 - 6.72 (m, 1H), 6.63 - 6.52 (m, 2H), 6.23 - 5.98 (m, 1H), 2.55 (d, J= 2.4 Hz, 1H), 2.22 (s, 3H).

Example 277: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(naphthale n-l- yl)prop-2-yn-l-yl)benzamide (Compound 448)

276A-3 Compound 448

Step 1: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(naphthale n-l-yl)prop- 2-yn-

1-yl)benzamide (Compound 448)

To a mixture of l-(l-naphthyl)prop-2-yn-l -amine (50.0 mg, 229 pmol, 1.0 eq, HC1 salt) and

2-methyl-5-[(l-methylazetidin-2-yl)methoxy]benzoic acid (54.0 mg, 229 pmol, 1.0 eq) in DMF (1.0 mL) were added DIEA (89.1 mg, 689 pmol, 120 pL, 3.0 eq) and HATU (131 mg, 345 pmol, 1.5 eq) at 25 °C, the reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD Cl 8 (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-Methyl-5-[(l- methylazetidin-2-yl)methoxy]-A-[l-(l-naphthyl)prop-2-ynyl]be nzamide (34.7 mg, 84.1 pmol, 37% yield) was obtained as a brown solid. M + H ⁺ = 399.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.13 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.86 - 7.76 (m, 2H), 7.55 - 7.38

(m, 3H), 6.99 (d, J= 8.4 Hz, 1H), 6.83 - 6.69 (m, 3H), 6.09 (br d, J= 8.8 Hz, 1H), 3.87 - 3.77 (m, 2H), 3.33 (quin, J= 5.6 Hz, 1H), 3.27 - 3.18 (m, 1H), 2.74 (q, J= 8.2 Hz, 1H), 2.56 (d, J = 2.4 Hz, 1H), 2.28 (d, J= 3.6 Hz, 3H), 2.26 (d, J= 2.0 Hz, 3H), 1.99 - 1.86 (m, 2H).

Example 278: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(3-(naphthalen-l-yl)az etidin-3- yl)benzamide (Compound 453)

278A-5 Compound 453

Step 1: tert-Butyl 3-hydroxy-3-(naphthalen-l-yl)azetidine-l-carboxylate (278A-1) To a solution of 1 -bromonaphthalene (5.00 g, 24.2 mmol, 3.36 mL, 1.0 eq) in THF (30 mL) was added w-BuLi (2.5 M in hexane, 29.0 mL, 3.0 eq) dropwise at -78 °C under a N2 atomosphere. The mixture was stirred at -78 °C for 1 h. To the mixture was added dropwise the solution of tert-butyl 3 -oxoazetidine- 1 -carboxylate (6.20 g, 36.2 mmol, 1.5 eq) in THF (30 mL) at -78 °C. The mixture was stirred at -78 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (40 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. tert-Butyl 3 -hydroxy-3 -(naphthalen-l-yl)azetidine-l -carboxylate (3.80 g, 8.89 mmol, 37% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 244.0 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.00 - 7.86 (m, 3H), 7.63 - 7.43 (m, 4H), 4.46 (d, J= 9.1 Hz, 2H), 4.33 - 4.15 (m, 2H), 1.37 (s, 9H).

Step 2: tert-Butyl 3-chloro-3-(naphthalen-l-yl)azetidine-l-carboxylate (278A-2)

To a solution of tert-butyl 3 -hydroxy-3 -(naphthal en-l-yl)azeti dine- 1 -carboxylate (1.00 g, 3.34 mmol, 1.0 eq) in DCM (10 mL) was added TEA (676 mg, 6.68 mmol, 930 pL, 2.0 eq), followed by MsCl (765 mg, 6.68 mmol, 517 pL, 2.0 eq) dropwise at 0 °C. The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. tert- Butyl 3 -chi oro-3 -(naphthal en-l-yl)azeti dine- 1 -carboxylate (520 mg, 1.64 mmol, 50% yield) was obtained as a colourless oil. M - 56 + H ⁺ = 262.1 (LCMS).

Step 3: tert-Butyl 3-azido-3-(naphthalen-l-yl)azetidine-l-carboxylate (278A-3)

To a solution of tert-butyl 3-chloro-3-(naphthalen-l-yl)azetidine-l-carboxylate (500 mg, 1.57 mmol, 1.0 eq) in DMF (6.0 mL) was added NaNi (205 mg, 3.15 mmol, 2.0 eq) in portions at 0 °C. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using pure DCM. tert-Butyl 3 -azi do-3 -(naphthal en-1- yl)azeti dine- 1 -carboxylate (400 mg, 1.23 mmol, 78% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 269.1 (LCMS). Step 4: tert-Butyl 3-amino-3-(naphthalen-l-yl)azetidine-l-carboxylate (278A-4)

To a solution of tert-butyl 3 -azido-3 -(naphthal en-l-yl)azeti dine- 1 -carboxylate (400 mg, 1.23 mmol, 1.0 eq) in TFE (6.0 mL) was added 10% palladium on carbon (40.0 mg) under a N2 atmosphere. The resulting mixture was stirred at 20 °C under a H2 (15 psi) atmosphere for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give the crude product tert-butyl 3 -amino-3 -(naphthal en-l-yl)azeti dine- 1- carboxylate (330 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 299.2 (LCMS).

Step 5: tert-Butyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methyl benzamido)-3-(naphthalen-l-yl)azetidine-l-carboxylate (278A-5)

To a solution of tert-butyl 3 -amino-3 -(naphthalen-l-yl)azetidine-l -carboxylate (150 mg, 503 pmol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2 -methylbenzoic acid (171 mg, 553 pmol, 1.1 eq) in DMF (1.0 mL) were added HATU (287 mg, 754 pmol, 1.5 eq) and DIEA (195 mg, 1.51 mmol, 263 pL, 3.0 eq). The mixture was stirred at 20 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude tert-butyl 3-(5-(2-((/ert-butoxycarbonyl)(methyl)amino)ethoxy)-2- methylbenzamido)-3-(naphthalen-l-yl)azetidine-l-carboxylate (160 mg, 271 pmol, 54% yield) as a yellow oil. M + H ⁺ = 590.6 (LCMS).

Step 6: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(3-(naphthalen-l-yl)az etidin-3-yl)benz amide (Compound 453)

To a solution of tert-butyl 3-(5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methyl benzamido)-3 -(naphthal en-l-yl)azeti dine- 1 -carboxylate (160 mg, 244 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (1.06 g, 9.26 mmol, 686 pL, 38 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-7V-(3-(naphthalen- l-yl)azeti din-3 -yl)benzamide (86.4 mg, 222 pmol, 91% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 390.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.65 (s, 1H), 9.58 - 9.44 (m, 1H), 9.01 - 8.84 (m, 1H), 8.63 (br s, 2H), 8.06 - 8.01 (m, 1H), 7.96 (br d, J= 8.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.80 (br d, J= 7.1 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.13 (d, J = 8.6 Hz, 1H), 6.94 (dd, J= 2.2, 8.3 Hz, 1H), 6.76 (d, J= 2.1 Hz, 1H), 4.84 (br s, 2H), 4.79 - 4.67 (m, 2H), 4.12 (br t, J= 4.6 Hz, 2H), 3.29 (br s, 2H), 2.61 (br s, 3H), 2.06 (s, 3H). Example 279: 2-Methyl-/V-(l-methyl-3-(naphthalen-l-yl)azetidin-3-yl)-5-(2 -

(methylamino) ethoxy)benzamide (Compound 499)

Step 6

279A-5 Compound 499 Step 1: tert-Butyl 3-(((benzyloxy)carbonyl)amino)-3-(naphthalen-l-yl)azetidine- l- carboxylate (279A-1)

To a solution of tert-butyl 3 -amino-3-(naphthalen-l-yl)azetidine-l -carboxylate (180 mg, 603 pmol, 1.0 eq) in DCM (1.0 mL) were added DIEA (85.8 mg, 664 pmol, 116 pL, 1.1 eq) and CbzCl (226 mg, 1.33 mmol, 189 pL, 2.2 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/5, R/= 0.5). te/7-Butyl 3 -(((benzyloxy)carbonyl)amino)-3 -(naphthal en-l-yl)azeti dine -1 -carboxylate (80.0 mg, 185 pmol, 31% yield) was obtained as a yellow oil. M + H ⁺ = 433.3 (LCMS).

Step 2: Benzyl (3-(naphthalen-l-yl)azetidin-3-yl)carbamate (279A-2)

To a solution of tert-butyl 3 -(((benzyloxy)carbonyl)amino)-3 -(naphthal en-l-yl)azeti dine- 1- carboxylate (80.0 mg, 166 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude product benzyl (3 -(naphthal en-l-yl)azeti din-3 -yl)carbamate (50.0 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 333.1 (LCMS).

Step 3: Benzyl (l-methyl-3-(naphthalen-l-yl)azetidin-3-yl)carbamate (279A-3)

To a solution of benzyl (3 -(naphthal en-l-yl)azeti din-3 -yl)carbamate (50.0 mg, 150 pmol, 1.0 eq) in MeOH (1.0 mL) was added formaldehyde (6.77 mg, 226 pmol, 6.22 pL, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (56.7 mg, 903 pmol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/10, R/ = 0.3). Benzyl (l-methyl-3-(naphthalen-l-yl)azetidin-3-yl)carbamate (50.0 mg, 144 pmol, 96% yield) was obtained as a white solid. M + H ⁺ = 347.2 (LCMS).

Step 4: l-Methyl-3-(naphthalen-l-yl)azetidin-3-amine (279A-4)

To a solution of benzyl (l-methyl-3-(naphthalen-l-yl)azeti din-3 -yl)carbamate (50.0 mg, 130 pmol, 1.0 eq) in DCM (500 pL) was added TMSI (130 mg, 450 pmol, 88.4 pL, 5.0 eq) in portions at 0 °C. The resulting mixture was stirred at 20 °C for 8 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was poured into saturated aqueous NH4CI (5.0 mL) and extracted with DCM (10 mL x 3). But the desired compound was hydrophilic. The aqueous layer was lyophilized to give the crude product 1- methyl-3 -(naphthal en-l-yl)azeti din-3 -amine (25.0 mg), which was used in the next step without any further purification. M + H ⁺ = 213.1 (LCMS).

Step 5: /c/7-Butylmethyl(2-(4-methyl-3-(( 1 -methyl-3-(naphthalen-l -yl)azetidin-3-yl) carbamoyl)phenoxy)ethyl)carbamate (279A-5)

To a solution of 5-(2-((/ert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (32.1 mg, 104 pmol, 1.1 eq) in acetonitrile (1.0 mL) were added TCFH (31.7 mg, 113 pmol, 1.2 eq), 1 -methylimidazole (23.2 mg, 283 pmol, 22.5 pL, 3.0 eq) and 1 -methyl-3 -(naphthalen-

1-yl)azeti din-3 -amine (20.0 mg, 94.2 pmol, 1.0 eq). The resulting mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into water (5.0 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.5). ter/-Butylmethyl(2-(4-methyl-3-((l -methyl-3 -(naphthal en-l-yl)azeti din-3 -yl)carbamoyl) phenoxy)ethyl)carbamate (40.0 mg, 79.4 pmol, 84% yield) was obtained as a yellow oil. M + H ⁺ = 504.3 (LCMS).

Step 6: 2-Methyl-/V-(l-methyl-3-(naphthalen-l-yl)azetidin-3-yl)-5-(2 -(methylamino) ethoxy)benzamide (Compound 499)

To a solution of /cv7-butylmethyl(2-(4-methyl-3-(( l -methyl-3 -(naphthal en-l-yl)azeti din-3 - yl)car bamoyl) phenoxy) ethyl)carbamate (35.0 mg, 62.6 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (875 pL) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm)); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile).

2-Methyl-7V-(l -methyl-3- (naphthalen-l-yl)azetidin-3-yl)-5-(2-(methylamino) ethoxy) benzamide (7.50 mg, 18.0 pmol, 29% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 404.1 (LCMS), 'H NMR (400 MHz, DMSO ) 6 9.40 (br s, 1H), 8.81 - 8.34 (m, 1H), 8.05 - 7.99 (m, 1H), 7.96 (d, J= 8.2 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.74 (br s, 1H), 7.60 - 7.55 (m, 3H), 7.12 (d, J= 8.4 Hz, 1H), 6.94 (dd, J = 2.8, 8.4 Hz, 1H), 6.80 (d, J= 2.7 Hz, 1H), 5.17 - 4.69 (m, 4H), 4.16 (t, J = 5.2 Hz, 2H), 3.29 (t, J = 5.2 Hz, 2H), 2.95 (br s, 3H), 2.64 (s, 3H), 2.07 (s, 3H). Example 280: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(3-(naphthalen-l-yl)ox etan-3- yl)benzamide (Compound 451)

Compound 451

Step 1: 5-Hydroxy-2-methyl-/V-(3-(naphthalen-l-yl)oxetan-3-yl)benzam ide (280A-1)

To a solution of 3-(naphthalen-l-yl)oxetan-3-amine (250 mg, 1.25 mmol, 0.80 eq) and 5- hydroxy-2-methylbenzoic acid (239 mg, 1.57 mmol, 1.0 eq) in DMF (8.0 mL) were added TEA (159 mg, 1.57 mmol, 218 pL, 1.0 eq), EDCI (316 mg, 1.65 mmol, 1.0 eq) and HOBt (42.4 mg, 314 pmol, 0.20 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-Hydroxy-2-methyl-7V-(3-(naphthalen-l-yl)oxetan-3-yl)benz amide (80.0 mg, 216 pmol, 14% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 334.1 (LCMS).

Step 2: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(3-(naphthalen-l-yl)ox etan-3-yl)benz amide (Compound 451)

To a solution of 5-hydroxy-2-methyl-7V-(3-(naphthalen-l-yl)oxetan-3-yl)benzam ide (70.0 mg, 210 pmol, 1.0 eq) and 2-(methylamino)ethanol (15.8 mg, 210 pmol, 16.9 pL, 1.0 eq) in toluene (6.0 mL) were added TMAD (108 mg, 630 pmol, 3.0 eq) and PPI13 (165 mg, 630 pmol, 3.0 eq) under a N2 atmosphere. The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- Methyl-5-(2-(methylamino)ethoxy)-7V-(3 -(naphthal en- 1 -yl)oxetan-3-yl)benzamide (6.00 mg, 15.4 pmol, 7% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 391.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.72 (s, 1H), 8.01 - 7.96 (m, 1H), 7.88 (d, J= 8.2 Hz, 1H), 7.78 (br d, J= 6.6 Hz, 2H), 7.57 - 7.49 (m, 3H), 7.05 (d, J= 8.4 Hz, 1H), 6.86 (dd, J= 2.6, 8.3 Hz, 1H), 6.67 (d, J= 2.7 Hz, 1H), 5.28 - 5.18 (m, 4H), 3.91 (t, J= 5.6 Hz, 2H), 2.75 (t, J= 5.6 Hz, 2H), 2.29 (s, 3H), 1.93 (s, 3H).

Example 281: /V-(3-(3-Methoxynaphthalen-l-yl)oxetan-3-yl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 450)

Compound 450

281A-3

Step 1 : /V-(3-(3-Methoxynaphthalen-l-yl)oxetan-3-yl)-2-methylpropane -2-sulfinamide (281A-2)

To a solution of l-bromo-3 -methoxynaphthalene (500 mg, 2.11 mmol, 1.0 eq) in THF (5.0 mL) was added w-BuLi (2.5 M in hexane, 1.01 mL, 1.2 eq) dropwise at -78 °C under a N2 atmosphere, the resulting mixture was stirred at -78 °C for 1 h, then a solution of 2-methyl-A- (oxetan-3-ylidene)propane-2-sulfinamide (554 mg, 3.16 mmol, 1.5 eq) in THF (5.0 mL) was added dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was quenched by addition of saturated aqueous NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. N-(3 -(3 -Methoxynaphthal en-l-yl)oxetan-3 -yl)-2- methylpropane-2-sulfmamide (252 mg, 740 pmol, 35% yield) was obtained as a yellow oil. M + H ⁺ = 334.2 (LCMS).

Step 2: 3-(3-Methoxynaphthalen-l-yl)oxetan-3-amine (281A-3)

To a solution of N-(3 -(3 -methoxynaphthal en-1 -yl)oxetan-3-yl)-2-methylpropane-2- sulfinamide (252 mg, 756 pmol, 1.0 eq) in MeOH (3.0 mL) was added HCl/dioxane (4 M, 1.51 mL, 8.0 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a crude product 3-(3-methoxynaphthalen-l-yl)oxetan-3-amine (200 mg, HC1 salt) as a yellow solid. M + H ⁺ = 230.2 (LCMS).

Step 3: /V-(3-(3-Methoxynaphthalen-l-yl)oxetan-3-yl)-2-methyl-5-((l- methylazetidin-2- yl)methoxy)benzamide (Compound 450)

To a solution of 3-(3-methoxynaphthalen-l-yl)oxetan-3-amine (40.0 mg, 151 pmol, 1.0 eq, HC1 salt) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (40.9 mg, 151 pmol, 1.0 eq, HC1 salt) in DMF (2.0 mL) were added HBTU (143 mg, 376 pmol, 2.5 eq) and DIEA (97.3 mg, 753 pmol, 131 pL, 5.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 x 40 mm, 10 pm); flow rate: 50 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). N-(3-(3- Methoxy naphthal en- l-yl)oxetan-3-yl)-2-methyl-5-((l-methylazeti din-2 -yl)methoxy) benzamide (5.60 mg, 12.5 pmol, 8% yield) was obtained as an off-white gum. M + H ⁺ = 447.3 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 7.85 (d, J = 8.3 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.38 - 7.30 (m, 1H), 7.27 - 7.21 (m, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.89 - 6.80 (m, 1H), 6.69 (d, J= 2.6 Hz, 1H), 5.57 - 5.11 (m, 4H), 3.98 - 3.85 (m, 5H), 3.54 - 3.35 (m, 2H), 2.99 - 2.89 (m, 1H), 2.47 - 2.32 (m, 3H), 2.15 - 1.91 (m, 5H). Example 282: 5-(2-Acetamidoethoxy)-2-methyl-/V-( l-(naphthalen-l-yl)cyclopropyl) benzamide (Compound 425)

Compound 425

Step 1: 5-(2-Acetamidoethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclop ropyl) benzamide

(Compound 425)

To a solution of 5-(2-aminoethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (100 mg, 277 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (112 mg, 1.11 mmol, 154 pL, 4.0 eq) and acetic anhydride (56.6 mg, 555 pmol, 52.0 pL, 2.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 40% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5-(2- Acetamidoethoxy)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl )benzamide (21.2 mg, 52.4 pmol, 19% yield) was obtained as a white solid. M + H ⁺ = 403.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.10 (s, 1H), 8.66 (br d, J= 8.3 Hz, 1H), 8.06 (br s, 1H), 7.93 (br d, J= 7.6 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.61 - 7.41 (m, 3H), 7.03 (br d, J= 7.9 Hz, 1H), 6.99 - 6.99 (m, 1H), 6.83 (br d, J= 7.8 Hz, 1H), 6.62 (br s, 1H), 3.87 (br s, 2H), 3.34 (br d, J= 5.0 Hz, 2H), 1.96 (s, 3H), 1.80 (s, 3H), 1.35 (br s, 2H), 1.23 - 1.07 (m, 2H). Example 283: 2-Methyl-5-(2-(methylsulfonamido)ethoxy)-/V-(l-(naphthalen-l - yl)cyclopropyl)benzamide (Compound 424)

Compound 215 Compound 424

Step 1: 2-Methyl-5-(2-(methylsulfonamido)ethoxy)-/V-(l-(naphthalen-l -yl)cyclopropyl)b enzamide (Compound 424)

To a solution of 5-(2-aminoethoxy)-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (100 mg, 277 pmol, 1.0 eq) in DCM (4.0 mL) were added TEA (28.1 mg, 277 pmol, 38.6 pL, 1.0 eq) and MsCl (25.4 mg, 222 pmol, 17.2 pL, 0.8 eq) at 0 °C. The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 45% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2- Methyl-5-(2-(methylsulfonamido)ethoxy)-A-(l -(naphthal en- 1 -yl)cyclopropyl)benzamide (37.2 mg, 84.8 pmol, 30% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 439.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.11 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.9 Hz, 1H), 7.81 (t, J= 7.8 Hz, 2H), 7.62 - 7.42 (m, 3H), 7.25 (t, J = 5.9 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.84 (dd, J= 2.7, 8.3 Hz, 1H), 6.62 (d, J= 2.6 Hz, 1H), 3.93 (t, J= 5.5 Hz, 2H), 3.29 - 3.23 (m, 2H), 2.91 (s, 3H), 1.95 (s, 3H), 1.35 (s, 2H), 1.20 - 1.13 (m, 2H).

Example 284: 5-(((21?,45)-4-Hydroxy-l-methylpyrrolidin-2-yl)methoxy)-2-me thyl-A-(l- (naphthalen-l-yl)cyclopropyl)benzamide (Comppound 439)

Compound 414 Compound 439 Step 1: 5-(((27?,45)-4-Hydroxy-l-methylpyrrolidin-2-yl)methoxy)-2-me thyl-/V-(l-(naph thalen-l-yl)cyclopropyl)benzamide (Compound 439)

To a solution of (5-(((2A,45)-4-hydroxypyrrolidin-2-yl)methoxy)-2-methyl-7V-( l-(naphthalen- l-yl)cyclopropyl)benzamide (60.0 mg, 144 pmol, 1.0 eq) in MeOH (6.0 mL) was added TEA (20 pL), followed by the addition of formaldehyde (16.1 pL, 216 pmol, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (54.3 mg, 864 pmol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NazSC . filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- (((27?,45)-4-Hydroxy- 1 -methyl pyrrol i di n-2-yl )m ethoxy )-2-methyl -N-( 1 -(naphthalen- 1 - yl)cyclopropyl)benzamide (35.6 mg, 81.6 pmol, 57% yield) was obtained as a white solid. M + H ⁺ = 431.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 6 10.21 (br d, J= 5.1 Hz, 1H), 9.10 (s, 1H), 8.65 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.4 Hz, 1H), 7.83 (t, J= 6.6 Hz, 2H), 7.59 - 7.44 (m, 3H), 7.08 (d, J= 8.6 Hz, 1H), 6.90 (dd, J = 2.8, 8.4 Hz, 1H), 6.69 (d, J= 2.6 Hz, 1H), 5.66 - 5.48 (m, 1H), 4.46 - 4.34 (m, 1H), 4.32 - 4.23 (m, 1H), 4.18 (dd, J= 7.6, 10.9 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.69 (td, J= 5.9, 11.5 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.96 (d, J = 4.8 Hz, 3H), 2.14 - 2.07 (m, 1H), 1.99 - 1.91 (m, 4H), 1.36 (br s, 2H), 1.20 - 1.15 (m, 2H).

Example 285: 5-(((21?,41?)-4-Hydroxy-l-methylpyrrolidin-2-yl)methoxy)-2-m ethyl-/V-(l-

(naphthalen-l-yl)cyclopropyl)benzamide (Compound 440)

Compound 416 Compound 440 Step 1 : 5-(((21?,41?)-4-Hydroxy-l-methylpyrrolidin-2-yl)methoxy)-2-m ethyl-/V-(l-(napht halen-l-yl)cyclopropyl)benzamide (Compound 440)

To a solution of 5-(((2A,4A)-4-hydroxypyrrolidin-2-yl)methoxy)-2-methyl-7V-(l -(naphthalen- l-yl)cyclopropyl)benzamide (150 mg, 360 pmol, 1.0 eq) in MeOH (2.0 mL) was added TEA (50 pL), followed by the addition of formaldehyde (40.2 pL, 540 pmol, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (136 mg, 2.16 mmol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over NazSC . filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- (((2A,4A)-4-Hydroxy-l-methylpyrrolidin-2-yl)methoxy)-2-methy l-A-(l -(naphthal en-1- yl)cyclopropyl)benzamide (86.5 mg, 201 pmol, 56% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 431.2 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 10.10 (br d, J= 5.1 Hz, 1H), 9.10 (s, 1H), 8.66 (br d, J= 7.8 Hz, 1H), 7.93 (br d, J= 7.8 Hz, 1H), 7.83 (br t, J= 6.9 Hz, 2H), 7.62 - 7.42 (m, 3H), 7.08 (br d, J= 8.1 Hz, 1H), 6.95 - 6.85 (m, 1H), 6.69 (br s, 1H), 5.55 (br s, 1H), 4.41 (br s, 1H), 4.30 - 4.21 (m, 1H), 4.20 - 4.11 (m, 1H), 3.89 - 3.75 (m, 1H), 3.46 - 3.36 (m, 2H), 3.21 - 3.16 (m, 1H), 2.91 (br d, J = 2.3 Hz, 3H), 1.96 (s, 3H), 1.73 - 1.62 (m, 1H), 1.36 (br s, 2H), 1.19 (br s, 2H).

Example 286: 5-(((21?,41?)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-/V-( l- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 438)

260A-1 286A-1

Compound 438

Step 1: (2R,4R)-tert-Butyl 4-fluoro-2-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-l-carboxylate (286A-1)

A solution of (2/ ,4A')-/c/7-butyl 4-hydroxy-2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opro pyl)carbamoyl)phenoxy)methyl)pyrrolidine-l -carboxylate (130 mg, 352 pmol, 1.0 eq) in DCM (2.0 mL) was degassed and purged with N2 three times. To this solution was added DAST (101 mg, 629 pmol, 83.1 pL, 2.5 eq) dropwise at -78 °C. The mixture was warmed to room temperature and stirred under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude (2/ ,4/ )-tert-butyl 4-fluoro-2-((4- methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l- carboxylate (120 mg, 231 pmol, 92% yield) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 519.3 (LCMS).

Step 2: 5-(((21?,41?)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl-/V-( 1 -(naphthalen-l-yl) cyclopropyl)benzamide (Compound 438)

To a solution of (2/ ,4/ )-tert-butyl 4-fluoro-2-((4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl) carbamoyl)phenoxy)methyl)pyrrolidine-l -carboxylate (120 mg, 208 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCI/EtOAc (4 M, 3.6 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(((2A ^> ,4A ^> )-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-/'/-( l -(naphthal en-1- yl)cyclopropyl)benzamide (16.2 mg, 37.0 pmol, 18% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 419.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.08 - 9.85 (m, 1H), 9.47 - 9.25 (m, 1H), 9.12 (s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.83 (t, J= 6.6 Hz, 2H), 7.61 - 7.43 (m, 3H), 7.08 (d, J= 8.5 Hz, 1H), 6.89 (dd, J= 2.8, 8.3 Hz, 1H), 6.67 (d, J= 2.6 Hz, 1H), 5.58 - 5.31 (m, 1H), 4.25 - 4.13 (m, 1H), 4.08 - 3.93 (m, 2H), 3.63 - 3.47 (m, 1H), 3.47 - 3.35 (m, 1H), 2.63 - 2.54 (m, 1H), 2.10 - 1.99 (m, 1H), 1.97 (s, 3H), 1.36 (s, 2H), 1.22 - 1.13 (m, 2H).

Example 287: 5-(((21?,41?)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-2-me thyl-/V-(l- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 437)

Compound 438 Compound 437

Step 1 : 5-(((21?,41?)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-2-me thyl-/V-(l-(naphtha lene-l-yl)cyclopropyl)benzamide (Compound 437)

To a solution of 5-(((2A,4A)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl-7V-(l -(naphthal en-1- yl)cyclopropyl)benzamide (40.0 mg, 95.6 pmol, 1.0 eq) in MeOH (6.0 mL) was added TEA (13 pL), followed by the addition of formaldehyde (10.7 pL, 143 pmol, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (36.0 mg, 573 pmol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- (((2A,4A)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-2-methyl -A-(l -(naphthalene- 1- yl)cyclopropyl)benzamide (15.3 mg, 34.1 pmol, 36% yield) was obtained as a white solid. M + H ⁺ = 433.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 6 10.55 - 10.26 (m, 1H), 9.10 (s, 1H), 8.65 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.60 - 7.43 (m, 3H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.70 (br d, J= 2.4 Hz, 1H), 5.59 - 5.30 (m, 1H), 4.36 - 4.23 (m, 1H), 4.15 (br d, J= 9.8 Hz, 1H), 3.99 - 3.75 (m, 2H), 3.55 - 3.39 (m, 1H), 2.96 (br s, 3H), 2.82 - 2.72 (m, 1H), 2.14 - 1.98 (m, 1H), 1.96 (s, 3H), 1.36 (s, 2H), 1.18 (br s, 2H). Example 288: 5-(((2/?.4.S)-4-I luoropyrrolidin-2-yl)methoxy)-2-methyl- \-( 1- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 442)

Compound 442

Step 1: (27?,45)-tert-Butyl4-fluoro-2-((4-methyl-3-((l-(naphthalen-l -yl)cyclopropyl) carb amoyl)phenoxy)methyl)pyrrolidine-l-carboxylate (288A-1)

A solution of (2/?,4/?)-Zc77-butyl 4-hydroxy-2-((4-methyl-3-((l -(naphthal en-l-yl) cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-l -carboxylate (400 mg, 774 pmol, 1.0 eq) in DCM (10 mL) was degassed and purged with N2 three times. To this solution was added DAST (312 mg, 1.94 mmol, 256 pL, 2.5 eq) dropwise at -78 °C. The mixture was warmed to 20 °C and stirred another 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude (2/?,4b')-/c77-butyl 4-fluoro- 2-((4-methyl-3-((l-(naphthalen-l-yl) cyclopropyl) carbarn oyl)phenoxy)methyl)pyrrolidine-l- carboxylate (350 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 519.2 (LCMS).

Step 2: 5-(((2/?.4.S)-4-I luoropyrrolidin-2-yl)methoxy)-2-methyl- \-( 1 -(naphthalen-l-yl)cy clopropyl)benzamide (Compound 442)

To a solution of (2/?,4b')-/c77-butyl 4-fluoro-2-((4-methyl-3-((l-(naphthalen-l-yl) cyclopropyl) carbamoyl)phenoxy)methyl)pyrrolidine-l -carboxylate (350 mg, 675 pmol, 1.0 eq) in EtOAc (7.0 mL) was added HCI/EtOAc (4 M, 14 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B : acetonitrile). 5-(((2A,45)-4-Fluoropyrrolidin-2-yl)methoxy)-2-methyl-A-(l -(naphthal en-1 - yl)cyclopropyl)benzamide (300 mg, 659 pmol, 98% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 419.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.98 (br d, J= 2.2 Hz, 1H), 9.68 - 9.40 (m, 1H), 9.18 - 9.12 (m, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.44 (m, 3H), 7.11 - 7.05 (m, 1H), 6.92 - 6.86 (m, 1H), 6.67 (d, J = 2.6 Hz, 1H), 5.65 - 5.30 (m, 1H), 4.28 - 4.00 (m, 3H), 3.47 (br d, J= 8.6 Hz, 2H), 2.47 - 2.18 (m, 2H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.23 - 1.13 (m, 2H).

Example 289: 5-(((21?,45)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-2-met hyl-A-(l- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 441)

Compound 441

Step 1: 5-(((27?,45)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-2-met hyl-/V-(l-(naphthal en-l-yl)cyclopropyl)benzamide (Compound 441)

To a solution of 5-(((2A,48)-4-fluoropyrrolidin-2-yl)methoxy)-2-methyl-7V-(l -(naphthal en-1- yl)cyclopropyl)benzamide (240 mg, 573 pmol, 1.0 eq) in MeOH (9.0 mL) was added TEA (80.0 pL), followed by the addition of HCHO (93.1 mg, 1.15 mmol, 85.4 pL, 37% purity in water, 2.0 eq). The resulting mixture was treated with a small amount of AcOH (34.4 mg, 573 pmol, 32.8 pL, 1.0 eq) to adjust the pH to 6. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (72.1 mg, 1.15 mmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(((2A,48)-4-Fhioro-l- m ethyl pyrrol i di n-2-yl )methoxy )-2-methyl -/'/-( I -(naphthaalen- l -yl)cyclopropyl) benzamide

(J2.1 mg, 144 pmol, 25% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 433.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 11.43 - 11.24 (m, 1H), 9.14 (s, 1H), 8.66 (br d, J = 8.3 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.63 - 7.41 (m, 3H), 7.08 (d, J= 8.5 Hz, 1H), 6.96 - 6.83 (m, 1H), 6.77 - 6.66 (m, 1H), 5.61 - 5.26 (m, 1H), 4.47 - 4.18 (m,

3H), 4.08 - 3.97 (m, 1H), 3.56 - 3.35 (m, 1H), 2.96 (br d, J= 4.8 Hz, 3H), 2.78 - 2.65 (m, 1H), 2.22 - 2.03 (m, 1H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.18 (br s, 2H).

Example 290: 5-((l-Benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-/V- (l- (naphthalen-l-yl)cyclopropyl)benzamide (Compound 492) and 5-((l-benzyl-5,5- dimethylpyrro lidin-3-yl)oxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl) benzamide (Compound 491)

Compound 491

Step 1: 2-(Benzylamino)-2-methylpropan-l-ol (290A-2)

To a solution of benzaldehyde (11.9 g, 112 mmol, 11.3 mL, 1.0 eq) and 2-amino-2- methylpropan-l-ol (10.0 g, 112 mmol, 10.7 mL, 1.0 eq) in DCM (100 mL) was added 4 A molecular sieve (15.0 g). The mixture was stirred at 20 °C for 16 h. Then the mixture was filtered through a pad of cotton and concentrated under vacuum to give a residue. To this residue was added MeOH (50 mL), followed by NaBJL (5.09 g, 135 mmol, 1.2 eq) at 0 °C. After the addition, the mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH4CI (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-(Benzylamino)-2-methylpropan-l-ol (3.00 g, 16.7 mmol, 15% yield) was obtained as a white solid. M + H ⁺ = 180.1 NMR (400 MHz, CDCL) 8 7.39 - 7.22 (m, 5H), 3.68 (s, 2H), 3.34 (s, 2H), 1.15 (s, 6H).

Step 2: 2-(Benzyl(l-hydroxy-2-methylpropan-2-yl)amino)acetonitrile (290A-3)

To a solution of 2-(benzylamino)-2-methylpropan-l-ol (3.00 g, 16.7 mmol, 1.0 eq) in acetonitrile (50 mL) were added 2-bromoacetonitrile (5.62 g, 46.9 mmol, 3.12 mL, 2.8 eq) and K2CO3 (3.47 g, 25.1 mmol, 1.5 eq). The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 2-(Benzyl(l-hydroxy-2-methylpropan-2-yl)amino) acetonitrile (3.50 g, 16.0 mmol, 96% yield) was obtained as a white solid. 'H NMR (400 MHz, DMSO-tL) 8 7.44 - 7.16 (m, 5H), 4.75 (t, J= 5.2 Hz, 1H), 3.81 (s, 2H), 3.52 (s, 2H), 3.42 (d, J= 5.1 Hz, 2H), 1.14 (s, 6H).

Step 3: l-Benzyl-4,4-dimethylazetidine-2-carbonitrile (290A-4)

To a solution of 2-(benzyl(l -hydroxy -2-methylpropan-2-yl)amino)acetonitrile (1.70 g, 7.79 mmol, 1.0 eq) in THF (17 mL) was added dimethyl phosphorochloridate (2.25 g, 15.6 mmol, 1.68 mL, 2.0 eq) at -20 °C under a N2 atomosphere, then KHMDS (1 M in THF, 19.5 mL, 2.5 eq) was added dropwise keeping the temperature below -15 °C. The mixture was stirred at - 20 °C for 1 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 1- Benzyl-4,4-dimethylazetidine-2-carbonitrile (640 mg, 3.20 mmol, 41% yield) was obtained as a colorless oil. M + H ⁺ = 201.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.39 - 7.20 (m, 5H), 4.13 (dd, J= 6.9, 8.1 Hz, 1H), 3.73 - 3.65 (m, 1H), 3.61 - 3.53 (m, 1H), 2.26 - 2.19 (m, 1H), 2.16 - 2.09 (m, 1H), 1.20 (d, J= 8.3 Hz, 6H).

Step 4: l-Benzyl-4,4-dimethylazetidine-2-carboxylic acid (290A-5)

To a solution of l-benzyl-4,4-dimethylazetidine-2-carbonitrile (300 mg, 1.50 mmol, 1.0 eq) in EtOH (1.5 mL) and H2O (0.8 mL) was added NaOH (120 mg, 3.00 mmol, 2.0 eq) at room temperature. The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with MTBE (3.0 mL x 3). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with MeOH/DCM (V/V = 10/1, 10 mL) then filtered. The filter cake was washed with MeOH/DCM (3.0 mL x 2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give 1 -benzyl-4,4- dimethylazetidine-2-carboxylic acid (200 mg, 912 pmol, 61% yield) as a white solid. M + H ⁺ = 220.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.40 (d, J= 7.1 Hz, 2H), 7.32 - 7.17 (m, 3H), 3.86 - 3.70 (m, 3H), 2.06 (t, J= 9.6 Hz, 1H), 2.01 - 1.88 (m, 1H), 1.28 (s, 3H), 1.05 (s, 3H).

Step 5: (l-Benzyl-4,4-dimethylazetidin-2-yl)methanol (290A-6)

To a solution of l-benzyl-4,4-dimethylazetidine-2-carboxylic acid (150 mg, 684 pmol, 1.0 eq) in THF (3.0 mL) was added LiAlH4 (1 M in THF, 1.37 mL, 2.0 eq) dropwise at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred another 15 min at this temperature. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH4CI (10 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude (l-benzyl-4,4-dimethylazetidin-2-yl)methanol (75.0 mg, 365 pmol, 53% yield) as a yellow gum. M + H ⁺ = 206.1(LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.35 - 7.16 (m, 5H), 4.18 - 4.03 (m, 1H), 3.66 (d, J= 13.6 Hz, 1H), 3.49 (d, J= 13.5 Hz, 1H), 3.23 - 3.06 (m, 3H), 1.78 (dd, J= 7.4, 10.1 Hz, 1H), 1.66 - 1.56 (m, 1H), 1.19 (s, 3H), 0.98 (s, 3H).

Step 6: 5-((l-Benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-/V- (l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 492) and 5-((l-benzyl-5,5-dimethylpyrrolidin-3- yl)oxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (Compound 491)

A mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 315 pmol, 1.0 eq), (l-benzyl-4,4-dimethylazeti din-2 -yl)m ethanol (64.7 mg, 315 pmol, 1.0 eq), and CMBP (114 mg, 473 pmol, 1.5 eq) in toluene (5.0 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 50% - 70% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-((l-Benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-7V- (l-(naphthalen-l-yl)cyclopropyl)benzamide (16.2 mg, 31.8 pmol, 10% yield) was obtained as a white solid. M + H ⁺ = 505.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.04 (s, 1H), 8.66 (d, J= 8.3 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.82 (t, J= 6.6 Hz, 2H), 7.59 - 7.43 (m, 3H), 7.26 (d, J= 7.1 Hz, 2H), 7.13 (t, = 7.4 Hz, 2H), 7.08 - 7.01 (m, 1H), 6.96 (d, = 8.5 Hz, 1H), 6.65 (dd, J= 2.6, 8.4 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 3.74 - 3.63 (m, 2H), 3.60 - 3.40 (m, 3H), 1.94 (s, 3H), 1.86 (dd, J = 7.6, 10.1 Hz, 1H), 1.67 (dd, J = 8.2, 9.8 Hz, 1H), 1.34 (br s, 2H), 1.23 - 1.13 (m, 5H), 1.00 (s, 3H). 5-((l-Benzyl-5,5-dimethylpyrrolidin-3-yl)oxy)-2-methyl-A- (l-(naphthalen-l-yl)cyclopropyl)benzamide (6.50 mg, 12.8 pmol, 4% yield) was obtained as a yellow solid. M + H ⁺ = 505.3(LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.04 (s, 1H), 8.63 (br d, J= 7.9 Hz, 1H), 7.93 (br d, J= 7.1 Hz, 1H), 7.86 - 7.72 (m, 2H), 7.62 - 7.38 (m, 3H), 7.36 - 7.12 (m, 5H), 6.97 (br d, J= 8.3 Hz, 1H), 6.71 (br dd, J= 2.1, 8.3 Hz, 1H), 6.46 (br d, J = 2.1 Hz, 1H), 4.72 (br s, 1H), 3.57 (br d, J = 13.0 Hz, 1H), 3.46 - 3.35 (m, 1H), 3.32 (s, 2H), 2.96 - 2.76 (m, 1H), 2.10 (br dd, J= 8.0, 12.8 Hz, 1H), 1.93 (s, 3H), 1.71 (br dd, = 2.9, 13.0 Hz, 1H), 1.33 (br s, 2H), 1.16 (s, 4H), 1.05 (s, 3H).

Example 291: 5-((4,4-Dimethylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(napht halen-l- yl)cyclopropyl)benzamide (Compound 534)

Compound 492 Compound 534

Step 1 : 5-((4,4-Dimethylazetidin-2-yl)methoxy)-2-methyl-/V-(l-(napht halen-l-yl)cyclo propyl)benzamide (Compound 534)

To a solution of 5-((l-benzyl-4,4-dimethylazetidin-2-yl)methoxy)-2-methyl-7V- (l-(naphthalen- l-yl)cyclopropyl)benzamide (110 mg, 218 pmol, 1.0 eq) in TFE (20 mL) was added 10% palladium on carbon (100 mg) under a N2 atomosphere. The suspension was degassed and purged with H2 several times. The mixture was stirred at 20 °C for 16 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL x 3). The combined organic layers were concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-((4,4- Dimethylazeti din-2 -yl)methoxy)-2-methyl-7V-(l -(naphthal en- 1 -yl)cyclopropyl)benzamide (7.20 mg, 17.4 pmol, 8% yield) was obtained as a white solid. M + H ⁺ = 415.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.07 (s, 1H), 8.66 (d, J= 8.5 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.82 (t, J= 8.3 Hz, 2H), 7.60 - 7.42 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 6.81 (dd, J= 2.7, 8.3 Hz, 1H), 6.59 (d, J= 2.6 Hz, 1H), 3.90 - 3.72 (m, 3H), 2.03 (dd, = 7.9, 10.7 Hz, 1H), 1.96 (s, 3H), 1.76 (dd, J= 7.3, 10.8 Hz, 1H), 1.38 - 1.33 (m, 2H), 1.30 (s, 3H), 1.17 (br t, J= 5.4 Hz, 2H), 1.13 (s, 3H).

Example 292: 5-((5,5-Dimethylpyrrolidin-3-yl)oxy)-2-methyl-/V-(l-(naphtha len-l- yl)cyclopropyl)benzamide (Compound 533)

Compound 491 Compound 533

Step 1: 5-((5,5-Dimethylpyrrolidin-3-yl)oxy)-2-methyl-/V-(l-(naphtha len-l-yl) cyclopropyl)benzamide (Compound 533)

To a solution of 5-((l-benzyl-5,5-dimethylpyrrolidin-3-yl)oxy)-2-methyl-7V-(l -(naphthalen-l- yl)cyclopropyl)benzamide (100 mg, 198 pmol, 1.0 eq) in TFE (20 mL) was added 10% palladium on carbon (100 mg) under a N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 20 °C for 16 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL x 3). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-((5,5- Dimethylpyrrolidin-3-yl)oxy)-2-methyl-7V-(l-(naphthalen-l-yl )cyclopropyl)benzamide (21.8 mg, 52.2 pmol, 26% yield) was obtained as a white solid. M + H ⁺ = 415.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.07 (s, 1H), 8.66 (br d, J= 8.0 Hz, 1H), 7.93 (br d, J= 7.9 Hz, 1H), 7.81 (br dd, J= 7.7, 11.2 Hz, 2H), 7.60 - 7.42 (m, 3H), 7.01 (br d, J= 8.6 Hz, 1H), 6.76 (br d, ./= 7,8 Hz, 1H), 6.51 (br s, 1H), 4.75 (br s, 1H), 3.19 - 3.11 (m, 1H), 2.87 - 2.78 (m, 1H), 1.96 (s, 3H), 1.84 (br dd, J = 7.4, 13.4 Hz, 1H), 1.54 (br d, J = 13.3 Hz, 1H), 1.35 (br s, 2H), 1.17 (br s, 2H), 1.12 (s, 3H), 1.06 (s, 3H). Example 293: 4-Amino-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(n aphthalen- l-yl)cyclopropyl)benzamide (Compound 487)

293A-5 Compound 487

Step 1: 5-Hydroxy-2-methyl-4-nitrobenzoic acid (293 A-l)

A solution of 5-hydroxy-2-methylbenzoic acid (5.00 g, 32.9 mmol, 1.0 eq) in H2SO4 (50 mL, 98% purity) was cooled to 0 °C and to this mixture was added KNO3 (3.49 g, 34.5 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The mixture was treated with ice water (40 mL) slowly and extracted with DCM (20 mL x 5). The combined organic layers were dried over NazSC . filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 5-Hydroxy-2-methyl-4-nitrobenzoic acid (640 mg, 3.25 mmol, 10% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCh) 8 10.29 - 10.19 (m, 1H), 8.07 - 7.99 (m, 1H), 7.90 - 7.80 (m, 1H), 2.67 - 2.58 (m, 3H).

Step 2: 5-Hydroxy-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-4-nit robenzamide (293A-2)

To a solution of 5-hydroxy-2-methyl-4-nitrobenzoic acid (600 mg, 3.04 mmol, 1.0 eq and 1- (naphthalen-l-yl)cyclopropanamine (502 mg, 2.74 mmol, 0.90 eq) in DMF (30 mL) were added TEA (308 mg, 3.04 mmol, 424 pL, 1.0 eq), EDCI (613 mg, 3.20 mmol, 1.1 eq and HOBt (82.3 mg, 609 pmol, 0.20 eq . The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into brine (50 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-Hydroxy-2-methyl-7V-(l-(naphthalen-l-yl) cyclopropyl)-4-nitrobenzamide (460 mg, 1.27 mmol, 42% yield) was obtained as a yellow solid. M + H ⁺ = 363.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 10.41 - 10.24 (m, 1H), 8.48 - 8.40 (m, 1H), 7.96 - 7.89 (m, 2H), 7.86 - 7.80 (m, 2H), 7.64 - 7.44 (m, 3H), 6.93 - 6.89 (m, 1H), 6.53 - 6.44 (m, 1H), 2.14 - 2.09 (m, 3H), 1.63 - 1.57 (m, 2H), 1.47 - 1.40 (m, 2H).

Step 3: tert-Butyl 2-((4-methyl-5-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-2 - nitrophenoxy)methyl)azetidine-l-carboxylate (293A-3)

To a mixture of 5-hydroxy-2-methyl-7V-(l -(naphthal en-l-yl)cyclopropyl)-4-nitrobenzamide (140 mg, 386 pmol, 1.0 eq) and /c/7-butyl 2-(hydroxymethyl)azetidine-l -carboxylate (72.3 mg, 386 pmol, 1.0 eq) in toluene (8.0 mL) was added CMBP (933 mg, 5.42 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. /c/7-Butyl 2-((4-methyl-5-((l -(naphthal en-l-yl) cyclopropyl)carbamoyl)-2-nitrophenoxy)methyl)azetidine-l-car boxylate (90.0 mg, 169 pmol, 44% yield) was obtained as a yellow oil. M + H ⁺ = 532.3 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 9.28 (s, 1H), 8.61 (d, = 8.3 Hz, 1H), 7.94 (d, = 7.8 Hz, 1H), 7.83 (dd, = 7.7, 11.7 Hz, 2H), 7.69 (s, 1H), 7.61 - 7.43 (m, 3H), 7.04 (s, 1H), 4.45 - 4.32 (m, 2H), 4.11 (br d, J = 8.3 Hz, 1H), 3.70 (br s, 2H), 2.34 - 2.21 (m, 1H), 2.17 - 2.05 (m, 1H), 1.92 (s, 3H), 1.43 - 1.21 (m, 13H).

Step 4: 5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(naphthalen-l-yl)cyc lopropyl)-4-nitro benzamide (293A-4)

To a solution of tert-butyl 2-((4-methyl-5-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)-2 - nitrophenoxy)methyl)azetidine-l -carboxylate (70.0 mg, 132 pmol, 1.0 eq) in DCM (3.0 mL) was added TFA (1.08 g, 9.45 mmol, 700 pL, 72 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude product 5- (azetidin-2-ylmethoxy)-2-methyl-N-(l -(naphthal en-l-yl)cy cl opropyl)-4-nitrobenzamid (90.0 mg, TFA salt) as a yellow oil. M + H ⁺ = 432.1 (LCMS).

Step 5: 2-Methyl-5-(( l-methylazetidin-2-yl)methoxy)-/V-(l-(naphthalen-l-yl)cyclop ropyl) -4-nitrobenzamide (293A-5)

To a solution of 5 -(azetidin-2-ylmethoxy)-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)-4- nitrobenzamide (90.0 mg, 165 pmol, 1.0 eq) in MeOH (4.0 mL) was added TEA (23.0 pL), followed by the addition of formaldehyde (26.8 mg, 330 pmol, 24.6 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (20.7 mg, 330 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for another 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.4). 2-Methyl-5-((l-methylazetidin- 2 -yl)methoxy)-7V-(l -(naphthal en-l-yl)cyclopropyl)-4-nitrobenzamide (60.0 mg, 135 pmol, 82% yield) was obtained as a yellow solid. M + H ⁺ = 446.1 (LCMS).

Step 6: 4-Amino-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(n aphthalen-l-yl) cyclopropyl)benzamide (Compound 487)

To a stirred solution of 2-methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(naphthale n-l- yl)cyclopropyl)-4-nitrobenzamide (60.0 mg, 135 pmol, 1.0 eq) in a mixture of MeOH (6.0 mL) and H2O (1.2 mL) was added iron powder (37.6 mg, 673 pmol, 5.0 eq), followed by NH4CI (36.0 mg, 673 pmol, 5.0 eq). The mixture was stirred at 70 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, filtered through a pad of Celite. The filtrate was poured into H2O (10 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 4-Amino-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-A- (l-(naphthalen-l-yl)cyclopropyl)benzamide (24.0 mg, 52.3 pmol, 39% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 416.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.93 (br s, 1H), 8.67 (d, J= 8.4 Hz, 1H), 7.93 (d, J= 7.8 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.60 - 7.43 (m, 3H), 6.84 - 6.70 (m, 2H), 4.71 - 4.60 (m, 1H), 4.31 - 4.18 (m, 2H), 4.05 (dt, J= 4.4, 9.7 Hz, 1H), 3.90 - 3.82 (m, 1H), 2.83 (s, 3H), 2.48 - 2.30 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.18 (br s, 2H).

Example 294: 5-((Azetidin-3-yloxy)methyl)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 435)

Compound 435 290A-4 Step 1: 5-(Bromomethyl)-2-methylbenzoic acid (294A-2)

To a solution of 2-methylbenzoic acid (4.00 g, 29.4 mmol, 3.77 mL, 1.0 eq) in phosphoric acid (0.5 mL) were added paraformaldehyde (2.50 g) and HBr (19.4 g, 79.0 mmol, 13.0 mL, 33% purity in HO Ac, 2.7 eq) at 20 °C. The mixture was stirred at 115 °C for 15 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL). The resulting solid was collected by filtration, washed with H2O (20 mL) and dried under vacuum to give a crude product 5-(bromomethyl)-2-methylbenzoic acid (6.00 g) as a white solid. M + H ⁺ = 229.0 (LCMS).

Step 2: 5-(((l-(tert-Butoxycarbonyl)azetidin-3-yl)oxy)methyl)-2-meth ylbenzoic acid (294A-3)

To a solution of 5-(bromomethyl)-2-methylbenzoic acid (300 mg, 1.31 mmol, 1.0 eq) in THF (10 mL) was added NaH (105 mg, 2.62 mmol, 60% purity, 2.0 eq). The mixture was stirred at 0 °C for 30 min, then tert-butyl 3 -hydroxyazetidine-1 -carboxylate (340 mg, 1.96 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 0 °C for 2 h. LCMS indicated that 3% of the starting material was remaining and 66% of desired compound was detected. The mixture was treated with H2O (10 mL) and extracted with DCM (10 mL x 2). The organic phase was discarded. The aqueous layer was acidified to pH 5 by using HC1 (1 M aqueous) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give residue which was purified by preparative HPLC (Cl 8-1 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 35%-80%, B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (((l-(tert- Butoxycarbonyl)azetidin-3-yl)oxy)methyl)-2 -methylbenzoic acid (1.10 g, 3.22 mmol, 49% yield) was obtained as a white solid. M - 100 + H ⁺ = 222.2 (LCMS).

Step 3: tert-Butyl 3-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)be nzyl) oxy)azetidine-l-carboxylate (294A-4)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (214 mg, 1.17 mmol, 1.5 eq) in DCM (10 mL) were added HOBt (263 mg, 1.94 mmol, 2.5 eq), TEA (236 mg, 2.33 mmol, 325 pL, 3.0 eq), EDCI (373 mg, 1.94 mmol, 2.5 eq) and 5-(((l-(tert-butoxycarbonyl)azeti din-3 - yl)oxy)methyl)-2-methylbenzoic acid (250 mg, 778 pmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 35% - 80% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). Zc/V-Butyl 3 -((4-methyl-3-((l -(naphthal en-1- yl)cyclopropyl)carbamoyl)benzyl)oxy)azetidine-l -carboxylate (250 mg, 488 pmol, 63% yield) was obtained as a white amorphous solid. M - 100 + H ⁺ = 387.2 (LCMS).

Step 4: 5-((Azetidin-3-yloxy)methyl)-2-methyl-/V-(l-(naphthalen-l-yl )cyclopropyl) benzamide (Compound 435)

To a solution of tert-butyl 3-((4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) benzyl)oxy)azetidine-l -carboxylate (100 mg, 206 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (23.4 mg, 206 pmol, 15.2 pL, 1.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-((Azetidin-3- yloxy)methyl)-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (23.5 mg, 46.9 pmol, 23% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 387.1 (LCMS); NMR (400 MHz, DMSO-tL) 89.23 - 9.07 (m, 1H), 8.71 - 8.52 (m, 2H), 7.99 - 7.80 (m, 3H), 7.65 - 7.44 (m, 3H), 7.34 - 6.79 (m, 3H), 4.47 - 4.32 (m, 3H), 4.15 - 4.03 (m, 2H), 3.79 (m, 2H), 2.03 (m, 1H), 1.98 - 1.94 (m, 1H), 2.09 - 1.93 (m, 1H), 1.37 (m, 2H), 1.26 - 1.12 (m, 2H).

Example 295: 2-Methyl-5-(((l-methylazetidin-3-yl)oxy)methyl)-/V-(l-(napht halen-l- yl)cyclopropyl)benzamide (Compound 447)

Compound 435 Compound 447

Step 1: 2-Methyl-5-(((l-methylazetidin-3-yl)oxy)methyl)-/V-(l-(napht halen-l-yl) cyclopropyl)benzamide (Compound 447)

To a solution of 5-((azetidin-3-yloxy)methyl)-2-methyl-A-(l-(naphthalen-l- yl)cyclopropyl)benzamide (80.0 mg, 207 pmol, 1.0 eq, TFA salt) in MeOH (2.0 mL) were added formaldehyde (16.8 mg, 207 pmol, 15.4 pL, 37% purity in water, 1.0 eq), TEA (20.9 mg, 207 pmol, 28.8 pL, 1.0 eq) and HOAc (1.24 mg, 20.7 pmol, 1.18 pL, 0.10 eq). The mixture was stirred at 20 °C for 1 h. Then NaBHiCN (32.5 mg, 517 pmol, 2.5 eq) was added to the mixture. The resulting mixture was stirred at 20 °C for 11 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD Cl 8 column (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 2-Methyl-5-(((l-methylazetidin-3- yl)oxy)methyl)-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (16.3 mg, 40.7 pmol, 20% yield) was obtained as a white solid. M + H ⁺ = 401.1 NMR (400 MHz, CDCh) 8 7.64 - 7.55 (m, 1H), 7.54 - 7.44 (m, 2H), 7.21 - 7.13 (m, 1H), 7.13 - 7.03 (m, 2H), 6.50 (m, 1H), 4.32 - 4.31 (m, 1H), 4.33 - 4.25 (m, 2H), 4.16 - 4.03 (m, 1H), 3.63 - 3.50 (m, 2H), 2.87 (m, 2H), 2.34 (m, 3H), 2.17 (m, 3H), 1.63 - 1.52 (m, 2H), 1.45 - 1.34 (m, 2H).

Example 296: 5-(2-(Azetidin-2-yl)ethyl)-2-methyl-/V-(l-(naphthalen-l-yl)c yclopropyl) benzamide (Compound 449)

Compound 449 Step 1: tert-Butyl 2-((3-(methoxycarbonyl)-4-methylphenyl)ethynyl)azetidine-l-c arboxy late (296A-2)

To a solution of tert-butyl 2-ethynylazetidine-l -carboxylate (270 mg, 1.49 mmol, 1.0 eq) in TEA (5.0 mL) were added methyl 5 -iodo-2-m ethylbenzoate (411 mg, 1.49 mmol, 1.0 eq), Cui (5.67 mg, 29.8 pmol, 0.02 eq), and Pd(PPh3)2C12 (20.9 mg, 29.8 pmol, 0.02 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. tert-Butyl 2-((3-(methoxycarbonyl)-4-methyl phenyl)ethynyl)azetidine-l -carboxylate (220 mg, 655 pmol, 44% yield) was obtained as a colorless oil. M - 100 + H ⁺ = 230.1 (LCMS).

Step 2: tert-Butyl 2-(3-(methoxycarbonyl)-4-methylphenethyl)azetidine-l-carboxy late (296A-3)

To a solution of tert-butyl 2-((3-(m ethoxy carbonyl)-4-methylphenyl)ethynyl)azeti dine- 1- carboxylate (200 mg, 607 pmol, 1.0 eq) in MeOH (10 mL) was added 10% palladium on carbon (30.0 mg). The mixture was stirred at 50 °C for 2 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a crude product tert-butyl 2-(3-(m ethoxy carbonyl)-4-methylphenethyl)azeti dine- 1 -carboxylate (200 mg) as a colorless oil. M - 100 + H ⁺ = 234.1 (LCMS).

Step 3: 5-(2-(l-(tert-Butoxycarbonyl)azetidin-2-yl)ethyl)-2-methylbe nzoic acid (296A-4)

To a solution of tert-butyl 2-(3-(m ethoxy carbonyl)-4-methylphenethyl)azeti dine- 1 -carboxy late (200 mg, 599 pmol, 1.0 eq) in THF (1.0 mL) were added LiOH.EEO (176 mg, 4.20 mmol, 7.0 eq), MeOH (500 pL) and H2O (500 pL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (5.0 mL) and extracted with DCM (5.0 mL x 2). The organic phase was discarded. The aqueous layer was acidified to pH 5 by using HC1 (1 M aqueous) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product 5-(2-(l-(tert- butoxycarbonyl)azetidin-2-yl)ethyl)-2-methylbenzoic acid (200 mg) as a colorless oil. M- 100 + H ⁺ = 220.1 (LCMS). Step 4: tert-Butyl 2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenethyl) azetidine-l-carboxylate (296A-5)

To a solution of 1 -(naphthal en-l-yl)cy cl opropanamine (86.1 mg, 469 pmol, 1.0 eq) in DCM (2.0 mL) were added HOBt (159 mg, 1.17 mmol, 2.5 eq), TEA (143 mg, 1.41 mmol, 196 pL, 3.0 eq), EDCI (225 mg, 1.17 mmol, 2.5 eq) and 5-(2-(l-(tert-butoxycarbonyl)azetidin-2- yl)ethyl)-2-methylbenzoic acid (150 mg, 469 pmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product tert-butyl 2-(4-methyl-3-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenethyl)azetidine-l -carboxylate (400 mg) as a yellow oil. M - 100 + H ⁺ = 385.2 (LCMS).

Step 5: 5-(2-(Azetidin-2-yl)ethyl)-2-methyl-/V-(l-(naphthalen-l-yl)c yclopropyl) benz amide (Compound 449)

To a solution of tert-butyl 2-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenethyl)azetidine-l -carboxylate (300 mg, 619 pmol, 1.0 eq) in DCM (3.0 mL) was added TFA (70.6 mg, 619 pmol, 45.8 pL, 1.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 15% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-(Azetidin-2-yl)ethyl)-2-methyl-7V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (66.0 mg, 130 pmol, 21% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 385.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 9.11 - 9.04 (m, 1H), 8.68 - 8.63 (m, 1H), 7.97 - 7.91 (m, 1H), 7.87 - 7.81 (m, 2H), 7.61 - 7.43 (m, 3H), 7.12 - 7.04 (m, 2H), 6.97 - 6.88 (m, 1H), 4.28 - 4.16 (m, 1H), 3.96 - 3.80 (m, 1H), 3.76 - 3.65 (m, 1H), 2.47 - 2.28 (m, 4H), 2.21 - 2.09 (m, 1H), 2.08 (m, 1H), 1.99 (m, 3H), 1.96 - 1.85 (m, 1H), 1.39 - 1.32 (m, 2H). Example 297: 2-Methyl-5-(2-(l-methylazetidin-2-yl)ethyl)-/V-(l-(naphthale n-l-yl)cyclo propyl)benzamide (Compound 455)

Compound 455

Step 1: 2-Methyl-5-(2-(l-methylazetidin-2-yl)ethyl)-/V-(l-(naphthale n-l-yl)cyclo propyl)benzamide (Compound 455)

To a solution of 5-(2-(azetidin-2-yl)ethyl)-2-methyl-A-(l-(naphthalen-l-yl)cy clopropyl) benzamide (40.0 mg, 104 pmol, 1.0 eq, TFA salt) in MeOH (1.0 mL) were added formaldehyde (8.44 mg, 104 pmol, 7.74 pL, 37% purity in water, 1.0 eq), TEA (10.5 mg, 104 pmol, 14.5 pL, 1.0 eq) and HO Ac (624 pg, 10.4 pmol, 0.1 eq). The mixture was stirred at 20 °C for 1 h. Then NaBHiCN (16.3 mg, 260 pmol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B : acetonitrile). 2 -Methyl-5-(2-(l -methylazetidin-2-yl)ethyl)-A-(l -(naphthal en-1 - yl)cyclopropyl)benzamide (20.8 mg, 52.2 pmol, 50% yield) was obtained as a white solid. M + H ⁺ = 399.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.52 - 8.44 (m, 1H), 7.98 - 7.88 (m, 2H), 7.84 - 7.77 (m, 1H), 7.61 - 7.43 (m, 3H), 7.08 - 6.94 (m, 3H), 6.53 - 6.44 (m, 1H), 3.42 - 3.33 (m, 1H), 2.95 - 2.83 (m, 1H), 2.76 - 2.67 (m, 1H), 2.51 - 2.42 (m, 2H), 2.27 (m, 3H), 2.15 (m, 3H), 2.00 - 1.91 (m, 1H), 1.88 - 1.74 (m, 2H), 1.73 - 1.62 (m, 1H), 1.62 - 1.55 (m, 2H), 1.44 - 1.37 (m, 2H). Example 298: Methyl 3-(4-methyl-3-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenyl)propanoate (Compound 431)

Compound 431

Step 1: (E)-Methyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe nyl) acrylate (298A-1)

To a solution of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (120 mg, 316 pmol, 1.0 eq), Pd(OAc)2 (708 mg, 3.16 pmol, 0.01 eq) and PPhs (1.66 mg, 6.31 pmol, 0.02 eq) in DMF (6.0 mL) was added methyl acrylate (272 mg, 3.16 mmol, 284 pl, 10 eq), followed by TEA (63.9 mg, 631 pmol, 87.8 pL, 2.0 eq) under a N2 atmosphere. The mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. (E)-Methyl 3- (4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)pheny l)acrylate (104 mg, 270 pmol, 29% yield) was obtained as a yellow oil. M + H ⁺ = 386.1 (LCMS).

Step 2: Methyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)phe nyl) propanoate (Compound 431)

To a solution of (£)-methyl 3-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl) phenyl)acrylate (90.0 mg, 234 pmol, 1.0 eq) in EtOAc (10 mL) was added 10% palladium on carbon (10 mg). The mixture was degassed and purged with EE three times, and then the mixture was stirred at 20 °C for 2 h under a EE (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (2.0 mL x 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 65% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). Methyl 3- (4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl) carbamoyl)phenyl)propanoate (21.5 mg, 54.2 pmol, 24% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 388.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 6 9.10 - 9.01 (m, 1H), 8.70 - 8.60 (m, 1H), 7.97 - 7.89 (m, 1H), 7.87 - 7.77 (m, 2H), 7.61 - 7.42 (m, 3H), 7.13 - 7.07 (m, 1H), 7.06 - 6.99 (m, 1H), 6.91 (d, J= 1.3 Hz, 1H), 3.52 (s, 3H), 2.79 - 2.70 (m, 2H), 2.56 (s, 2H), 2.01 - 1.93 (m, 3H), 1.40 - 1.31 (m, 2H), 1.21 - 1.12 (m, 2H).

Example 299: 5-(3-Amino-3-oxopropyl)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 452)

Compound 452

Step 1 : 5-(3-Amino-3-oxopropyl)-2-methyl-/V-(l-(naphthalen-l-yl)cycl opropyl) benzamide (Compound 452)

To a solution of methyl 3 -(4-methyl-3-((l -(naphthal en-l-yl)cy cl opropyl)carbamoyl)phenyl) propanoate (320 mg, 826 pmol, 1.0 eq) in MeOH (3.0 mL) was added NH /MeOH (7 M, 32 mL, 271 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 25 mm, 5 pm); flow rate: 40 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(3-Amino-3-oxopropyl)-2-methyl-7V-(l- (naphthalen-l-yl)cyclopropyl)benzamide (25.9 mg, 69.5 pmol, 8% yield) was obtained as a white solid. M + H ⁺ = 373.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.06 (s, 1H), 8.71 - 8.60 (m, 1H), 7.98 - 7.90 (m, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.63 - 7.42 (m, 3H), 7.27 - 7.18 (m, 1H), 7.05 (br d, J= 17.9 Hz, 2H), 6.90 (s, 1H), 6.77 - 6.64 (m, 1H), 2.76 - 2.63 (m, 2H), 2.32 - 2.20 (m, 2H), 1.97 (s, 3H), 1.35 (br s, 2H), 1.23 - 1.11 (m, 2H).

Example 300: 5-(3-Aminopropyl)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 472)

Compound 472

Step 1: 5-(2-Cyanoethyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )benzamide (300A- 1)

A mixture of 5-(3-amino-3-oxopropyl)-2-methyl-7V-(l-(naphthalen-l-yl)cycl opropyl)benz amide (68.0 mg, 183 pmol, 1.0 eq) in DMF (5.0 mL) was degassed and purged with N2 three times, and to this solution was added (COC1)2 (69.5 mg, 548 pmol, 47.9 pL, 3.0 eq) at 0 °C. The mixture was stirred at 0 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.5). Crude 5-(2- cyanoethyl)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benz amide (76.0 mg) was obtained as a yellow oil. M + H ⁺ = 355.2 (LCMS).

Step 2: 5-(3-Aminopropyl)-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (Compound 472)

To a solution of 5-(2-cyanoethyl)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl )benzamide (61.0 mg, 172 pmol, 1.0 eq) in THF (20 mL) was added Raney-Ni (14.7 mg), followed by NH3.H2O (24.1 mg, 172 pmol, 26.5 pL, 25% purity 1.0 eq). The mixture was degassed and purged with H2 three times. The mixture was stirred at 30 °C for 16 h under a H2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- (3-Aminopropyl)-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl) benzamide (9.00 mg, 22.7 pmol, 13% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 359.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.09 (s, 1H), 8.71 - 8.61 (m, 1H), 7.93 (d, J= 7.4 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.73 (br s, 3H), 7.48 (d, J = 7.5 Hz, 3H), 7.12 - 7.04 (m, 2H), 6.93 - 6.88 (m, 1H), 2.77 - 2.63 (m, 2H), 2.58 - 2.52 (m, 2H), 1.99 (s, 3H), 1.80 - 1.69 (m, 2H), 1.35 (br d, J= 1.5 Hz, 2H), 1.18 (br d, J = 1.4 Hz, 2H).

Example 301: 5-(4-Aminopiperidin-l-yl)-2-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl) benzamide (Compound 463)

Compound 463

301A-1

Step 1: te/7- Butyl (l-(4-methyl-3-((l-(naphthalen-l-yl)cyclopropyl)carbamoyl)ph enyl) piperidin-4-yl)carbamate (301A-1)

A mixture of 5-bromo-2-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)benzamid e (100 mg, 263 pmol, 1.0 eq) and tert-butyl piperidin-4-ylcarbamate (79.0 mg, 394 pmol, 4.38 pL, 1.5 eq) in THF (4.0 mL) was degassed and purged with N2 three times. To this mixture were added t- BuONa (75.8 mg, 789 pmol, 3.0 eq) and /-BuXPhos Pd G3 (20.9 mg, 26.3 pmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/5. ter/-Butyl(l-(4-methyl-3-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenyl) piperidin-4-yl)carbamate (80.0 mg, 160 pmol, 20% yield) was obtained as a brown solid. M + H ⁺ = 500.3 (LCMS).

Step 2: 5-(4-Aminopiperidin-l-yl)-2-methyl-/V-(l-(naphthalen-l-yl)cy clopropyl)benz amide (Compound 463)

To a solution of tert-butyl (l-(4-methyl-3-((l-(naphthalen-l- yl)cyclopropyl)carbamoyl)phenyl) piperidin-4-yl)carbamate (75.0 mg, 150 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 7.5 mL). The resulting mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(4-Aminopiperidin-l-yl)-2-methyl-7V-(l- (naphthalen-l-yl)cyclopropyl)benzamide (13.0 mg, 32.5 pmol, 22% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 400.1 (LCMS); ¹ H NMR (400 MHz, DMSO ) 8 9.08 (br s, 1H), 8.66 (d, J= 8.4 Hz, 1H), 8.09 - 7.98 (m, 3H), 7.93 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 7.9, 11.1 Hz, 2H), 7.63 - 7.39 (m, 3H), 7.02 (br d, J= 3.9 Hz, 1H), 6.92 - 6.57 (m, 1H), 3.58 (br d, J= 12.5 Hz, 2H), 3.25 - 3.08 (m, 1H), 2.94 - 2.63 (m, 2H), 1.93 (s, 5H), 1.77 - 1.44 (m, 2H), 1.35 (br s, 2H), 1.18 (br s, 2H).

Example 302: 5-(4-(2-Hydroxyethyl)piper:izin-l-yl)-2-methyl- \-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 505)

Step 1

50A-1

Compound 505

Step 1: 5-(4-(2-Hydroxyethyl)piperazin-l-yl)-2-methyl-/V-(l-(naphtha len-l-yl)cyclopro pyl)benzamide (Compound 505)

A mixture of 5-bromo-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl)benzamide (150 mg, 394 pmol, 1.0 eq) and 2-(piperazin-l-yl)ethanol (61.6 mg, 473 pmol, 58.0 pL, 1.2 eq) in tert- amylalcohol (3.0 mL) was degassed and purged with N2 three times. To the mixture were added XPhos Pd G3 (33.4 mg, 39.4 pmol, 0.1 eq) and CS2CO3 (257 mg, 788 pmol, 2.0 eq). The resulting mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(4-(2-Hydroxyethyl)piperazin-l-yl)-2-methyl-A-(l-(naphthal en-l-yl)cyclopropyl) benzamide (3.30 mg, 2.92 pmol, HC1 salt) was obtained as a white solid. M + H ⁺ = 430.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.68 - 9.55 (m, 1H), 9.03 (s, 1H), 8.66 (d, J= 8.5 Hz, 1H), 7.93 (d, J= 7.4 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.60 - 7.43 (m, 3H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.64 (d, J= 2.8 Hz, 1H), 3.80 - 3.72 (m, 2H), 3.70 - 3.64 (m, 2H), 3.57 - 3.53 (m, 2H), 3.24 - 3.20 (m, 2H), 3.16 - 3.07 (m, 2H), 3.01 - 2.90 (m, 2H), 1.93 (s, 3H), 1.38 - 1.32 (m, 2H), 1.21 - 1.14 (m, 2H).

Example 303: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l-yl)cycl opropyl) benzo [d]oxazole-6-carboxamide (Compound 426)

293A-2 303A-1

Step 4

303A-3 Compound 426

Step 1 : 4-Amino-5-hydroxy-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropy l)benzamide (301A-1)

To a stirred solution of 5-hydroxy-2-methyl-A-(l-(naphthalen-l-yl) cyclopropyl)-4-nitrobenz amide (230 mg, 635 pmol, 1.0 eq) in a mixture of MeOH (8.0 mL) and H2O (1.6 mL) was added iron powder (355 mg, 6.35 mmol, 10 eq) in one portion, followed by NH4CI (340 mg, 6.35 mmol, 10 eq). The mixture was stirred at 70 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL), filtered, and the filtrate was extracted with DCM (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petr oleum ether from 0/1 to 1/0. 4-Amino-5- hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (130 mg, 391 pmol, 31% yield) was obtained as a yellow solid. M + H ⁺ = 333.1 (LCMS).

Step 2: 4-(2-Chloroacetamido)-5-hydroxy-2-methyl-/V-(l-(naphthalen-l -yl)cyclopropyl) benzamide (301A-2)

To a solution of 4-amino-5-hydroxy-2-methyl-A-(l-(naphthalen-l-yl)cyclopropyl )benzamide (120 mg, 361 pmol, 1.0 eq) in DCM (4.0 mL) was added TEA (110 mg, 1.08 mmol, 151 pL, 3.0 eq) at 0 °C, followed by 2 -chloroacetyl chloride (28.5 mg, 253 pmol, 20.1 pL, 0.7 eq) in DCM (1.0 mL). The resulting mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether =1/1, R = 0.4). 4-(2-Chloroacetamido)-

5-hydroxy-2-methyl-N-( l -(naphthalen- l -yl)cyclopropyl)benzamide (40.0 mg, 97.8 pmol, 27% yield) was obtained as a yellow solid. M + H ⁺ = 409.1 (LCMS); ¹ H NMR (400 MHz,CDCh) 8 8.52 - 8.41 (m, 1H), 7.96 - 7.79 (m, 3H), 7.64 - 7.41 (m, 4H), 7.10 - 7.04 (m, 1H), 6.87 - 6.77 (m, 1H), 6.63 - 6.47 (m, 1H), 5.39 - 5.25 (m, 1H), 4.26 - 4.19 (m, 2H), 2.14 (br d, J = 2.1 Hz, 3H), 1.40 - 1.39 (m, 2H), 1.30 - 1.29 (m, 2H).

Step 3: 2-(Chloromethyl)-5-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl )benzo[J]oxazole-

6-carboxamide (301A-3)

To a solution of 4-(2-chloroacetamido)-5-hydroxy-2-methyl-A-(l -(naphthal en-l-yl)cy cl opro pyl)benzamide (60.0 mg, 147 pmol, 1.0 eq) in toluene (6.0 mL) was added TSOH.H2O (12.6 mg, 73.4 pmol, 0.5 eq). The resulting mixture was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified via preparative TLC (EtOAc/petroleum ether =1/3, R/= 0.5). 2- (Chloromethyl)-5-methyl-7V-(l-(naphthaalen-l-yl)cyclopropyl) benzo[ ]oxazole-6- carboxamide (20.0 mg, 51.2 pmol, 35% yield) was obtained as a yellow solid. M + H ⁺ = 391.1 (LCMS).

Step 4: 5-Methyl-2-((methylamino)methyl)-/V-(l-(naphthalen-l-yl)cycl opropyl) benzo[ | oxazole-6-carboxamide (Compound 426)

To a solution of 2-(chloromethyl)-5-methyl-A-(l-(naphthaalen-l-yl)cyclopropyl )benzo[J] oxazole-6-carboxamide (20.0 mg, 51.2 pmol, 1.0 eq) in acetonitrile (2.0 mL) was added methanamine hydrochloride (13.8 mg, 205 pmol, 4.0 eq), followed by KI (1.70 mg, 10.2 pmol, 0.20 eq) and K2CO3 (14.1 mg, 102 pmol, 2.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-Methyl-2-((methylamino)methyl)-A-(l- (naphthalen-l-yl)cyclopropyl)benzo[d]oxazole-6-carboxamide (3.20 mg, 7.20 pmol, 14% yield, FA salt) was obtained as a white solid. M + H ⁺ = 386.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.20 - 9.14 (m, 1H), 8.68 - 8.61 (m, 1H), 7.98 - 7.89 (m, 1H), 7.87 - 7.78 (m, 2H), 7.62 - 7.43 (m, 4H), 7.38 - 7.34 (m, 1H), 3.91 - 3.86 (m, 2H), 2.30 - 2.26 (m, 3H), 2.13 - 2.09 (m, 3H), 1.42 - 1.36 (m, 2H), 1.23 - 1.17 (m, 2H).

Example 304: /V-(l-(2,3-Dihydrobenzo[/>][l,4]dioxin-5-yl)cyclopropyl)- 2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 432)

Compound 432

Step 1: 2,3-Dihydrobenzo[6][l,4]dioxine-5-carboxamide (304A-2)

To a solution of 2,3-dihydrobenzo[Z>][l,4]dioxine-5-carboxylic acid (2.00 g, 11.1 mmol, 1.0 eq) in THF (50 mL) were added NMM (1.24 g, 12.2 mmol, 1.34 mL 1.1 eq) and isobutyl chloroformate (1.67 g, 12.2 mmol, 1.60 mL, 1.1 eq) at 0 °C under a N2 atmosphere. The mixture was stirred at 0 °C for 30 min. NHi/MeOH (7 M, 10 mL, 6.3 eq) was added slowly. The mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely consumed. The mixture was treated with H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 100/1. 2,3-Dihydrobenzo[Z>][l,4]dioxine-5-carboxamide (1.80 g, 10.1 mmol, 90% yield) was obtained as a white solid. MHz, DMSO-tL) 8 7.52 (br s, 2H), 7.29 (dd, J= 1.7, 7.7 Hz, 1H), 6.97 (dd, J= 1.7, 7.9 Hz, 1H), 6.91 - 6.82 (m, 1H), 4.38 - 4.32 (m, 2H), 4.30 - 4.24 (m, 2H).

Step 2: 2,3-Dihydrobenzo[/>][l,4]dioxine-5-carbonitrile (304A-3)

A solution of 2,3-dihydrobenzo[Z>][l,4]dioxine-5-carboxamide (500 mg, 2.79 mmol, 1.0 eq) in SOCh (2.5 mL) was stirred at 80 °C for 6 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give crude product which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 100/1. 2,3-Dihydrobenzo[Z>][l,4]dioxine-5-carbonitrile (300 mg, 1.86 mmol, 67% yield) was obtained as a white solid. 'H NMR (400 MHz, DMSO- d ₆ ) 6 7.32 - 7.15 (m, 2H), 7.03 - 6.92 (m, 1H), 4.47 - 4.38 (m, 2H), 4.37 - 4.29 (m, 2H).

Step 3: l-(2,3-Dihydrobenzo[/>][l,4]dioxin-5-yl)cyclopropanamine (304A-4)

A mixture of 2,3-dihydrobenzo[Z>][l,4]dioxine-5-carbonitrile (150 mg, 931 pmol, 1.0 eq) in anhydrous Et2O (15 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (291 mg, 1.02 mmol, 302 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 683 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (264 mg, 1.86 mmol, 230 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (10 mL) and MTBE (5 mL) and extracted with MTBE (5.0 mL x 3). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.6). l-(2,3-Dihydrobenzo[Z>][l,4]dioxin-5-yl)cyclopropane amine (90.0 mg, 471 pmol, 51% yield) was obtained as a brown oil. M + H ⁺ = 192.0 (LCMS). Step 4: A-(l-(2,3-Dihydrobenzo[6][l,4]dioxin-5-yl)cyclopropyl)-2-met hyl-5-((l-methyl azetidin-2-yl)methoxy)benzamide (Compound 432)

To a solution of l-(2,3-dihydrobenzo[Z>][l,4]dioxin-5-yl)cyclopropanamine (50.0 mg, 261 pmol, 1.0 eq) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (61.5 mg, 261 pmol, 1.0 eq) in DMF (5.0 mL) were added DIEA (101 mg, 784 pmol, 137 pL, 3.0 eq) and HBTU (99.2 mg, 261 pmol, 1.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(2,3-Dihydrobenzo[Z>][l,4]dioxin-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (29.2 mg, 65.6 pmol, 25% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 409.2 (LCMS); ^T H NMR (400 MHz, DMSO-t/e) 6 10.54 - 10.40 (m, 1H), 8.66 - 8.57 (m, 1H), 7.15 - 7.09 (m, 1H), 7.03 (dd, J= 3.0, 6.3 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.82 (d, J= 2.6 Hz, 1H), 6.76 - 6.69 (m, 2H), 4.64 (dt, J= 2.5, 6.9 Hz, 1H), 4.41 - 4.32 (m, 1H), 4.30 - 4.27 (m, 2H), 4.25 - 4.21 (m, 2H), 4.19 - 4.10 (m, 1H), 4.09 - 3.97 (m, 1H), 3.93 - 3.81 (m, 1H), 2.85 (d, J= 5.1 Hz, 3H), 2.40 - 2.30 (m, 2H), 2.13 (s, 3H), 1.09 (br d, J= 6.5 Hz, 4H).

Example 305: /V-(l-(2-Isopropylnaphthalen-l-yl) cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl) methoxy) benzamide (Compound 457) compound 457

Step 1: 2-Isopropylnaphthalene (305A-2)

To a mixture of 2-isopropenylnaphthalene (3.00 g, 17.8 mmol, 1.0 eq) in MeOH (20 mL) was added 10% palladium on carbon (3.00 g) at 25 °C, the reaction mixture was stirred at 25 °C for 3 h under a H2 (15 psi) atmosphere. HPLC indicated that the starting material was completely consumed. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a crude product 2-isopropylnaphthalene (3.00 g) as a yellow oil.

Step 2: l-Bromo-2-isopropylnaphthalene (305A-3)

To a mixture of 2-isopropylnaphthalene (3.00 g, 17.6 mmol, 1.0 eq) in CH3CN (60 mL) was added NBS (3.45 g, 19.3 mmol, 1.1 eq) at 0 °C, the reaction mixture was stirred at 60 °C for 2 h. HPLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into saturated aqueous NazSOs (50 ml), extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 (75 x 30 mm, 3 mm); flow rate: 25 mL/min; gradient: 40% - 90% B over 10 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). l-Bromo-2-isopropyl-naphthalene (1.20 g, 4.82 mmol, 27% yield) was obtained as a yellow oil.

Step 3: 2-Isopropyl-l-naphthonitrile (305A-4)

To a mixture of l-bromo-2-isopropyl-naphthalene (1.15 g, 4.62 mmol, 1.0 eq) in DMF (40 mL) were added Pd(PPh3)4 (533 mg, 461 pmol, 0.1 eq) and Zn(CN)2 (2.17 g, 18.4 mmol, 1.17 mL, 4.0 eq) at 25 °C. The reaction mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (50 ml) and extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 35% - 75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Isopropylnaphthalene-l- carbonitrile (800 mg, 4.10 mmol, 88% yield) was obtained as a yellow oil. M + H ⁺ = 196.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.10 (d, J = 8.4 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.52 (dt, J= 1.1, 7.6 Hz, 1H), 7.46 - 7.33 (m, 2H), 3.55 (td, J= 6.8, 13.6 Hz, 1H), 1.27 (d, J= 6.8 Hz, 6H).

Step 4: l-(2-Isopropylnaphthalen-l-yl) cyclopropanamine (305A-5)

A mixture of 2-isopropylnaphthalene-l -carbonitrile (200 mg, 1.02 mmol, 1.0 eq) in anhydrous Et20 (30 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (320 mg, 1.13 mmol, 332 pL, 1.1 eq) slowly, and then EtMgBr (3 M, 751 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was completed, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF ₃ .Et2O (290 mg, 2.05 mmol, 252 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (50 mL) and MTBE (30 mL) and extracted with MTBE (30 mL x 2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (10 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 45% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO ₃ , mobile phase B: acetonitrile). l-(2- Isopropyl-1 -naphthyl) cyclopropanamine (50.0 mg, 222 pmol, 10% yield) was obtained as a yellow solid. M + H ⁺ = 226.2 (LCMS).

Step 5: \-( 1 -(2- Isopropy lnapht lialen- 1 -y l ) cyclopropyl)-2-methyl-5-((l-methylazetidin- 2-yl) methoxy) benzamide (Compound 457)

To a mixture of l-(2-isopropyl-l-naphthyl)cyclopropanamine (45.0 mg, 200 pmol, 1.0 eq) and 2-methyl-5-[(l-methylazetidin-2-yl)methoxy]benzoic acid (47.0 mg, 200 pmol, 1.0 eq) in DMF (1.0 mL) were added HATU (114 mg, 299 pmol, 1.5 eq) and DIEA (77.4 mg, 599 pmol, 104 pL, 3.0 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Phenomenex Luna C18 (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 7V-(l-(2- isopropylnaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-methyla zetidin-2- yl)methoxy)benzamide (16.5 mg, 36.1 pmol, 18% yield, HC1 salt) as a brown solid. M + H ⁺ = 443.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.38 (br s, 1H), 8.02 (d, J= 8.0 Hz, 1H), 7.87 (dd, J= 8.4, 16.0 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.53 - 7.42 (m, 2H), 7.17 (d, J= 8.3 Hz, 1H), 7.03 - 6.92 (m, 2H), 6.84 (q, J= 7.2 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.41 - 4.30 (m, 1H), 4.28 - 4.16 (m, 2H), 3.99 (d, J= 10.0 Hz, 1H), 3.52 - 3.43 (m, 1H), 2.98 (s, 3H), 2.65 - 2.52 (m, 2H), 2.34 (s, 3H), 1.44 - 1.30 (m, 10H).

Example 306: 5-(2-Aminopropoxy)-/V-(l-(3-methoxynaphthalen-l-yl)cycloprop yl)-2- methylbenzamide (Compound 445)

Compound 445 Step 1: Methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (306A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (1.05 g, 6.02 mmol, 1.0 eq) in toluene (20 mL) was added tert-butyl (l-hydroxypropan-2-yl)carbamate (1.00 g, 6.02 mmol, 1.0 eq), followed by TMAD (3.11 g, 18.1 mmol, 3.0 eq) and PPhi (4.74 g, 18.1 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was allowed to cool room temperature, poured into water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 6/100. Methyl 5-(2-((tert- butoxycarbonyl)amino)propoxy)-2-methylbenzoate (500 mg, 1.39 mmol, 23% yield) was obtained as a white solid. M - 100 + H ⁺ = 224.1 (LCMS).

Step 2: 5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (306A-2)

To a solution of methyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (618 mg, 1.91 mmol, 1.0 eq) in a mixture of THF (5.0 mL), MeOH (3.5 mL) and H2O (2.5 mL) was added LiOH.EEO (246 mg, 5.73 mmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex luna Cl 8 column (250 x 50 mm, 10 pm); flow rate: 60 mL/min; gradient: 40% - 80% B over 10 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-((tert-

Butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (98.0 mg, 317 pmol, 17% yield, TFA salt) was obtained as a white solid. M - 100 + H ⁺ = 210.2 (LCMS).

Step 3: tert-Butyl (l-(3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)propan-2-yl)carbamate (306A-3)

To a solution of 1 -(3 -methoxynaphthal en-l-yl)cyclopropanamine (20.0 mg, 93.8 pmol, 1.0 eq, TFA salt) in DMF (2.0 mL) was added 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2- methylbenzoic acid (34.8 mg, 113 pmol, 1.2 eq), followed by HBTU (107 mg, 218 mmol, 3.0 eq) and DIEA (121 mg, 938 mmol, 163 pL, 10 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product tert-butyl ( 1 -(3 -((1 -(3 -methoxynaphthal en- 1 -yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (47.0 mg) as a yellow oil. M - 56 + H ⁺ = 449.2 (LCMS).

Step 4: 5-(2-Aminopropoxy)-/V-(l-(3-methoxynaphthalen-l-yl)cycloprop yl)-2- methylbenzamide (Compound 445)

To a solution of tert-butyl (l-(3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)propan-2-yl)carbamate (47.0 mg, 93.1 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (775 mg, 6.80 mmol, 503 pL, 73 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-Aminopropoxy)-7V-(l-(3-methoxynaphthalen-l-yl)cycloprop yl)-2- methylbenzamide (33.4 mg, 64.4 mmol, 41% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 405.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 ppm 9.10 (s, 1H), 8.53 (d, = 8.41 Hz, 1H), 7.94 (br s, 2H), 7.83 (d, J= 8.16 Hz, 1H), 7.50 - 7.36 (m, 3H), 7.24 (d, J= 2.26 Hz, 1H), 7.08 (d, J = 8.41 Hz, 1H), 6.90 (br d, J= 2.51 Hz, 1H), 6.67 (d, J = 2.51 Hz, 1H), 4.02 (dd, J= 10.23, 3.70 Hz, 1H), 3.87 (s, 3H), 3.86 - 3.81 (m, 1H), 3.54 (br d, J= 1.25 Hz, 1H), 1.98 (s, 3H), 1.32 (br s, 2H), 1.22 (d, J= 6.65 Hz, 3H), 1.17 (br s, 2H).

Example 307 : 5-(((2»S,41?)-4-Fluoropyrrolidin-2-yl)methoxy)-/V-(l-(3-met hoxy naphthalen-l-yl)cyclopropyl)-2-methylbenzamide (Compound 490)

7A-1 307A-1

Compound 490

Step 1 : (25,41?)-tert-Butyl4-fluoro-2-((3-(methoxycarbonyl)-4-methyl phenoxy)methyl)p yrrolidine-l-carboxylate (307A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (1.17 g, 7.02 mmol, 1.1 eq) and (25,4/?)- /c/V-butyl 4-fluoro-2-(hydroxymethyl)pyrrolidine-l -carboxylate (1.40 g, 6.39 mmol, 1.0 eq) in toluene (14 mL) were added TMAD (3.30 g, 19.2 mmol, 3.0 eq) and PPhi (5.02 g, 19.2 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times and then was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. (25,4/?)-/c/7-Butyl 4-fluoro-2-((3-

(methoxycarbonyl)-4-methylphenoxy)methyl)pyrrolidine-l -carboxylate (1.20 g, 3.27 mmol, 51% yield) was obtained as a yellow oil. M + H ⁺ = 368.1 (LCMS); ¹ HNMR (400 MHz, DMSO- d ₆ ) 8 7.34 (d, J = 2.9 Hz, 1H), 7.23 (br d, J = 8.4 Hz, 1H), 7.09 (dd, J = 2.3, 8.3 Hz, 1H), 5.41 - 5.18 (m, 1H), 4.22 - 4.09 (m, 3H), 3.83 - 3.62 (m, 4H), 3.32 (s, 2H), 2.42 (s, 3H), 1.38 (s, 9H), 1.24 - 1.14 (m, 1H). Step 2: 5-(((25,41?)-l-(tert-Butoxycarbonyl)-4-fluoropyrrolidin-2-yl )methoxy)-2-methyl benzoic acid (307A-2)

To a solution of (2,S',4/?)-/c77-butyl 4-fluoro-2-((3-(methoxycarbonyl)-4- methylphenoxy)methyl)pyrrolidine-l -carboxylate (1.20 g, 3.27 mmol, 1.0 eq) in a mixture of THF (15 mL) and MeOH (5.0 mL) was added NaOH (2 M in aqueous, 2.0 mL, 1.2 eq). The mixture was stirred at 70 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with MTBE (5 mL x 3). The aqueous was basified to pH 5 by using HC1 (1 M, aqueous). The product was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude 5-(((25,47?)-l-(terLbutoxycarbonyl)-4- fhioropyrrolidin-2-yl)methoxy)-2-methylbenzoic acid (1.10 g, 3.11 mmol, 95% yield) as a yellow oil. M - 100 + H ⁺ = 254.1 (LCMS).

Step 3: (2.S.4/?)-/c/7-Butyl 4-fluoro-2-((3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)pyrrolidine-l- carboxylate (307A-3)

To a solution of 5-(((2,S',4/?)- l -(/c77-butoxycarbonyl)-4-tluoropyrrolidin-2-yl)methoxy)-2- methylbenzoic acid (200 mg, 565 pmol, 1.0 eq) and 1 -(3 -methoxynaphthal en-1- yl)cyclopropanamine (121 mg, 566 pmol, 1.0 eq) in DMF (2.0 mL) were added DIEA (219 mg, 1.70 mmol, 296 pL , 3.0 eq) and HATU (323 mg, 849 pmol , 1.5 eq). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. (2S,4R)-tert- Butyl 4-fluoro-2-((3-((l-(3-methoxynaphthalen-l-yl)cyclopropyl)car bamoyl)-4-methyl phenoxy)methyl)pyrrolidine-l -carboxylate (200 mg, 364 pmol , 64% yield) was obatined as a yellow oil. M + H ⁺ = 549.1 (LCMS).

Step 4: 5-(((2»S,41?)-4-Fluoropyrrolidin-2-yl)methoxy)-/V-(l-(3-met hoxynaphthalen-l-yl) cyclopropyl)-2-methylbenzamide (Compound 490)

To a solution of (2,S',4/?)-/c77-butyl 4-fluoro-2-((3-((l-(3-methoxynaphthalen-l- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)pyrrolidine -l -carboxylate (200 mg, 364 prnol, 1.0 eq) in EtOAc (3.0 mL) was added EtOAc/HCl (4 M, 3.0 mL). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(((25,4A)-4-Fluoropyrrolidin-2-yl)methoxy)-A- (1 -(3 -m ethoxynaphthal en-l-yl)cyclopropyl)-2-methylbenzamide (110 mg, 245 pmol, 67% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 449.1 (LCMS); ¹ H NMR (400 MHz, DMS0- _e ) 8 10.12 - 9.90 (m, 1H), 9.66 - 9.40 (m, 1H), 9.13 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.63 - 7.32 (m, 3H), 7.24 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.89 (dd, J = 2.6, 8.4 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 5.57 - 5.37 (m, 1H), 4.27 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 4.08 - 4.00 (m, 1H), 3.87 (s, 3H), 3.45 (br s, 2H), 2.44 - 2.30 (m, 1H), 2.07 (s, 1H), 1.98 (s, 3H), 1.34 (br s, 2H), 1.16 (br s, 2H).

Example 308: 5-(((2»S,41?)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-/V- (l-(3-methoxy naphthalen-l-yl)cyclopropyl)-2-methylbenzamide (Compound 489)

Compound 489

Step 1: 5-(((2»S,41?)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-/V- (l-(3-methoxy naphthalen-l-yl)cyclopropyl)-2-methylbenzamide (Compound 489)

To a solution of 5-(((2£,47?)-4-fluoropyrrolidin-2-yl)methoxy)-7V-(l-(3-meth oxynaphthalen-l- yl)cyclopropyl)-2-methylbenzamide (60.0 mg, 133 pmol, 1.0 eq) in MeOH (1.0 mL) was added TEA (20.1 pL), followed by formaldehyde (16.3 mg, 200 pmol, 14.5 pL, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBH CN (50.4 mg, 803 pmol, 6.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(((25,4A)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-A-(l- (3 -m ethoxynaphthal en-l-yl)cyclopropyl)-2-methylbenzamide (50.0 mg, 108 pmol, 81% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 463.2 (LCMS) ; ^T H NMR (400 MHz, DMSO- d ₆ ) 8 11.1 - 10.9 (m, 1H), 9.11 (s, 1H), 8.54 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.49 - 7.37 (m, 3H), 7.25 - 7.23 (m, 1H), 7.10 - 7.07 (m, 1H), 6.93 - 6.89 (m, 1H), 6.70 (d, J = 2.5 Hz, 1H), 5.53 - 5.36 (m, 1H), 4.35 - 4.25 (m, 2H), 3.94 (br s, 2H), 3.87 (s, 3H), 3.53 - 3.42 (m, 1H), 2.96 (br s, 3H), 2.46 - 2.19 (m, 1H), 2.07 (s, 1H), 1.96 (s, 3H), 1.33 (br s, 2H), 1.19 - 1.14 (m, 2H).

Example 309: /V-(l-(3-Hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 433)

Compound 433

Step 1 : /V-(l-(3-Hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-y l)methoxy)benzamide (Compound 433)

To a mixture of A-(l-(3-methoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-m ethylazetidin -2-yl)methoxy)benzamide (70.0 mg, 163 pmol, 1.0 eq) in DCM (5.0 mL) was added dropwise the solution of BBr, (326 mg, 1.30 mmol, 125 pL, 8.0 eq) in DCM (500 pL) at -78 °C under a N2 atmosphere. The mixture was stirred at -78 °C for 1 h then stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was diluted with MeOH (3.0 mL) and then acidified to pH 8 by using ammonium hydroxide (25% aqueous). The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). V-( 1 -(3 -Hydroxynaphthal en- 1 -yl)cyclopropyl)-2-methyl-5 -(( 1 -methylazetidin- 2-yl)methoxy)benzamide (5.30 mg, 11.2 pmol, 8% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.52 - 8.48 (m, 1H), 8.46 - 8.41 (m, 1H), 7.67 (br d, J= 7.6 Hz, 1H), 7.51 (d, J= 2.3 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.09 - 7.05 (m, 2H), 6.89 (br dd, J= 2.5, 8.4 Hz, 1H), 6.70 (d, J= 2.3 Hz, 1H), 4.27 - 4.03 (m, 3H), 3.90 - 3.81 (m, 1H), 3.65 - 3.47 (m, 1H), 2.72 (s, 3H), 2.41 - 2.32 (m, 2H), 2.03 (s, 3H), 1.43 - 1.28 (m, 4H).

Example 310: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3- propoxynaphthalen-l-yl)cyclopropyl)benzamide (Compound 474)

Compound 474

Step 1 : 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-propoxy naphthalen-l- yl)cyclopropyl)benzamide (Compound 474)

A mixture of A-(l-(3-hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-m ethylazetidin-2- yl)methoxy)benzamide (100 mg, 240 pmol, 1.0 eq), propan-l-ol (15.9 mg, 264 pmol, 19.8 pL, 1.1 eq) and PPI13 (189 mg, 720 pmol, 3.0 eq) in toluene (5.0 mL) was degassed and purged with N2 three times. To the mixture was added TMAD (124 mg, 720 pmol, 3.0 eq) at 20 °C. The resulting mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (200 x 40 mm, 10 pm); flow rate: 75 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(3-propoxyn aphthalen-l-yl)cyclopropyl) benzamide (14.9 mg, 32.0 pmol, 13% yield, FA salt) was obtained as a white solid. M + H ⁺ = 459.2 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.17 - 8.98 (m, 1H), 8.57 - 8.49 (m, 1H), 8.20 - 8.17 (m, 1H), 7.84 - 7.78 (m, 1H), 7.48 - 7.34 (m, 3H), 7.24 - 7.20 (m, 1H), 7.05 - 6.99 (m, 1H), 6.88 - 6.80 (m, 1H), 6.61 - 6.57 (m, 1H), 4.06 - 4.00 (m, 2H), 3.89 - 3.84 (m, 2H), 3.30 - 3.24 (m, 2H), 2.81 - 2.70 (m, 1H), 2.25 - 2.21 (m, 3H), 2.00 - 1.77 (m, 7H), 1.36 - 1.30 (m, 2H), 1.19 - 1.13 (m, 2H), 1.07 - 1.00 (m, 3H).

Example 311: /V-(l-(3-Bromonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 461)

Compound 461 Step 1: 3-Bromo-l-naphthamide (311A-2)

To a solution of 3 -bromo- 1 -naphthoic acid (3.00 g, 12.0 mmol, 1.0 eq) in THF (30 mL) was added CDI (2.90 g, 17.9 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 1.5 h. Then NH3.H2O (9.10 g, 64.9 mmol, 10.0 mL, 25% purity, 5.4 eq) was added to the mixture, the resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue. The residue was triturated in H2O (15 mL) at 20 °C for 15 min. The mixture was filtered and the filter cake was washed subsequently by H2O (8.0 mL x 2) and HC1 (I M aqueous) (10 mL x 1). The filter cake was then concentrated under vacuum to give a crude product 3 -bromo- 1 -naphthamide (2.92 g) as a white solid. M + H ⁺ = 250.1 (LCMS).

Step 2: 3-Bromo-l-naphthonitrile (311A-3)

To a solution of 3 -bromo- 1 -naphthamide (240 mg, 960 pmol, 1.0 eq) in DMF (5.0 mL) were added TEA (400 mg, 3.95 mmol, 550 pL, 4.1 eq) and TFAA (410 mg, 1.95 mmol, 271 pL, 2.0 eq) at 0 °C. The mixture was stirred at 20 °C for 6 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 8/100 to give 3 -bromo- 1 -naphthonitrile (188 mg, 810 pmol, 84% yield) as a white solid. 'H NMR (400 MHz, CDCh) 8 8.38 - 8.14 (m, 2H), 8.07 - 7.94 (m, 1H), 7.93 - 7.81 (m, 1H), 7.79 - 7.60 (m, 2H).

Step 3: l-(3-Bomonaphthalen-l-yl)cyclopropanamine (311A-4)

A mixture of 3 -bromo- 1 -naphthonitrile (180 mg, 776 mmol, 1.0 eq) in anhydrous Et2O (10 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (331 mg, 1.16 mmol, 343 pL, 1.5 eq) slowly, and then EtMgBr (3 M, 595 pL, 2.3 eq) was added dropwise to maintain the temperature between -78 °C and - 75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (220 mg, 1.55 mmol, 191 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and desired mass was detected. The reaction mixture was poured into HC1 (I M aqueous) (7.0 mL), and the mixture was extracted with EtOAc (5.0 mL x 3). The organic phase was discarded. The aqueous layer was basified to pH 8 by using saturated Na2CC>3 aqueous solution and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with EtOAc several times. The combined filtrate was extracted with EtOAc (8.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product l-(3-bomonaphthalen-l- yl)cyclopropanamine (80.0 mg) as a yellow oil. M + H ⁺ = 262.4 (LCMS).

Step 4: /V-(l-(3-Bromonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-me thylazetidin-2- yl)methoxy)benzamide (Compound 461)

To a solution of l-(3-bromonaphthalen-l-yl)cyclopropanamine (111 mg, 425 pmol, 1.0 eq) in DMF (2.0 mL) was added 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (100 mg, 425 pmol, 1.0 eq), followed by HBTU (322 mg, 850 pmol, 2.0 eq) and DIEA (164 mg, 1.28 mmol, 222 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that 8% starting material remained and 37% desired compound was detected. The mixture was filtered and the filtrate was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give A-(l -(3 -bromonaphthal en-l-yl)cy cl opropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (95.0 mg, 156 pmol, 38% yield, TFA salt) as a yellow solid. M + H ⁺ = 479.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 ppm 13.35 - 12.45 (m, 1H), 8.67 - 8.43 (m, 1H), 8.11 - 8.02 (m, 1H), 8.00 - 7.92 (m, 1H), 7.83 - 7.75 (m, 1H), 7.61 - 7.48 (m, 2H), 7.40 (br s, 1H), 7.09 - 6.90 (m, 1H), 6.81 - 6.53 (m, 2H), 4.36 - 4.31 (m, 2H), 4.27 - 4.08 (m, 1H), 3.97 - 3.83 (m, 1H), 3.75 - 3.57 (m, 1H), 2.94 - 2.71 (m, 3H), 2.63 - 2.38 (m, 2H), 2.15 (s, 3H), 1.63 - 1.51 (m, 2H), 1.45 - 1.29 (m, 2H).

Example 312: (5)-5-(2-Aminopropoxy)-/V-(l-(3-bromonaphthalen-l-yl)cyclopr opyl)-2- methylbenzamide (Compound 541)

Step 2 Step 3

312A-2

Compound 541

Step 1: (S)-M ethyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (312A- 1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (10.5 g, 60.2 mmol, 1.0 eq) in toluene (200 mL) was added (S)-/ert-butyl (l-hydroxypropan-2-yl)carbamate (1.00 g, 6.02 mmol, 1.0 eq), followed by TMAD (31.1 g, 180 mmol, 3.0 eq) and PPhi (47.4 g, 181 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was allowed to cool to room temperature, poured into water (30 mL), and then extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. fS')-Methyl 5-(2-((lerl- butoxycarbonyl)amino)propoxy)-2-methylbenzoate (4.30 g, 12.5 mmol, 21% yield) was obtained as a white solid. M - 100 + H ⁺ = 224.1 (LCMS).

Step 2: (5)-5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzoi c acid (312A-2)

To a solution of fS')-m ethyl 5-(2-((/c/7-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (3.50 g, 10.8 mmol, 1.0 eq) in a mixture of THF (16 mL), MeOH (12 mL) and H2O (8.0 mL) was added LiOH.LEO (1.36 g, 32.5 mmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The organic phase was discarded. The aqueous layer was acidified to pH 6 by using HC1 (1 M aqueous) and then extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product CS')-5-(2-((/c77-butoxycarbonyl)amino)propoxy)-2-methylbenzo ic acid (3.10 g) as a white solid. M - 100 + H ⁺ = 210.2 (LCMS).

Step 3: (S)-/c/7-Butyl (l-(3-((l-(3-bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (312A-3)

To a solution of l-(3-bromonaphthalen-l-yl)cyclopropanamine (150 mg, 572 pmol, 1.0 eq) in DMF (2.0 mL) was added CS')-5-(2-((/c77-butoxycarbonyl)amino)propoxy)-2-methylbenzo ic acid (212 mg, 686 pmol, 1.2 eq), followed by HBTU (434 mg, 1.14 mmol, 2.0 eq) and DIEA (221 mg, 1.72 mmol, 299 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 13/100. fS')-/c/7-Butyl (1 -(3 -((1 -(3 -bromonaphthal en- 1 -yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (420 mg, 759 pmol, 79% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 497.1 (LCMS).

Step 4: (S)-5-(2-Aminopropoxy)-N-(l-(3-bromonaphthalen-l-yl)cyclopro pyl)-2- methylbenzamide (Compound 541)

To a solution of HCl/EtOAc (4 M, 4.0 mL) was added (b')-/c77-butyl (l-(3-((l-(3- bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4-methylphenoxy) propan-2-yl)carbamate (360 mg, 650 pmol, 1.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). S)- 5-(2-Aminopropoxy)-7V-(l-(3-bromonaphthalen-l-yl)cyclopropyl )-2-methylbenzamide (161 mg, 328 pmol, HC1 salt) was obtained as a white solid. M + H ⁺ = 453.1 (LCMS); ^T H NMR (400 MHz, DMSO ) 6 9.21 (s, 1H), 8.68 - 8.59 (m, 1H), 8.15 (s, 1H), 8.09 (br s, 2H), 7.94 (d, J= 7.89 Hz, 1H), 7.88 (d, J= 1.97 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.08 (d, J= 8.33 Hz, 1H), 6.89 (dd, J= 8.33, 2.63 Hz, 1H), 6.68 (d, J= 2.63 Hz, 1H), 4.03 (dd, J= 10.41, 3.84 Hz, 1H), 3.88 (dd, J= 10.19, 6.91 Hz, 1H), 3.58 - 3.45 (m, 1H), 1.96 (s, 3H), 1.35 (br s, 2H), 1.23 (d, J = 6.58 Hz, 5H). Example 313: /V-(l-(3-Cyanonaphthalen-l-yl)cyclopropyl)-5-(2- (dimethylamino)ethoxy)-2-methylbenzamide (Compound 443)

Compound 443

Step 1: /V-(l-(3-Cyanonaphthalen-l-yl)cyclopropyl)-5-(2-(dimethylami no)ethoxy)-2- methylbenzamide (Compound 443)

To a solution of 4-(l-(5-(2-(dimethylamino)ethoxy)-2-methylbenzamido)cyclopro pyl) naphthal en-2-yl trifluoromethanesulfonate (65.0 mg, 121 pmol, 1.0 eq) in DMF (3.0 mL) were added Zn(CN)2 (28.5 mg, 242 pmol, 15.4 pL, 2.0 eq), BrettPhos (11.0 mg, 12.1 pmol, 0.10 eq) and BrettPhos Pd G3 (13.0 mg, 24.2 pmol, 0.20 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). A-(l-(3-Cyanonaphthalen-l-yl)cyclopropyl)-5-(2-(dimethylamin o)ethoxy)-2- methylbenzamide (8.50 mg, 20.6 pmol, 17% yield) was obtained as a white solid. M + H ⁺ = 414.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.19 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.98 (d, J= 1.5 Hz, 1H), 7.85 - 7.76 (m, 1H), 7.73 - 7.65 (m, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.94 (t, J= 5.8 Hz, 2H), 2.55 (t, J= 5.8 Hz, 2H), 2.17 (s, 6H), 1.93 (s, 3H), 1.37 (br s, 2H), 1.26 (br s, 2H).

Example 314: /V-(l-(3-Cyanonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 484)

Compound 484

Step 1: /V-(l-(3-Cyanonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-me thylazetidin-2- yl)methoxy)benzamide (Compound 484)

To a solution of 4-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (100 mg, 182 pmol, 1.0 eq) in DMF (4.0 mL) were added ZnCN2 (64.2 mg, 547 pmol, 34.7 pL, 3.0 eq), BrettPhos (19.6 mg, 36.5 pmol, 0.2 eq) and BrettPhos Pd G3 (16.5 mg, 18.2 pmol, 0.1 eq) under a N2 atmosphere. The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). A-(l-(3-Cyanonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-2- yl)methoxy)benzamide (20.5 mg, 42.9 pmol, 24% yield, FA salt) was obtained as a white solid. M + H ⁺ = 426.1 (LCMS); 'H NMR (400 MHz, DMSO )) 6 9.19 (s, 1H), 8.73 (d, J= 8.5 Hz, 1H), 8.53 (s, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.99 (d, J= 1.4 Hz, 1H), 7.88 - 7.75 (m, 1H), 7.74 - 7.60 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.87 (dd, J= 2.6, 8.3 Hz, 1H), 6.65 (d, J= 2.5 Hz, 1H), 3.99 (br d, J= 5.3 Hz, 2H), 3.68 (br s, 2H), 3.10 (br s, 1H), 2.42 (s, 3H), 2.01 (s, 2H), 1.94 (s, 3H), 1.38 (br s, 2H), 1.28 (br s, 2H).

Example 315: tert-Butyl (4-(l-(2-methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (Compound 482)

Compound 482

Step 1: tert-Butyl (4-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido) cyclopropyl)naphthalen-2-yl)carbamate (Compound 482)

To a solution of V-(1 -(3 -bromonaphthal en-l-yl)cy cl opropyl)-2-methyl-5 -((1-methylazeti din- 2-yl)methoxy)benzamide (100 mg, 209 pmol, 1.0 eq) and tert-butyl carbamate (29.3 mg, 250 pmol, 1.2 eq) in Z-AmylOH (1.0 mL) were added Xphos Pd G3 (35.3 mg, 41.7 pmol, 0.2 eq) and CS2CO3 (272 mg, 834 pmol, 4.0 eq). The mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). tert-Butyl (4-(l-(2-methyl-5-((l-methylazetidin- 2-yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl)carbamate (13.0 mg, 20.7 pmol, 10% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 516.3 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 8 9.20 (s, 1H), 8.51 - 8.42 (m, 1H), 7.99 (br s, 1H), 7.83 - 7.74 (m, 2H), 7.48 - 7.38 (m, 2H), 7.10 (d, J= 8.50 Hz, 1H), 6.93 (dd, J= 8.38, 2.75 Hz, 1H), 6.71 (d, J= 2.75 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.29 - 4.21 (m, 1H), 4.20 - 4.10 (m, 2H), 3.94 (q, 9.55 Hz, 1H), 2.92

(s, 3H), 2.60 - 2.47 (m, 2H), 2.04 (s, 3H), 1.56 (s, 9H), 1.46 - 1.40 (m, 2H), 1.36 - 1.28 (m, 2H). Example 316: /V-(l-(3-Aminonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 496)

Compound 496

Step 1: /V-(l-(3-Aminonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-me thylazetidin-2-yl) methoxy)benzamide (Compound 496)

To a solution of tert-butyl (4-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy) benzamido)cyclopropyl)naphthalen-2-yl)carbamate (170 mg, 330 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 7V-(l-(3- aminonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-methylazeti din-2-yl)methoxy) benzamide (36.8 mg, 68.9 pmol, 21% yield, TFA salt) as a pale yellow solid. M + H ⁺ = 416.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.38 - 9.28 (m, 1H), 8.61 - 8.54 (m, 1H), 7.95 - 7.90 (m, 1H), 7.80 (d, J= 2.3 Hz, 1H), 7.73 - 7.66 (m, 1H), 7.65 - 7.56 (m, 2H), 7.10 (d, J= 8.5 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.76 (d, J= 2.6 Hz, 1H), 4.73 - 4.62 (m, 1H), 4.30 - 4.14 (m, 3H), 4.02 - 3.89 (m, 1H), 3.00 - 2.90 (m, 3H), 2.60 - 2.50 (m, 2H), 1.99 - 1.96 (m, 3H), 1.51 - 1.46 (m, 2H), 1.37 - 1.32 (m, 2H). Example 317: /V-(l-(3-(Dimethylamino)naphthalen-l-yl)cyclopropyl)-2-methy l-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 495)

Compound 495

Step 1: /V-(l-(3-(Dimethylamino)naphthalen-l-yl)cyclopropyl)-2-methy l-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 495)

To a solution of V-(1 -(3 -aminonaphthal en-l-yl)cy cl opropyl)-2-methyl-5 -((1-methylazeti din- 2-yl)methoxy)benzamide (60.0 mg, 144 pmol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (20 pL), followed by formaldehyde (25.8 mg, 318 pmol, 23.6 pL, 37% purity in water, 2.2 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (22.7 mg, 361 pmol, 2.5 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). A-(l-(3-(Dimethylamino)naphthalen-l- yl)cyclopropyl)-2-methyl-5-((l -methyl azetidin-2-yl)methoxy)benzamide (23.1 mg, 41.1 pmol, 28% yield, TFA salt) was obtained as a yellow gum. M + H ⁺ = 444.2 (LCMS); ¹ H NMR (400 MHz, CD ₃ OD) 69.33 - 9.23 (m, 1H), 8.50 (br d, J= 7.8 Hz, 1H), 7.93 - 7.82 (m, 2H), 7.61 - 7.41 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 7.01 - 6.90 (m, 1H), 6.74 (d, J = 2.6 Hz, 1H), 4.75 - 4.60 (m, 1H), 4.30 - 4.24 (m, 1H), 4.24 - 4.11 (m, 2H), 4.00 - 3.91 (m, 1H), 3.26 - 3.24 (m, 6H), 3.03 - 2.88 (m, 3H), 2.59 - 2.50 (m, 2H), 2.02 - 1.98 (m, 3H), 1.51 - 1.44 (m, 2H), 1.39 - 1.32 (m, 2H). Example 318: 4-(l-(2-Methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl)-2-naphthamide (Compound 520)

Compound 520

Step 1: 4-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl)-2- naphthamide (Compound 520)

To a solution of A-(l-(3-cyanonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-2- yl)methoxy)benzamide (30.0 mg, 70.5 pmol, 1.0 eq) in a mixture of DMSO (0.3 mL) and EtOH (0.9 mL) were added H2O2 (35.9 mg, 212 pmol, 30.5 pL, 20% purity in H2O, 3.0 eq) and NaOH (8.46 mg, 212 pmol, 3.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (1.0 mL) and extracted with EtOAc (0.5 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 45% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 4-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido) cyclopropyl)-2-naphthamide (6.30 mg, 13.8 pmol, 20% yield, FA salt) was obtained as a white solid. M + H ⁺ = 444.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e)) 8 9.13 (s, 1H), 8.68 (d, J = 8.1 Hz, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 8.19 - 8.08 (m, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.78 - 7.62 (m, 1H), 7.59 (br d, J= 7.1 Hz, 1H), 7.48 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.95 - 6.82 (m, 1H), 6.68 (d, J= 1.7 Hz, 1H), 4.25 - 4.05 (m, 2H), 3.92 - 3.70 (m, 1H), 2.72 - 2.62 (m, 2H), 2.49 - 2.40 (m, 3H), 2.31 - 2.08 (m, 2H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.26 (br s, 2H). Example 319: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-(thioph en-2- yl)naphthalen-l-yl)cyclopropyl)benzamide (Compound 481)

Compound 481

Step 1: tert- Butyl (l-(4-methyl-3-((l-(3-methylnaphthalen-l-yl)cyclopropyl)carb amoyl) phenoxy)propan-2-yl)carbamate (319 A- 1)

To a solution of tert-butyl (l-(3-((l-(3-bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (80.0 mg, 145 pmol, 1.0 eq) in DMF (2.0 mL) were added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (272 mg, 1.08 mmol, 303 pL, 50% purity, 7.5 eq), Pd(dppf)C12.CH2C12 (11.8 mg, 14.5 pmol, 0.1 eq) and CS2CO3 (155 mg, 477 pmol, 3.3 eq). The mixture was stirred at 110 °C for 3 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.5). tert- Butyl (l-(4-methyl-3-((l-(3-methylnaphthalen-l-yl)cyclopropyl)carb amoyl)phenoxy)propan- 2-yl)carbamate (90.0 mg, 120 pmol, 82% yield) was obtained as a yellow solid. M + H ⁺ = 289.4 (LCMS). Step 2: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(3-methylnaphthalen-l-yl)c yclopropyl) benzamide (Compound 481)

To a solution of tert-butyl (l-(4-methyl-3-((l -(3 -m ethylnaphthal en-l-yl) cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (90.0 mg, 184 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(2- aminopropoxy)-2-methyl-7V-(l-(3-methylnaphthalen-l-yl)cyclop ropyl)benzamide (20.4 mg, 40.6 pmol, 22% yield, TFA salt) as a yellow solid. M + H ⁺ = 389.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.09 (s, 1H), 8.62 - 8.55 (m, 1H), 7.92 (br s, 2H), 7.79 - 7.86 (m, 1H), 7.66 (d, J= 1.63 Hz, 1H), 7.60 (s, 1H), 7.51 - 7.43 (m, 2H), 7.08 (d, J= 8.50 Hz, 1H), 6.88 (dd, J = 8.32, 2.69 Hz, 1H), 6.66 (d, J= 2.75 Hz, 1H), 4.02 (dd, J= 10.26, 3.75 Hz, 1H), 3.84 (dd, J = 10.32, 7.19 Hz, 1H), 3.59 - 3.45 (m, 1H), 2.47 (s, 3H), 1.99 (s, 3H), 1.33 (br s, 2H), 1.21 (d, J= 6.63 Hz, 3H), 1.17 (br s, 2H).

Example 320: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-methyln aphthalen- l-yl)cyclopropyl)benzamide (Compound 501)

Compound 501

Step 1 : 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-methyln aphthalen-l- yl)cyclopropyl)benzamide (Compound 501)

To a solution of 7V-(1 -(3 -bromonaphthal en-l-yl)cy cl opropyl)-2-methyl-5-((l-methylazetidin- 2-yl)methoxy)benzamide (80.0 mg, 167 pmol, 1.0 eq), 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane (83.8 mg, 334 pmol, 93.3 pL, 50% purity, 2.0 eq) and CS2CO3 (179 mg, 551 pmol, 3.3 eq) in DMF (1.0 mL) was added Pd(dppf)C12.CH2C12 (13.6 mg, 16.7 pmol, 0.1 eq). The mixture was stirred at 110 °C for 1 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-5-((l- methylazetidin-2-yl)methoxy)-A- (1 -(3 -methylnaphthal en-l-yl)cy cl opropyl) benzamide (35.0 mg, 66.1 pmol, 39% yield, TFA salt) was obtained as a pale yellow solid. M + H ⁺ = 415.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.90 (br s, 1H), 9.09 (s, 1H), 8.62 - 8.54 (m, 1H), 7.87 - 7.78 (m, 1H), 7.66 (d, J= 1.50 Hz, 1H), 7.61 (s, 1H), 7.53 - 7.42 (m, 2H), 7.09 (d, J= 8.50 Hz, 1H), 6.90 (dd, J= 8.38, 2.75 Hz, 1H), 6.69 (d, J= 2.63 Hz, 1H), 4.60 (br d, J= 4.38 Hz, 1H), 4.28 - 4.15 (m, 2H), 4.08 - 3.95 (m, 1H), 3.91 - 3.82 (m, 1H), 2.83 (d, J= 4.63 Hz, 3H), 2.47 (s, 3H), 2.42 - 2.25 (m, 2H), 1.99 (s, 3H), 1.33 (br s, 2H), 1.17 (br s, 2H).

Example 321: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-(prop-l -en-2-yl) naphthalen-l-yl)cyclopropyl)benzamide (Compound 508)

Compound 508

Step 1: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-(prop-l -en-2-yl) naphthalen-l-yl)cyclopropyl)benzamide (Compound 508)

To a solution of 4-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (200 mg, 365 pmol, 1.0 eq) and 4,4,5,5-tetramethyl- 2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (129 mg, 766 pmol, 2.1 eq) in a mixture of dioxane (12 mL) and H2O (2.0 mL) were added Pd(dppf)C12.CH2C12 (29.8 mg, 36.5 pmol, 0.1 eq) and ISfeCCh (88.9 mg, 839 pmol, 2.3 eq). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-((l -methylazeti din-2 -yl)methoxy)-A-(l -(3-(prop-l-en-2-yl) naphthal en-l-yl)cy cl opropyl) benzamide (18.4 mg, 40.9 pmol, 11% yield, HC1 salt) was obtained as a yellow oil. M + H ⁺ = 441.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.24 - 10.11 (m, 1H), 9.11 (s, 1H), 8.62 (d, J= 7.6 Hz, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.99 - 7.93 (m, 1H), 7.89 (s, 1H), 7.58 - 7.48 (m, 2H), 7.09 (d, J= 8.5 Hz, 1H), 6.90 (dd, J= 2.5, 8.1 Hz, 1H), 6.69 (d, J= 2.4 Hz, 1H), 5.62 (s, 1H), 5.25 (s, 1H), 4.66 - 4.55 (m, 1H), 4.31 - 4.18 (m, 2H), 4.05 - 3.79 (m, 2H), 2.86 - 2.65 (m, 3H), 2.39 - 2.22 (m, 5H), 1.99 (s, 3H), 1.37 (br s, 2H), 1.23 (br s, 2H).

Example 322: /V-(l-(3-Isopropylnaphthalen-l-yl)cyclopropyl)-2-methyl-5-(( l-methyl azetidin-2-yl)methoxy)benzamide (Compound 521)

Compound 508 Compound 521

Step 1 : /V-(l-(3-Isopropylnaphthalen-l-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 521)

To a solution of 2-methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(3-(prop-l -en-2- yl)naphthalen-l-yl)cyclopropyl)benzamide (90.0 mg, 204 pmol, 1.0 eq) in EtOAc (7.0 mL) was added 10% palladium on carbon (90.0 mg). The suspension was degassed and purged with H2 several times. The mixture was stirred at 20 °C for 2 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(3- Isopropylnaphthal en-l-yl)cy cl opropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy) benzamide (18.0 mg, 37.0 pmol, 18% yield, HC1 salt) was obtained as a red solid. M + H ⁺ = 443.2 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 10.13 - 10.01 (m, 1H), 9.06 (s, 1H), 8.60 (br d, J= 6.6 Hz, 1H), 7.87 (br d, J= 8.6 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.52 - 7.44 (m, 2H), 7.09 (br d, J= 8.8 Hz, 1H), 6.90 (br dd, J= 1.4, 7.9 Hz, 1H), 6.69 (br s, 1H), 4.59 (br dd, J= 3.0, 7.8 Hz, 1H), 4.29 - 4.17 (m, 2H), 4.06 - 3.94 (m, 1H), 3.90 - 3.77 (m, 1H), 3.08 - 3.01 (m, 1H), 2.81 (br s, 3H), 2.37 - 2.32 (m, 2H), 2.00 (s, 3H), 1.35 (br s, 2H), 1.31 (br d, J= 6.8 Hz, 6H), 1.19 (br s, 2H).

Example 323: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylsulfinyl)naphthal en-l-yl) cyclopropyl)-2-methylbenzamide (Compound 423)

Compound 423

Step 1: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylsulfinyl)naphthal en-l-yl) cyclopropyl) -2-methylbenzamide (Compound 423)

To a solution of 5-(2-(dimethyllamino)ethoxy)-A-(l-(3-(ethylthio)naphthalen-l -yl)cyclo propyl)-2-methylbenzamide (60.0 mg, 134 pmol, 1.0 eq) in MeOH (300 pL) were added NalCh (28.6 mg, 134 pmol, 1.0 eq) and H2O (1.5 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with saturated aqueous NaHSO, (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 12% - 42% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2- (Di methyl ami no)ethoxy)-/f-( 1 -(3 -(ethylsulfinyl)naphthalen- 1 -yl)cyclopropyl)-2-methyl benzamide (20.2 mg, 39.3 pmol, 29% yield, FA salt) was obtained as a white solid. M + H ⁺ = 465.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.57 - 8.51 (m, 1H), 8.45 - 8.40 (m, 1H), 8.24 - 8.20 (m, 1H), 8.03 - 7.95 (m, 2H), 7.71 - 7.57 (m, 2H), 7.03 - 6.97 (m, 1H), 6.83 - 6.70 (m, 3H), 4.16 - 4.04 (m, 2H), 3.14 - 3.00 (m, 1H), 2.97 - 2.81 (m, 3H), 2.48 (s, 6H), 2.08 (s, 3H), 1.64 - 1.52 (m, 2H), 1.49 - 1.34 (m, 2H), 1.30 - 1.18 (m, 3H).

Example 324: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylsulfonyl)naphthal en-l-yl) cyclopropyl)-2-methylbenzamide (Compound 471)

Compound 471

Step 1: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylthio)naphthalen-l -yl)cyclopropyl)-2- methylbenzamide hydrochloride (324A-1)

To a solution of 5-(2-(dimethylamino)ethoxy)-7V-(l-(3-(ethylthio)naphthalene- l-yl)cyclopro pyl)-2-methylbenzamide (75.0 mg, 167 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 6.0 mL). The mixture was stirred at 20 °C for 30 min. TLC indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give the crude product 5-(2-(dimethylamino)ethoxy)-7V-(l-(3-(ethylthio)naphthalen-l - yl)cyclopropyl)-2-methylben zamide hydrochloride (80.0 mg, HC1 salt) as a white solid, which was used in the next step without any further purification. Step 2: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-(ethylsulfonyl)naphthal en-l-yl) cyclopro pyl)-2-methylbenzamide (Compound 471)

To a solution of 5-(2-(dimethylamino)ethoxy)-A-(l-(3-(ethylthio)naphthalen-l- yl)cyclopro pyl)-2-methylbenzamide hydrochloride (80.0 mg, 165 pmol, 1.0 eq, HC1 salt) in DCM (2.0 mL) was added m-CPBA (83.7 mg, 412 pmol, 85% purity, 2.5 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with saturated aqueous NaHSCL (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 5-(2-(Dimethylamino)ethoxy)-A-(l-(3-(ethylsulfonyl)naphthale n-l-yl)cyclo propyl)-2-methyl benzamide (4.30 mg, 8.55 pmol, 5% yield, FA salt) was obtined as a white solid. M + H ⁺ = 481.1 (LCMS); ^X H NMR (400 MHz, CDCh) 5 8.77 - 8.61 (m, 1H), 8.47 - 8.43 (m, 1H), 8.36 - 8.30 (m, 2H), 8.08 - 8.02 (m, 1H), 7.82 - 7.74 (m, 1H), 7.71 - 7.62 (m, 1H), 7.11 - 6.94 (m, 2H), 6.84 - 6.56 (m, 2H), 4.33 - 4.18 (m, 2H), 3.30 - 3.22 (m, 2H), 3.20 - 3.12 (m, 2H), 2.75 -2.61 (m, 6H), 2.19 - 2.03 (m, 3H), 1.64 - 1.56 (m, 2H), 1.48 - 1.41 (m, 2H), 1.37 - 1.31 (m, 3H).

Example 325: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(3-(thiophen-2-yl)n aphthalen- l-yl)cyclopropyl)benzamide (Compound 486)

325A-2

Compound 486

Step 1: tert-Butyl (2-(3-((l-(3-bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4-m ethyl phenoxy)ethyl)(methyl)carbamate (325A-1)

To a solution of 5-(2-((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (236 mg, 763 pmol, 1.0 eq) in DMF (15 mL) were added l-(3-bromonaphthalen-l-yl)cyclo propanamine (200 mg, 763 pmol, 1.0 eq), EDCI (219 mg, 1.14 mmol, 1.5 eq), HOBt (155 mg, 1.14 mmol, 1.5 eq) and TEA (154 mg, 153 mmol, 212 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (10 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. tert-Butyl (2- (3-((l-(3-bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4-meth ylphenoxy)ethyl)(methyl) carbamate (340 mg, 614 pmol, 81% yield) was obtained as a white solid. M + H ⁺ = 553.1 (LCMS).

Step 2: tert-Butyl methyl(2-(4-methyl-3-((l-(3-(thiophen-2-yl)naphthalen-l-yl)c yclo propyl)carbamoyl)phenoxy)ethyl)carbamate (325A-2)

To a solution of tert-butyl (2-(3-((l -(3 -bromonaphthal en-l-yl)cy cl opropyl)carbamoyl)-4- methyl phenoxy)ethyl)(methyl) carbamate (200 mg, 361 pmol, 1.0 eq) in DMSO (10 mL) were added thiophen-2-ylboronic acid (55.5 mg, 434 pmol, 1.2 eq), Pd(OAc)2 (8.11 mg, 36.1 pmol, 0.1 eq), KOAc (106 mg, 1.08 mmol, 3.0 eq) and CataCXium A (25.9 mg, 72.3 pmol, 0.2 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (6.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.4). tert-Butyl methyl(2-(4-methyl-3-((l-(3-(thiophen-2-yl)naphthalen-l- yl)cyclopropyl) carbamoyl)phenoxy)ethyl)carbamate (74.0 mg, 133 pmol, 37% yield) was obtained as a white solid. M + H ⁺ = 557.3 (LCMS).

Step 3: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(3-(thiophen-2-yl)n aphthalen-l-yl) cyclopropyl)benzamide (Compound 486)

To a solution of tert-butyl methyl(2-(4-methyl-3-((l -(3 -(thi ophen-2 -yl)naphthalen-l-yl)cyclo propyl)carbamoyl)phenoxy)ethyl)carbamate (74.0 mg, 133 pmol, 1.0 eq) in EtOAc (1.5 mL) was added HCl/EtOAc (4 M, 7.4 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-A-(l-(3-(thiophen-2-yl)na phthalen-l- yl)cyclopropyl)benzamide (36.4 mg, 71.5 pmol, 54% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 457.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.19 (s, 1H), 8.76 - 8.65 (m, 2H), 8.62 (br d, J= 8.9 Hz, 1H), 8.11 (d, = 7.6 Hz, 2H), 8.03 - 7.96 (m, 1H), 7.66 (d, J= 3.1 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.59 - 7.52 (m, 2H), 7.24 - 7.19 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.66 (d, = 2.6 Hz, 1H), 4.13 (t, = 4.8 Hz, 2H), 3.30 - 3.22 (m, 2H), 2.58 (br t, J= 5.1 Hz, 3H), 1.99 (s, 3H), 1.38 (br s, 2H), 1.27 (br s, 2H).

Example 326: (A)-5-(2-Aminopropoxy)-2-methyl-/V-(l-(3-(thiophen-2-yl) naphthalen-1- yl)cyclopropyl)benzamide (Compound 539)

326A-1

Compound 539

Step 1: A -terCButyl(l-(4-methyl-3-((l-(3-(thiophen-2-yl)naphthalen-l- yl) cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (326A-1)

To a solution of 6S -te/7-butyl (l-(3-((l-(3-bromonaphthalen-l-yl)cyclopropyl) carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (350 mg, 632 pmol, 1.0 eq) and thiophen-2-ylboronic acid (121 mg, 948 pmol, 1.5 eq) in DMSO (3.0 mL) were added Pd(OAc)2 (14.2 mg, 63.2 pmol, 0.1 eq), bis(l-adamantyl)-butyl-phosphane (45.3 mg, 126 pmol, 0.2 eq) and KOAc (186 mg, 1.90 mmol, 3.0 eq). The resulting mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. (5)-ter/-Butyl(l-(4-methyl-3-((l-(3-(thiophen-2- yl)naphthalen- l-yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (290 mg, 500 pmol, 79% yield) was obtained as a white solid. M - 56 + H ⁺ = 501.3 (LCMS).

Step 2: A -5-(2-Aminopropoxy)-2-methyl-/V-(l-(3-(thiophen-2-yl)naphtha len-l-yl) cyclopropyl)benzamide (Compound 539)

To a solution of (IS) -tert-butyl (l-(4-methyl-3-((l-(3-(thiophen-2-yl)naphthalen-l-yl) cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (290 mg, 521 pmol, 1.0 eq) in EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-5-(2-Aminopropoxy)-2-methyl-7V-(l-(3-(thiophen-2-yl)naph thalen-l- yl)cyclopropyl)benzamide (161 mg, 327 pmol, 63% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 457.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.18 (s, 1H), 8.66 - 8.60 (m, 1H), 8.13 - 8.06 (m, 4H), 8.03 - 7.98 (m, 1H), 7.67 - 7.65 (m, 1H), 7.62 (dd, J= 1.0, 5.1 Hz, 1H), 7.55 (s, 2H), 7.24 - 7.19 (m, 1H), 7.10 - 7.05 (m, 1H), 6.91 - 6.86 (m, 1H), 6.67 (d, J= 2.8 Hz, 1H), 4.06 - 3.99 (m, 1H), 3.91 - 3.84 (m, 1H), 3.59 - 3.47 (m, 1H), 1.99 (s, 3H), 1.39 (br s, 2H), 1.27 (br s, 2H), 1.23 (d, J= 6.8 Hz, 3H).

Example 327 : 2-Met hyl-5-(( 1 -met hylazet idin-2-yl)met hoxy )- \-( 1 -(3-( t hiophen-2- yl)naphthalen-l-yl)cyclopropyl)benzamide (Compound 468) bis( 1 -adamantyl)-butyl-phosphane DMSO Step 1 327A-1

Step 2 Compound 468

Step 1: l-(3-(Thiophen-2-yl)naphthalen-l-yl)cyclopropanamine (327A-1)

To a solution of 1 -(3 -bromonaphthal en-l-yl)cyclopropanamine (160 mg, 610 pmol, 1.0 eq) and thi ophen-2 -ylboronic acid (93.7 mg, 732 pmol, 1.2 eq) in DMSO (1.5 mL) were added Pd(OAc)2 (13.7 mg, 61.0 pmol, 0.1 eq), bis(l-adamantyl)-butyl-phosphane (43.7 mg, 122 pmol, 0.2 eq) and KOAc (179 mg, 1.83 mmol, 3.0 eq). The mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product l-(3-(thiophen-2- yl)naphthalen-l-yl)cyclopropanamine (402 mg) as a black oil. M + H ⁺ = 266.1 (LCMS).

Step 2: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-(thioph en-2-yl) naphthalen-l-yl)cyclopropyl)benzamide (Compound 468)

To a solution of l-(3-(thiophen-2-yl)naphthalen-l-yl)cyclopropanamine (28.0 mg, 105 pmol, 1.0 eq) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (27.3 mg, 116 pmol, 1.1 eq) in DMF (1.0 mL) were added HBTU (80.0 mg, 211 pmol, 2.0 eq) and DIEA (54.5 mg, 422 pmol, 73.5 pL, 4.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(3-(thiophe n-2- yl)naphthalen-l-yl)cyclopropyl)benzamide (6.40 mg, 10.6 pmol, 10% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 483.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.26 (s, 1H), 8.55 (d, J = 8.00 Hz, 1H), 8.25 (d, J = 1.63 Hz, 1H), 8.05 (s, 1H), 7.97 - 7.88 (m, 1H), 7.62 - 7.58 (m, 1H), 7.55 - 7.51 (m, 1H), 7.43 (d, J= 4.63 Hz, 1H), 7.19 - 7.06 (m, 2H), 6.93 (dd, J= 8.44, 2.56 Hz, 1H), 6.74 (d, J = 2.50 Hz, 1H), 4.71 - 4.59 (m, 1H), 4.32 - 4.22 (m, 1H), 4.21 - 4.08 (m, 2H), 3.99 - 3.87 (m, 1H), 2.92 (s, 3H), 2.59 - 2.47 (m, 2H), 2.05 (s, 3H), 1.53 - 1.45 (m, 2H), 1.41 - 1.33 (m, 2H).

Example 328: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(3-phenylnaphthalen-l- yl)cyclopropyl)benzamide (Compound 470)

328A-2

Compound 470

Step 1: tert-Butyl (l-(3-((l-(3-bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (328A-1)

To a solution of l-(3-bromonaphthalen-l-yl)cyclopropanamine (350 mg, 1.34 mmol, 1.0 eq) in DMF (2.0 mL) was added 5-(2-((/c77-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (454 mg, 1.47 mmol, 1.1 eq), followed by HBTU (1.01 g, 2.67 mmol, 2.0 eq) and DIEA (518 mg, 4.01 mmol, 698 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (8.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product te/7-butyl (l-(3-((l-(3-bromonaphthalen-l- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbam ate (1.64 g) as a yellow oil. M - 56 + H ⁺ = 479.1 (LCMS).

Step 2: tert-Butyl (l-(4-methyl-3-((l-(3-phenylnaphthalen-l-yl)cyclopropyl)carb amoyl) phenoxy)propan-2-yl)carbamate (328A-2)

To a solution of tert-butyl (l-(3-((l-(3-bromonaphthalen-l-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (55.0 mg, 99.4 pmol, 1.0 eq) and phenylboronic acid (18.2 mg, 149 pmol, 1.5 eq) in DMSO (1.0 mL) were added Pd(OAc)2 (2.23 mg, 9.94 pmol, 0.1 eq), bis(l-adamantyl)-butyl-phosphane (7.13 mg, 19.9 pmol, 0.2 eq) and KO Ac (29.3 mg, 298 pmol, 3.0 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that 3% starting material remained and 44% desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product tert-butyl (l-(4-methyl-3-((l- (3-phenylnaphthalen-l-yl)cyclopropyl)carbamoyl)phenoxy)propa n-2-yl)carbamate (110 mg) as a black oil. M - 56 + H ⁺ = 495.2 (LCMS). Step 3: 5-(2-Aminoethoxy)-/V-(l-(3-methoxynaphthalen-l-yl)cyclopropy l)-2-methyl benzamide (Compound 470)

To a solution of tert-butyl (l-(4-methyl-3-((l-(3-phenylnaphthalen-l-yl)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (110 mg, 200 pmol, 1.0 eq) in EtOAc (200 pL) was added HCl/EtOAc (4 M, 500 pL). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(2-aminoethoxy)-7V-(l -(3 -methoxynaphthal en-1- yl)cyclopropyl)-2-methyl benzamide (20.0 mg, 35.0 pmol, 16% yield, TFA salt) as a white solid. M + H ⁺ = 451.2 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 9.17 (s, 1H), 8.70 - 8.61 (m, 1H), 8.14 (s, 2H), 8.06 - 8.00 (m, 1H), 7.92 - 7.88 (m, 2H), 7.85 - 7.80 (m, 2H), 7.60 - 7.50 (m, 4H), 7.45 - 7.38 (m, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.66 (d, J = 2.8 Hz, 1H), 4.01 (dd, J = 3.8, 10.3 Hz, 1H), 3.83 (dd, J = 13, 10.4 Hz, 1H), 3.53 (br d, J= 4.1 Hz, 2H), 1.99 (s, 3H), 1.41 -.35 (m, 2H), 1.32 - 1.27 (m, 2H), 1.20 (d, J= 6.8 Hz, 3H).

Example 329: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-phenyln aphthalen- l-yl)cyclopropyl)benzamide (Compound 475)

Step 2

329A-1

Compound 475

Step 1 : 4-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (329A-1)

To a solution of 7V-(l-(3-hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methyl azetidin-2-yl)methoxy)benzamide (200 mg, 480 pmol, 1.0 eq) in THF (10 mL) was added t- BuOK (80.1 mg, 720 pmol, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. PhN(Tf)2 (257 mg, 720 pmol, 1.5 eq) was added in portions. The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (MeOH/DCM = 1/4, R/ = 0.4). 4-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthal en-2-yl trifluoromethanesulfonate (120 mg, 219 pmol, 46% yield) was obtained as a yellow solid. M + H ⁺ = 549.2 (LCMS).

Step 2: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-phenyln aphthalen-l- yl)cyclopropyl)benzamide (Compound 475)

To a solution of 4-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (100 mg, 182 pmol, 1.0 eq) and phenylboronic acid (27.8 mg, 228 pmol, 1.3 eq) in a mixture of toluene (5.0 mL) and EtOH (2.5 mL) were added ISfeCCL (2 M aqueous, 228 pL, 2.5 eq) and Pd(dppf)C12 (6.67 mg, 9.11 pmol, 0.05 eq) under a N2 atmosphere. The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with DCM (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (200 x 40 mm, 10 pm); flow rate: 75 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-5-((l- methylazetidin-2-yl)methoxy)-7V-(l-(3-phenoxynaphthalen-l-yl )cyclopropyl)benzamide (18.1 mg, 34.6 pmol, 19% yield, FA salt) was obtained as a white solid. M + H ⁺ = 477.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.15 - 9.09 (m, 1H), 8.71 - 8.64 (m, 1H), 8.20 - 8.16 (m, 1H), 8.15 - 8.11 (m, 2H), 8.05 - 7.99 (m, 1H), 7.87 - 7.80 (m, 2H), 7.62 - 7.51 (m, 4H), 7.45 - 7.37 (m, 1H), 7.06 - 7.00 (m, 1H), 6.86 - 6.79 (m, 1H), 6.63 - 6.59 (m, 1H), 3.90 - 3.83 (m, 2H), 3.28 - 3.24 (m, 2H), 2.80 - 2.72 (m, 1H), 2.25 - 2.21 (m, 3H), 2.03 - 1.82 (m, 5H), 1.42 - 1.36 (m, 2H), 1.32 - 1.26 (m, 2H).

Example 330: /V-(l-(7-Hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 477)

Compound 477

Step 1: 7-((/c/7-Butyldiniethylsilyl)oxy)-l -naphthonitrile (330A-2)

To a solution of 7-hydroxy-l -naphthonitrile (1.40 g, 8.28 mmol, 1.0 eq) in DMF (15 mL) were added TBSCI (1.50 g, 9.93 mmol, 1.22 mL, 1.2 eq) and imidazole (1.13 g, 16.6 mmol, 2.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-((/er/-Butyldimethylsilyl)oxy)-l-naphthonitrile (1.60 g, 5.64 mmol, 68% yield) was obtained as a yellow gum. M + H ⁺ = 284.1 (LCMS).

Step 2: l-(7-((tert-Butyldimethylsilyl)oxy)naphthalen-l-yl)cycloprop anamine (330A-3)

A solution of 7-((/er/-butyldimethylsilyl)oxy)-l-naphthonitrile (800 mg, 2.82 mmol, 1.0 eq) in anhydrous Et20 (70 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (1.20 g, 4.23 mmol, 1.25 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et20, 2.07 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (801 mg, 5.64 mmol, 697 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (10 mL) and MTBE (10 mL) and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. l -(7-((/c/7-Butyldimethylsilyl)oxy)naphthalen- l - yl)cyclopropanamine (390 mg, 1.24 mmol, 44% yield) was obtained as a yellow gum.

Step 3: N-( l-(7-((tert-Butyldimethylsilyl)oxy)naphthalen-l-yl)cycloprop yl)-2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (330 A-4)

To a solution of l-(7-((tert-butyldimethylsilyl)oxy)naphthalen-l-yl)cycloprop anamine (150 mg, 478 pmol, 1.0 eq) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (146 mg, 622 pmol, 1.3 eq) in DMF (6.0 mL) were added HBTU (181 mg, 478 pmol, 1.0 eq) and DIEA (186 mg, 1.44 mmol, 250 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.5). 7V-(l-(7-((ter/-Butyldimethyl silyl) oxy)naphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-methylazetid in-2-yl) methoxy) benzamide (150 mg, 283 pmol, 59% yield) was obtained as a yellow gum. M + H ⁺ = 531.6 (LCMS). Step 4: A-(l-(7-Hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-m ethylazetidin-2- yl)methoxy)benzamide (Compound 477)

To a solution of A-(l-(7-((tert-butyldimethylsilyl)oxy)naphthalen-l-yl)cyclop ropyl)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (150 mg, 283 pmol, 1.0 eq) in THF (7.0 mL) was added TBAF (1 M in THF, 848 pL, 3.0 eq) at 0 °C. The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were washed with brine (10 mL x 2), dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.2). A-(l-(7-Hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-m ethylazetidin-2-yl) methoxy )benzamide (6.30 mg, 14.7 pmol, 5% yield) was obtained as a white solid. M + H ⁺ = 417.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.60 (s, 1H), 9.02 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.77 - 7.64 (m, 3H), 7.20 (dd, J= 7.2, 8.1 Hz, 1H), 7.12 (dd, J= 2.3, 8.8 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.83 (dd, J= 2.8, 8.4 Hz, 1H), 6.63 (d, J= 2.8 Hz, 1H), 3.89 (br d, J = 5.3 Hz, 2H), 3.31 - 3.12 (m, 2H), 2.87 - 2.68 (m, 1H), 2.25 (s, 3H), 2.07 - 1.81 (m, 5H), 1.32 (s, 2H), 1.15 - 1.07 (m, 2H).

Example 331: 8-(l-(2-Methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl)-2-naphthoic acid (Compound 465)

331A-2

Compound 465

Step 1 : 8-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (331A-1)

To a solution of 7V-(l-(7-hydroxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin -2-yl)methoxy)benzamide (300 mg, 720 pmol, 1.0 eq) in THF (10 mL) was added PhN(Tf)2 (386 mg, 1.08 mmol, 1.5 eq) at 0 °C, followed by Z-BuOK (121 mg, 1.08 mmol, 1.5 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 8-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (300 mg, 547 pmol, 76% yield) was obtained as a yellow gum. M + H ⁺ = 549.3 (LCMS).

Step 2: Methyl 8-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclo propyl)-2-naphthoate (331A-2)

To a solution of 8-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl) naphthalen-2-yl trifluoromethanesulfonate (100 mg, 182 pmol, 1.0 eq) in MeOH (10 mL) were added Pd(dppf)C12 (13.3 mg, 18.2 pmol, 0.1 eq) and TEA (148 mg, 1.46 mmol, 203 pL, 8.0 eq). The suspension was degassed and purged with CO three times. The mixture was stirred at 80 °C for 16 h under a CO (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.35). Methyl 8-(l-(2-methyl-5-((l- methylazetidin -2-yl)methoxy)benzamido)cyclopropyl)-2-naphthoate (70.0 mg, 153 pmol, 84% yield) was obtained as a yellow gum. M + H ⁺ = 459.2 (LCMS); ^T H NMR (400 MHz, CDCL) 8 9.09 (s, 1H), 8.06 - 7.93 (m, 2H), 7.86 (d, J= 8.5 Hz, 1H), 7.76 (d, J= 8.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.79 - 6.61 (m, 3H), 3.98 - 3.80 (m, 5H), 3.65 - 3.38 (m, 2H), 2.47 - 2.34 (m, 2H), 2.19 - 2.05 (m, 1H), 2.02 (s, 3H), 1.98 (s, 3H), 1.51 (br s, 2H), 1.33 (br t, J= 5.3 Hz, 2H).

Step 3: 8-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclopropyl)-2- naphthoic acid (Compound 465)

To a solution of methyl 8-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclo propyl)-2-naphthoate (60.0 mg, 131 pmol, 1.0 eq) in a mixture of MeOH (1.0 mL) and THF (3.0 mL) was added NaOH (2 M aqueous, 262 pL, 4.0 eq). The reaction mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL), and washed with MTBE (10 mL x 3). The aqueous was adjusted to pH 6 with HC1 (1 M aqueous) and the mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna Cl 8 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 8-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido)c yclo propyl)-2- naphthoic acid (11.0 mg, 22.9 pmol, 17% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 445.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 13.18 - 12.83 (m, 1H), 10.56 - 10.21 (m, 1H), 9.29 (s, 2H), 8.14 - 7.83 (m, 4H), 7.61 (dd, J= 7.3, 8.0 Hz, 1H), 7.08 (d, J= 8.5 Hz, 1H), 6.90 (br d, J= 6.5 Hz, 1H), 6.70 (br s, 1H), 4.72 - 4.50 (m, 1H), 4.40 - 4.15 (m, 2H), 4.08 - 3.76 (m, 2H), 2.81 (br s, 3H), 2.44 - 2.19 (m, 2H), 1.96 (s, 3H), 1.42 (br s, 2H), 1.21 (br s, 2H).

Example 332: /V-(l-(7-Aminonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 483)

331A-1

Compound 483

Step 1: te/7- Butyl (8-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido) cyclopropyl)naphthalen-2-yl)carbamate (332A-1)

To a solution of 8-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido) cyclopropyl) naphthalen-2-yltrifluoromethanesulfonate (100 mg, 183 pmol, 182 pL, 1.0 eq) in 2- methylbutan-2-ol (4.0 mL) were added tert-butyl carbamate (25.6 mg, 219 pmol, 1.2 eq), CS2CO3 (119 mg, 365 pmol, 2.0 eq) and XPhos Pd G3 (15.4 mg, 18.2 pmol, 0.1 eq) under a N2 atmosphere. The mixture was stirred at 90 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.3). tert-Butyl (8-(l-(2-methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl)naphthalen-2-yl) carbamate (60.0 mg, 116 pmol, 64% yield) was obtained as a yellow gum. M + H ⁺ = 516.3 (LCMS).

Step 2: N-( l-(7-Aminonaphthalen-l-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 483)

To a solution of tert-butyl (8-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamido) cyclopropyl)naphthalen-2-yl)carbamate (100 mg, 194 pmol, 1.0 eq) in DCM (8.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was treated with NH4OH (25% aqueous) to adjust pH to 7. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 7V-(l-(7- Aminonaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-methylazeti din-2-yl)methoxy)benzamide (2.60 mg, 6.00 pmol, 3% yield) was obtained as a yellow solid. M + H ⁺ = 416.2 (LCMS); 'H NMR (400 MHz, DMSO ) 8 8.80 (s, 1H), 7.66 - 7.48 (m, 4H), 7.10 - 7.00 (m, 2H), 6.98 - 6.73 (m, 2H), 6.61 (d, J= 2.8 Hz, 1H), 5.09 (s, 2H), 3.86 (d, J= 5.5 Hz, 2H), 3.25 - 3.17 (m, 2H), 2.73 - 2.65 (m, 1H), 2.21 (s, 3H), 2.08 - 1.76 (m, 5H), 1.29 (br s, 2H), 1.17 - 1.04 (m, 2H).

Example 333: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(7-methoxyquinolin-5-yl)cy clopropyl)- 2-methylbenzamide (Compound 434)

Step 3

333A-3 Compound 434

Step 1: 7-Methoxyquinoline-5-carbonitrile (333A-2)

To a solution of 5 -bromo-7-m ethoxy quinoline (10.0 g, 42.0 mmol, 1.0 eq) in DMF (250 mL) were added Zn(CN)2 (9.86 g, 84.0 mmol, 2.0 eq) and Pd(PPh3)4 (4.85 g, 4.20 mmol, 0.1 eq). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was poured into H2O (1.0 L) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to the volume to 50 mL, and a precipitate was formed. The mixture was filtered, and the filter cake was washed with EtOAc (200 mL) to give a white solid. The solid was dissolved with DCM (300 mL) and stirred at room temperature for 30 min. The mixture was filtered, and the filtrate was concentrated under vacuum to give 7-methoxyquinoline-5-carbonitrile (6.25 g, 34.0 mmol, 81% yield) as a white solid.

Step 2: l-(7-Methoxyquinolin-5-yl)cyclopropanamine (333A-3)

A mixture of 7-methoxyquinoline-5-carbonitrile (2.00 g, 10.9 mmol, 1.0 eq) in anhydrous Et2O (160 mL) was degassed and purged with N2 three times. Then the white suspension was cooled to -78 °C. To this mixture was added Ti(z -PrO)4 (4.63 g, 16.3 mmol, 4.81 mL, 1.5 eq) slowly during a period of 5 min and stirred at -78 °C for 10 min. It still was a white suspension. EtMgBr (3 M, in Et2O, 7.96 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under aN2 atmosphere. The color of the mixture turned to brown after the addition was complete. The resulting mixture was stirred at the same temperature for 10 min and then warmed to room temperature (between 15-20 °C) slowly over 1.5 h. The mixture turned to black. To the mixture was added BF3.Et2O (3.08 g, 21.7 mmol, 2.68 mL, 2.0 eq) in portions at the same temperature with no obvious temperature change. The resulting mixture was stirred at room temperature for another 1 h. LCMS showed some SM remained and 33% desired product was detected. The reaction mixture was poured into a mixture of HC1 (I M aqueous) (100 mL) and MTBE (100 mL) and extracted with MTBE (80 mL x 2). The MTBE organic layers were discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. l-(7- Methoxyquinolin-5-yl)cyclopropanamine (1.00 g, 4.67 mmol, 43% yield) was obtained as a brown solid. M + H ⁺ = 215.0 (LCMS); ¹ H NMR (400 MHz, CDCh) 8 8.79 (dd, J= 1.6, 4.3 Hz, 1H), 8.61 (dd, J= 0.9, 8.4 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.21 (s, 1H), 7.18 (d, J= 2.5 Hz, 1H), 3.89 (s, 3H), 1.15 - 1.08 (m, 2H), 0.97 - 0.92 (m, 2H).

Step 3: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(7-methoxyquinolin-5-yl)cy clopropyl)-2- methylbenzamide (Compound 434)

To a solution of 5-(2-(dimethylamino)ethoxy)-2-methylbenzoic acid (400 mg, 1.79 mmol, 1.0 eq) and l-(7-methoxyquinolin-5-yl)cyclopropanamine (500 mg, 2.34 mmol, 1.3 eq) in DMF (20 mL) were added HATU (1.70 g, 4.48 mmol, 2.5 eq), and DIEA (694 mg, 5.38 mmol, 936 pL, 3.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 5/1, R/= 0.35) to give the free base product. The free base product was dealt with acetonitrile (1.0 mL), followed by HC1 (0.40% aqueous, 2.0 mL) and lyophilized to give 5-(2-(dimethylamino)ethoxy)-7V-(l-(7-methoxyquinolin-5- yl)cy cl opropyl)-2 -methylbenzamide (122 mg, 254 pmol, 14% yield, HC1 salt) as a white solid. M + H ⁺ = 420.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.12 (s, 1H), 8.95 (d, J= 8.4 Hz, 1H), 8.82 (dd, J= 1.6, 4.2 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.42 (dd, J = 4.2, 8.4 Hz, 1H), 7.31 (d, J= 2.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.86 (dd, J= 2.7, 8.4 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 4.05 (br t, J= 5.4 Hz, 2H), 3.92 (s, 3H), 2.88 (br d, J= 8.9 Hz, 2H), 2.39 (br s, 6H), 1.95 (s, 3H), 1.37 - 1.31 (m, 2H), 1.22 - 1.16 (m, 2H).

Example 334: ( )-5-(2-Aminopropoxy)-/V-(l-(7-methoxyquinolin-5-yl)cycloprop yl)-2- methylbenzamide (Compound 530)

Compound 530

Step 1: /cr/- Butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (334A-1)

To a solution of l-(7-methoxyquinolin-5-yl)cyclopropanamine (20.0 mg, 93.3 pmol, 1.0 eq) and (5)-5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoi c acid (28.9 mg, 93.4 pmol, 1.0 eq) in DMF (1.0 mL) were added HBTU (88.5 mg, 233 pmol, 2.5 eq) and DIEA (48.3 mg, 373 pmol, 65.0 pL, 4.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a curde product tert-butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)- 4-methylphenoxy)propan-2-yl)carbamate (120 mg) as a colorless oil. M + H ⁺ = 506.3 (LCMS).

Step 2: (5)-5-(2-Aminopropoxy)-/V-(l-(7-methoxyquinolin-5-yl)cyclopr opyl)-2-methylbe nzamide (Compound 530)

To a solution of tert-butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (120 mg, 237 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.62 g, 14.3 mmol, 1.05 mL, 60 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-5-(2-Aminopropoxy)-A-(l-(7-methoxyquinolin-5-yl)cyclopro pyl)- 2-methylbenzamide (4.04 mg, 7.54 pmol, 3% yield, TFA salt) was obtained as a pale yellow gum. M + H ⁺ = 406.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.16 (s, 1H), 9.10 (br d, J= 8.0 Hz, 1H), 8.92 (d, J= 3.5 Hz, 1H), 7.91 (br s, 2H), 7.60 - 7.53 (m, 2H), 7.36 (d, J= 2.4 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.90 (dd, J= 2.7, 8.4 Hz, 1H), 6.68 (d, J= 2.6 Hz, 1H), 4.03 (dd, J= 3.9, 10.3 Hz, 1H), 3.95 (s, 3H), 3.85 (dd, J= 7.2, 10.3 Hz, 1H), 3.60 - 3.51 (m, 1H), 1.96 (s, 3H), 1.38 - 1.32 (m, 2H), 1.22 (d, J= 6.6 Hz, 5H).

Example 335: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(me thylamino) ethoxy)benzamide (Compound 526)

56A-2

Compound 526

Step 1: / f/- Butyl (2-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-m ethyl phenoxy)ethyl)(methyl)carbamate (335A-1)

To a solution of 5-(2-((ter/-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (150 mg, 485 pmol, 1.0 eq) in DMF (6.0 mL) were added l-(7-methoxyquinolin-5- yl)cyclopropanamine (260 mg, 1.21 mmol, 2.5 eq), DIEA (188 mg, 1.45 mmol, 254 pL, 3.0 eq) and HATU (461 mg, 1.21 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. /c/V-Butyl (2-(3-((l-(7-methoxyquinolin- 5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)ethyl)(methyl)ca rbamate (200 mg, 396 pmol, 82% yield) was obtained as a brown oil. M + H ⁺ = 506.2 (LCMS).

Step 2: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(me thylamino) ethoxy)benzamide (Compound 526)

To a solution of /c/7-butyl (2-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)ethyl)(methyl)carbamate (200 mg, 396 pmol, 1.0 eq) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 3.0 mL). The resulting mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2- (methylamino) ethoxy )benzamide (110 mg, 243 pmol, 61% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 406.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.64 (br d, J= 8.4 Hz, 1H), 9.36 (s, 1H), 9.22 - 9.05 (m, 3H), 7.94 (dd, J= 5.3, 8.4 Hz, 1H), 7.71 (d, J= 2.4 Hz, 1H), 7.66 (d, J= 2.1 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 4.19 (t, J= 5.1 Hz, 2H), 4.01 (s, 3H), 3.24 (quin, J= 5.4 Hz, 2H), 2.57 (t, J= 5.4 Hz, 3H), 1.97 (s, 3H), 1.44 - 1.38 (m, 2H), 1.33 - 1.28 (m, 2H).

Example 336: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2- (methylamino)propoxy)benzamide (Compound 560)

Step 2 Compound 560

Step 1: (S)-/c/7-Butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)(methyl)carbamate (336A-1)

To a solution of l-(7-methoxyquinolin-5-yl)cyclopropanamine (30.0 mg, 140 pmol, 1.0 eq) and (8)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-meth ylbenzoic acid (45.3 mg, 140 pmol, 1.0 eq) in DMF (1.0 mL) were added DIEA (72.4 mg, 560 pmol, 97.5 pL, 4.0 eq) and HATU (133 mg, 350 pmol, 2.5 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product CS')-/c/7-butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-m ethylphenoxy) propan-2 - yl)(methyl)carbamate (80.0 mg) as a brown liquid. M + H ⁺ = 520.3 (LCMS). Step 2: (5)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2 -(methylamino) propoxy)benzamide (Compound 560)

To a solution of CS')-/c/7-butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)(methyl)carbamate (80.0 mg, 154 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-7V-(l-(7- Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2-(methylamino )propoxy)benzamide (15.8 mg, 33.5 pmol, 21% yield, HC1 salt) was obtained as a pale yellow gum. M + H ⁺ = 420.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.73 (d, J= 8.50 Hz, 1H), 9.43 - 9.36 (m, 1H), 9.34 - 9.25 (m, 1H), 9.20 (d, J= 4.50 Hz, 1H), 9.17 - 9.06 (m, 1H), 8.00 (dd, J = 8.38, 5.50 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.09 (d, J= 8.38 Hz, 1H), 6.92 (dd, J= 8.38, 2.63 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 4.18 - 4.13 (m, 1H), 4.11 - 4.07 (m, 1H), 4.02 (s, 3H), 3.56 - 3.45 (m, 1H), 2.56 - 2.52 (m, 3H), 1.96 (s, 3H), 1.42 (br s, 2H), 1.33 - 1.27 (m, 5H).

Example 337 : ( )-5-(2-(Dimethylamino)propoxy)-/V-(l-(7-methoxyquinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 575)

Compound 575

Step 1 : (5)-5-(2-(Dimethylamino)propoxy)-/V-(l-(7-methoxyquinolin-5- yl)cyclopropyl)-2- methylbenzamide (Compound 575)

To a solution of (5)-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(2- (methylamino)propoxy)benzamide (176 mg, 421 pmol, 1.0 eq) in MeOH (2.0 mL) was added formaldehyde (68.4 mg, 842 pmol, 62.7 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The resulting mixture was stirred at 20 °C for 30 min, then NaBHiCN (79.4 mg, 1.26 mmol, 3.0 eq) was added. The reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 60 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-5-(2-(Dimethylamino)propoxy)-7V- (l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (39.1 mg, 82.0 pmol, 19% yield) was obtained as a pale yellow solid. M + H ⁺ = 434.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.62 (br d, J= 1.3 Hz, 1H), 9.73 (d, J= 8.1 Hz, 1H), 9.39 (s, 1H), 9.19 (dd, J= 1.1, 5.4 Hz, 1H), 8.05 - 7.93 (m, 1H), 7.79 - 7.65 (m, 2H), 7.09 (d, J= 8.5 Hz, 1H), 6.93 (dd, J = 2.8, 8.4 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 4.21 - 4.18 (m, 2H), 4.02 (s, 3H), 3.74 - 3.68 (m, 1H), 2.73 (dd, J= 5.0, 8.9 Hz, 6H), 1.96 (s, 3H), 1.47 - 1.40 (m, 2H), 1.31 (d, J= 6.8 Hz, 5H).

Example 338: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-methoxyquinolin-5-yl)cyc lopropyl)-

2-methylbenzamide (Compound 511)

Compound 511 Step 1: (S)-/c/7-Butyl 2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)azetidine-l-carboxylate (338A-1)

To a solution of (5)-5-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth ylbenzoic acid (300 mg, 934 pmol, 1.0 eq) in DMF (10 mL) were added l-(7-methoxyquinolin-5- yl)cyclopropanamine (300 mg, 1.40 mmol, 1.5 eq), DIEA (362 mg, 2.80 mmol, 488 pL, 3.0 eq) and HATU (887 mg, 2.33 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/5. S)-terLButyl 2-((3-((l-(7- methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy) methyl)azetidine-l- carboxylate (400 mg, 773 pmol, 83% yield) was obtained as a yellow solid. M + H ⁺ = 518.2 (LCMS).

Step 2: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-methoxyquinolin-5-yl)c yclopropyl)-2- methylbenzamide (Compound 511)

To a solution of CS')-/c/7-butyl 2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)azetidine-l -carboxylate (400 mg, 773 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-5-(Azetidin-2-ylmethoxy)-7V-(l-(7-methoxyquinolin-5- yl)cyclopropyl)-2-methylbenzamide (48.9 mg, 116 pmol, 15% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 418.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.35 (br d, J= 8.4 Hz, 1H), 9.28 - 9.13 (m, 2H), 9.03 (br d, J= 3.8 Hz, 2H), 7.73 (dd, J= 4.9, 8.4 Hz, 1H), 7.62 (d, J= 2.5 Hz, 1H), 7.48 (d, J= 2.3 Hz, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.73 (d, J= 2.8 Hz, 1H), 4.65 (br d, J= 6.4 Hz, 1H), 4.28 (dd, J= 7.4, 11.1 Hz, 1H), 4.14 (dd, J= 3.3, 11.1 Hz, 1H), 3.98 (s, 3H), 3.95 - 3.76 (m, 2H), 2.48 - 2.27 (m, 2H), 1.97 (s, 3H), 1.43 - 1.34 (m, 2H), 1.30 - 1.22 (m, 2H). Example 339: (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l - methylazetidin-2-yl)methoxy)benzamide (Compound 527)

Compound 527

Step 1 : (5)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 527)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-7V-(l-(7-methoxyquinolin-5-yl)c yclopropyl)-2- methylbenzamide (250 mg, 599 pmol, 1.0 eq) in MeOH (10 mL) was added TEA (50.0 pL), followed by formaldehyde (36.0 mg, 1.20 mmol, 32.9 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (75.0 mg, 1.20 mmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin- 2-yl)methoxy)benzamide (87.2 mg, 183 pmol, 31% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 432.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.83 - 10.68 (m, 1H), 9.59 - 9.48 (m, 1H), 9.31 (s, 1H), 9.12 (br d, J= 4.9 Hz, 1H), 7.87 (br s, 1H), 7.69 (s, 1H), 7.58 (br s, 1H), 7.15 - 7.06 (m, 1H), 7.00 - 6.89 (m, 1H), 6.83 - 6.71 (m, 1H), 4.68 - 4.58 (m, 1H), 4.38 (br dd, J= 8.4, 10.8 Hz, 1H), 4.22 (dd, J = .2, 11.2 Hz, 1H), 4.01 (s, 3H), 3.85 (br dd, J = 6.7, 9.3 Hz, 2H), 2.81 (d, J = 5.0 Hz, 3H), 2.45 - 2.22 (m, 2H), 1.96 (s, 3H), 1.41 (br s, 2H), 1.30 (br s, 2H). Example 340: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyr rolidin-2- ylmethoxy)benzamide (Compound 462)

Compound 462

Step 1: (S)-/c/7-Butyl 2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)pyrrolidine-l-carboxylate (340A-1)

To a solution of l-(7-methoxyquinolin-5-yl)cyclopropanamine (192 mg, 895 pmol, 1.5 eq) and fS')-5-(( l -(/c77-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzo ic acid (200 mg, 596 pmol, 1.0 eq) in DMF (10 mL) were added DIEA (231 mg, 1.79 mmol, 312 pL, 3.0 eq) and HATU (567 mg, 1.49 mmol, 2.5 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (15 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/5. (A')-/c/7-Butyl 2-((3-((l-(7-methoxyquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy) methyl)pyrrolidine-l -carboxylate (254 mg, 478 pmol, 40% yield) was obtained as a yellow oil. M + H ⁺ = 532.3 (LCMS).

Step 2: (5)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(p yrrolidin-2- ylmethoxy)benzamide (Compound 462)

To a solution of CS')-/c77-butyl 2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)pyrrolidine-l -carboxylate (254 mg, 478 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(py rrolidin-2- ylmethoxy)benzamide (123 mg, 264 pmol, 55% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 432.1 (LCMS); flT NMR (400 MHz, DMSO ) 8 9.70 (d, J= 8.4 Hz, 2H), 9.36 (s, 1H), 9.14 (d, J= 5.3 Hz, 2H), 7.97 (dd, J= 5.5, 8.5 Hz, 1H), 7.74 (d, J= 2.4 Hz, 2H), 7.08 (d, J= 8.5 Hz, 1H), 6.90 (dd, J = 2.6, 8.4 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 4.22 - 4.13 (m, 2H), 4.10 - 3.97 (m, 3H), 3.86 - 3.79 (m, 1H), 3.25 - 3.11 (m, 2H), 2.15 - 2.03 (m, 1H), 2.02 - 1.81 (m, 5H), 1.68 (qd, J = 8.2, 12.7 Hz, 1H), 1.42 (br s, 2H), 1.30 (br s, 2H).

Example 341: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylpyrrolidin-2-yl)methoxy)benzamide (Compound 528)

Compound 528

Step 1: (5)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l-methylpyrrolidin- 2-yl)methoxy)benzamide (Compound 528)

To a solution of (8 -A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrro lidin-2- ylmethoxy)benzamide (70.0 mg, 150 pmol, 1.0 eq, HC1 salt) in MeOH (2.5 mL) was added TEA (0.30 mL), followed by formaldehyde (8.98 mg, 299 pmol, 8.24 pl, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min and NaBHsCN (18.8 mg, 299 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 15% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(py rrolidin-2- ylmethoxy)benzamide (22.1 mg, 45.9 pmol, 31% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 446.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 10.94 (br s, 1H), 9.72 (d, J = 8.5 Hz, 1H), 9.38 (s, 1H), 9.19 (d, J= 4.8 Hz, 1H), 7.99 (dd, J= 5.4, 8.4 Hz, 1H), 7.72 (dd, J= 2.3, 16.4 Hz, 2H), 7.09 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.77 (d, J= 2.6 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.28 - 4.22 (m, 1H), 4.02 (s, 3H), 3.74 (dt, J= 3.3, 8.0 Hz, 1H), 3.61 - 3.45 (m, 1H), 3.15 - 3.01 (m, 1H), 2.88 (d, J= 4.8 Hz, 3H), 2.28 - 2.14 (m, 1H), 2.03 - 1.87 (m, 5H), 1.83 - 1.69 (m, 1H), 1.42 (br s, 2H), 1.32 (br s, 2H).

Example 342: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methyl piperidin-2-yl)methoxy)benzamide (Compound 550)

Compound 550 Step 1: (S)-/c/7-Butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)piperidine-l- carboxylate (342A-1)

To a solution of methyl 5-hydroxy-2-methylbenzoate (300 mg, 1.81 mmol, 1.0 eq) and (5)- /c V-butyl 2-(hydroxymethyl)piperidine-l -carboxylate (583 mg, 2.70 mmol, 1.5 eq) in toluene (15 mL) were added TMAD (930 mg, 5.42 mmol, 3.0 eq), PPhi (1.40 g, 5.42 mmol, 3.0 eq). The resulting mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. fS')-/c 7-Butyl 2-((3-(m ethoxy carbonyl)-4-m ethylphenoxy )methyl)piperi dine- 1 -carboxylate (470 mg, 1.16 mmol, 72% yield) was obtained as a yellow solid. M - 100 + H ⁺ = 264.1 (LCMS); ^T H NMR (400 MHz, DMSO ) 8 7.34 (d, J= 2.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.09 (dd, J = 2.8, 8.4 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.17 - 4.05 (m, 2H), 3.92 - 3.83 (m, 1H), 3.81 (s, 3H), 2.84 (br t, J= 12.4 Hz, 1H), 2.42 (s, 3H), 1.78 (br d, J= 7.4 Hz, 1H), 1.64 - 1.48 (m, 4H), 1.35 (s, 9H), 1.32 - 1.25 (m, 1H).

Step 2: (S)-5-(( l-(/cr/-Biitoxyc:irboiiyl)piperidiii-2-yl)inethoxy)-2-niethy lbenzoic acid (342A-2)

To a solution of CS')-/c77-butyl 2-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)piperidine- 1-carboxylate (470 mg, 1.16 mmol, 1.0 eq) in a mixture of THF (3.0 mL) and MeOH (1.0 mL) was added NaOH (2 M aqueous, 2.33 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and washed with EtOAc (10 mL x 3). The aqueous layer was acidified to pH 3 with HC1 (1 M aqueous). The product was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product CS')-5-(( l -(/c77-Butoxycarbonyl)piperidin-2-yl)methoxy)-2-methylbenzoi c acid (260 mg) was obtained as a white solid, which was used in the next step without any further purification. M - 100 + H ⁺ = 250.1 (LCMS). Step 3: (S)-/c/7-Butyl 2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)piperidine-l-carboxylate (342A-3)

To a solution of fS')-5-(( l -(/c/7-butoxycarbonyl)piperidin-2-yl)methoxy)-2-methylbenzoi c acid (230 mg, 658 pmol, 1.0 eq) and l-(7-methoxyquinolin-5-yl)cyclopropanamine (141 mg, 658 pmol, 1.0 eq) in DCM (1.0 mL) were added EDCI (189 mg, 987 pmol, 1.5 eq), HOBt (133 mg, 987 pmol, 1.5 eq) and TEA (200 mg, 1.97 mmol, 275 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/0, R/= 0.5). (8)-/er/-Butyl2-((3-((l-(7-methoxyquinolin-5- yl)cyclopropyl)carbamoyl)-4-methyl phenoxy )methyl)piperi dine- 1 -carboxylate (200 mg, 367 pmol, 56% yield) was obtained as a yellow oil. M + H ⁺ = 546.3 (LCMS).

Step 4: (5)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(p iperidin-2-yl methoxy)benzamide (Compound 550)

To a solution of (k)-/c/7-butyl 2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)piperidine-l -carboxylate (200 mg, 330 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCl/EtOAc (4 M, 5.0 mL) slowly. The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was filtered, and the cake was washed with EtOAc (5.0 mL x 3). The cake was dried under vacuum to give (5)-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2- methyl-5-(piperidin-2-yl methoxy)benzamide (120 mg, 269 pmol, 82% yield, HC1 salt) as a yellow solid. M + H ⁺ = 446.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.65 (br d, J= 8.1 Hz, 1H), 9.36 (s, 1H), 9.17 (br d, J= 4.8 Hz, 1H), 9.12 (br s, 1H), 7.95 (dd, J = 5.3, 8.3 Hz, 1H), 7.72 (d, J= 2.3 Hz, 1H), 7.66 (d, J= 1.9 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.6, 8.3 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 4.15 - 4.10 (m, 1H), 4.08 - 4.04 (m, 1H), 4.02 (s, 3H), 3.45 - 3.33 (m, 1H), 3.22 (br d, J= 12.3 Hz, 1H), 2.88 (br d, J= 6.8 Hz, 1H), 1.96 (s, 3H), 1.86 - 1.76 (m, 2H), 1.75 - 1.60 (m, 2H), 1.59 - 1.45 (m, 2H), 1.41 (br s, 2H), 1.31 (br s, 2H). Example 343: 5-((4-Methoxypyridin-2-yl)methoxy)-/V-(l-(7-methoxyquinolin- 5- yl)cyclopropyl)-2-methylbenzamide (Compound 561)

Compound 561

Step 1: 5-Hydroxy-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy lbenzamide (343A-1)

To a solution of 5-hydroxy-2-methylbenzoic acid (700 mg, 4.60 mmol, 0.98 eq) and l-(7- methoxyquinolin-5-yl)cyclopropanamine (1.00 g, 4.67 mmol, 1.0 eq) in DMF (15 mL) were added TEA (472 mg, 4.67 mmol, 650 pL, 1.0 eq), EDCI (939 mg, 4.90 mmol, 1.05 eq) and HOBt (126 mg, 933 pmol, 0.2 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into H2O (40 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Naz SO4. filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-Hydroxy-7V- (l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (1.10 g, 3.16 mmol, 68% yield) was obtained as a yellow solid. M + H ⁺ = 349.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.27 (s, 1H), 9.07 (s, 1H), 8.97 - 8.92 (m, 1H), 8.82 (dd, J= 1.5, 4.3 Hz, 1H), 7.49 - 7.39 (m, 2H), 7.31 (d, J= 2.5 Hz, 1H), 6.91 (d, J= 8.4 Hz, 1H), 6.64 (dd, J= 2.6, 8.3 Hz, 1H), 6.44 (d, J= 2.6 Hz, 1H), 3.92 (s, 3H), 1.92 (s, 3H), 1.34 - 1.28 (m, 2H), 1.23 - 1.16 (m, 2H). Step 2: 5-((4-Methoxypyridin-2-yl)methoxy)-/V-(l-(7-methoxyquinolin- 5- yl)cyclopropyl)-2-methylbenzamide (Compound 561)

A mixture of 5-hydroxy-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy lbenzamide (70.0 mg, 201 pmol, 1.0 eq), (4-methoxypyridin-2-yl)methanol (55.9 mg, 402 pmol, 2.0 eq), and CMBP (72.7 mg, 302 pmol, 1.5 eq) in toluene (3.5 mL) was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-((4-Methoxypyridin-2-yl)methoxy)-A- (l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (81.9 mg, 153 pmol, 76% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 470.2 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 = 9.74 - 9.65 (m, 1H), 9.67 (br d, J= 8.5 Hz, 1H), 9.40 (s, 1H), 9.19 - 9.12 (m, 1H), 8.70 (d, J = 6.8 Hz, 1H), 7.95 (dd, J = 5.3, 8.4 Hz, 1H), 7.77 - 7.64 (m, 2H), 7.56 (d, J = 2.5 Hz, 1H), 7.46 (dd, J = 2.6, 6.6 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 7.00 (dd, J = 2.6, 8.4 Hz, 1H), 6.87 (d, J= 2.8 Hz, 1H), 5.36 (s, 2H), 4.03 (d, J= 13.5 Hz, 6H), 1.98 (s, 3H), 1.45 - 1.37 (m, 2H), 1.35 - 1.27 (m, 2H).

Example 344: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrid in-4- yloxy)benzamide (Compound 584)

343A-1 Compound 584

Step 1 : /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrid in-4- yloxy)benzamide (Compound 584)

To a solution of 5-hydroxy-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl benzamide (60.0 mg, 172 pmol, 1.0 eq) and 4-bromopyridine (81.6 mg, 517 pmol, 3.0 eq) in dioxane (4.0 mL) were added CS2CO3 (112 mg, 344 pmol, 2.0 eq), Pd2(dba)3 (15.8 mg, 17.2 pmol, 0.1 eq) and Xantphos (20.9 mg, 36.2 pmol, 0.2 eq). The mixture was degassed and purged with N2 three times. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (4.0 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 7V-(1 -(7 -Methoxy quinolin-5-yl)cy cl opropyl)-2-methyl-5-(pyridin-4- yloxy)benz amide (11.2 mg, 26.1 pmol, 15% yield) was obtained as a brown solid. M + H ⁺ = 426.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.18 (s, 1H), 8.91 (d, J= 8.3 Hz, 1H), 8.79 (dd, J = 1.3, 4.1 Hz, 1H), 8.43 (d, J= 6.1 Hz, 2H), 7.46 (d, J= 2.5 Hz, 1H), 7.38 (dd, J= 4.3, 8.4 Hz, 1H), 7.30 (d, J= 2.5 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 7.09 (dd, J= 2.5, 8.3 Hz, 1H), 6.89 (d, J= 2.5 Hz, 1H), 6.86 (d, J= 6.1 Hz, 2H), 3.91 (s, 3H), 2.04 (s, 3H), 1.40 - 1.27 (m, 2H), 1.23 - 1.13 (m, 2H).

Example 345: ( )-4-Amino-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy l-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 597) p

345A-3

Compound 597 Step 1: Methyl 5-fluoro-2-methyl-4-nitrobenzoate (345A-2)

To a solution of l-bromo-5-fluoro-2-methyl-4-nitrobenzene (500 mg, 2.14 mmol, 1.0 eq) in MeOH (10 mL) were added TEA (1.73 g, 17.1 mmol, 2.38 mL, 8.0 eq) and Pd(dppf)C12 (156 mg, 214 pmol, 0.1 eq). The mixture was degassed and purged with CO three times, then stirred at 80 °C for 16 h under a CO (50 psi) atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/5, R/= 0.5). Methyl 5-fluoro-2-methyl-4-nitrobenzoate (200 mg, 938 pmol, 44% yield) was obtained as a yellow solid. ^T H NMR (400 MHz, CDCh) 8 7.93 (d, J= 7.1 Hz, 1H), 7.83 (d, J= 11.2 Hz, 1H), 3.96 (s, 3H), 2.64 (s, 3H). Step 2: (S)-5-((l-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth yl-4-nitrobenzoic acid (345A-3) To a solution of methyl 5-fluoro-2-methyl-4-nitrobenzoate (180 mg, 844 pmol, 1.0 eq) and (S)- /c/V-butyl 2-(hydroxymethyl)azetidine-l -carboxylate (237 mg, 1.27 mmol, 1.5 eq) in DMSO (15 mL) were added CsF (257 mg, 1.69 mmol, 62.3 pL, 2.0 eq) and DIEA (327 mg, 2.53 mmol, 441 pL, 3.0 eq). The mixture was stirred at 120 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H2O (10 mL) and extracted with MTBE (6.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The mixture was extracted with EtOAc (6.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. CS')-5-(( l -(/c/7-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4- nitrobenzoic acid (200 mg, 546 pmol, 65% yield) was obtained as a yellow solid. M - 56 + H ⁺ = 311.0 (LCMS).

Step 3: (S)-/c/7-Butyl 2-((5-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-m ethy l-2-nitrophenoxy)methyl)azetidine-l-carboxylate (345A-4)

To a solution of CS')-5-(( l -(/c77-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4- nitrobenzoic acid (198 mg, 539 pmol, 1.0 eq) and l-(7-methoxyquinolin-5- yl)cyclopropanamine (57.8 mg, 270 pmol, 0.5 eq) in DMF (12 mL) were added TEA (54.6 mg, 539 pmol, 75.0 pL, 1.0 eq), EDCI (109 mg, 566 pmol, 1.05 eq) and HOBt (14.6 mg, 108 pmol, 0.2 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. (A')-/c77-Butyl 2-((5-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methyl-2-nitro phenoxy)methyl) azetidine-l-carboxylate (90.0 mg, 160 pmol, 30% yield) was obtained as a yellow solid. M + H ⁺ = 563.3 (LCMS).

Step 4: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-methoxyquinolin-5-yl)c yclopropyl)-2- methyl-4-nitrobenzamide (345A-5)

To a solution of CS')-/ 77-butyl 2-((5-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methyl-2-nitrophenoxy)methyl)azetidine-l -carboxylate (90.0 mg, 160 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.31 g, 20.3 mmol, 1.5 mL, 127 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to the crude (5)-5-(azetidin-2-ylmethoxy)-A-(l-(7-methoxyquinolin-5-yl)cy clopropyl)-2-methyl-4- nitrobenzamide (80.0 mg, 139 pmol, 87% yield, TFA salt) as a yellow oil. M + H ⁺ = 463.1 (LCMS).

Step 5: (5)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)-4-nitrobenzamide (345A-6)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-A-(l-(7-methoxyquinolin-5-yl)cy clopropyl)-2- methyl-4-nitrobenzamide (80.0 mg, 139 pmol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (30.0 pL), followed by formaldehyde (22.5 mg, 278 pmol, 7.65 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (17.4 mg, 278 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude S)- A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-2-yl)methoxy)-4- nitrobenzamide (65.0 mg) as a yellow oil. M + H ⁺ = 477.2 (LCMS).

Step 6: ( )-4-Amino-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy l-5-((l-methylaz etidin-2-yl)methoxy)benzamide (Compound 597)

To a solution of (5)-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l - methylazetidin-2-yl)methoxy)-4-nitrobenzamide (60.0 mg, 126 pmol, 1.0 eq) in MeOH (6.0 mL) and H2O (1.2 mL) were added NH4CI (33.7 mg, 630 pmol, 5.0 eq) and iron powder (35.2 mg, 630 pmol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (7.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD C18 (150 x 40 mm, 10 pm); flow rate: 50 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). S)- 4-Amino-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5 -((l-methylazeti din-2- yl)methoxy) benzamide (6.50 mg, 14.6 pmol, 12% yield) was obtained as a brown solid. M + H ⁺ = 447.3 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.01 (d, J = 8.3 Hz, 1H), 8.81 (d, J = 4.0 Hz, 1H), 8.70 (s, 1H), 7.53 - 7.36 (m, 2H), 7.29 (d, J= 2.3 Hz, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 4.98 - 4.83 (m, 2H), 3.91 (s, 3H), 3.87 - 3.74 (m, 2H), 3.25 (br d, J= 8.5 Hz, 2H), 2.78 - 2.69 (m, 1H), 2.22 (s, 3H), 2.03 - 1.84 (m, 5H), 1.31 (br s, 2H), 1.20 - 1.11 (m, 2H).

Example 346: (5)-/V-(l-(7-Isopropoxyquinolin-5-yl)cyclopropyl)-2-methyl-5 -((l- methylazetidin-2-yl)methoxy)benzamide (Compound 587)

Compound 587

Step 1: (5)-/V-(l-(7-Isopropoxyquinolin-5-yl)cyclopropyl)-2-methyl-5 -((l-methylazetidin- 2-yl)methoxy)benzamide (Compound 587)

To a solution of (5)-A-(l-(7-hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l - methylazetidin-2-yl)methoxy)benzamide (18.0 mg, 43.1 pmol, 1.0 eq) and propan-2-ol (7.77 mg, 129 pmol, 9.90 pL, 3.0 eq) in toluene (2.0 mL) were added TMAD (22.2 mg, 129 pmol, 3.0 eq) and PPhi (33.9 mg, 129 pmol, 3.0 eq) at 25 °C. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and then concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 60 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-7V-(l-(7-Isopropoxyquinolin-5-yl)cyclopropyl)-2-methyl-5 -((l- methylazetidin-2-yl)methoxy)benzamide (3.60 mg, 6.99 pmol, 16% yield) was obtained as a pale yellow gum. M + H ⁺ = 460.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 10.51 - 10.34 (m, 1H), 9.49 - 9.34 (m, 1H), 9.24 (s, 1H), 9.06 (br d, J= 2.8 Hz, 1H), 7.85 - 7.71 (m, 1H), 7.61 (br s, 1H), 7.52 - 7.46 (m, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.93 (br d, J= 2.5 Hz, 1H), 6.75 (d, J= 2.4 Hz, 1H), 4.86 (s, 1H), 4.67 - 4.58 (m, 1H), 4.35 - 4.29 (m, 1H), 4.24 (br d, J= 2.9 Hz, 1H), 4.04 - 3.98 (m, 1H), 3.89 - 3.82 (m, 1H), 2.84 - 2.81 (m, 3H), 2.33 (br d, J= 1.8 Hz, 2H), 1.96 (s, 3H), 1.41 (d, J= 6.0 Hz, 8H), 1.28 (br s, 2H). Example 347: ( )-/V-(l-(7-(Benzyloxy)quinolin-5-yl)cyclopropyl)-2-methyl-5- ((l-methyl azetidin-2-yl)methoxy)benzamide (Compound 598)

Compound 598

Step 1: 5-Bromoquinolin-7-ol (347A-1)

To a solution of 5-bromo-7-methoxy-quinoline (2.00 g, 8.40 mmol, 1.0 eq) in HBr (30.0 g, 110 mmol, 20 mL, 30% purity in H2O, 13 eq). The mixture was stirred at 130 °C for 24 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to 0 °C and slowly adjusted to pH 6 with saturated aqueous NaHCCh. The mixture was extracted with DCM (50 mL x 5). The combined organic layers were dried over Na2 SO4. filtered, and concentrated under vacuum to give a crude product, which was used in the next step without any further purification. 5-Bromoquinolin-7- ol (3.50 g) was obtained as a yellow solid. M + H ⁺ = 223.9 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.78 (dd, J= 1.4, 4.2 Hz, 1H), 8.31 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 2.3 Hz, 1H), 7.41 (dd, J= 4.2, 8.4 Hz, 1H), 7.26 (d, J= 1.9 Hz, 1H).

Step 2: 7-(Benzyloxy)-5-bromoquinoline (347A-2)

To a solution of 5-bromoquinolin-7-ol (1.00 g, 2.68 mmol, 1.0 eq) in DMF (20 mL) was added (bromomethyl)benzene (504 mg, 295 mmol, 350 pL 1.1 eq), followed by K2CO3 (1.11 g, 8.03 mmol, 3.0 eq). The resulting mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (50 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. 7-(Benzyloxy)-5- bromoquinoline (800 mg, 2.54 mmol, 95% yield) was obtained as yellow oil M + H ⁺ = 313.9 (LCMS).

Step 3: 7-(Benzyloxy)quinoline-5-carbonitrile (347A-3)

To a solution of 7-(benzyloxy)-5-bromoquinoline (500 mg, 1.59 mmol, 1.0 eq) in DMF (10 mL) were added Zn(CN)2 (374 mg, 3.18 mmol, 2.0 eq), and Pd(PPh3)4 (184 mg, 159 pmol, 0.1 eq). The resulting mixture was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (20 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 7-(Benzyloxy)quinoline-5-carbonitrile (400 mg, 1.54 mmol, 97% yield) was obtained as a white solid. ^X H NMR (400 MHz, DMSO ) 6 8.99 (dd, J= 1.5, 4.3 Hz, 1H), 8.41 (d, J= 8.1 Hz, 1H), 8.10 (d, J= 2.5 Hz, 1H), 7.87 (d, J= 2.3 Hz, 1H), 7.63 (dd, J = 4.3, 8.4 Hz, 1H), 7.53 (d, J= 7.3 Hz, 2H), 7.47 - 7.34 (m, 3H), 5.37 (s, 2H).

Step 4: l-(7-(Benzyloxy)quinolin-5-yl)cyclopropanamine (347A-4)

A mixture of 7-(benzyloxy)quinoline-5-carbonitrile(200 mg, 771 pmol, 1.0 eq) in anhydrous Et2O (20 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (329 mg, 1.16 mmol, 341 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 566 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (219 mg, 1.54 mmol, 190 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (I M aqueous) (10 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (MeOH/DCM = 1/10, R/= 0.2). l-(7- (Benzyloxy)quinolin-5-yl)cyclopropanamine (30.0 mg, 103 pmol, 13% yield) was obtained as a yellow oil. M + H ⁺ = 291.1 (LCMS).

Step 5: (5)-/V-(l-(7-(Benzyloxy)quinolin-5-yl)cyclopropyl)-2-methyl- 5-((l-methyl azetidin-2-yl)methoxy)benzamide (Compound 598)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (30.0 mg, 128 pmol, 1.0 eq) and l-(7-(benzyloxy)quinolin-5-yl)cyclopropanamine (39.0 mg, 134 pmol, 1.1 eq) in DMF (2.0 mL) were added HATU (145 mg, 383 pmol, 3.0 eq) and DIEA (33.0 mg, 255 pmol, 44.0 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-(Benzyloxy)quinolin-5-yl)cyclopropyl)-2-methyl-5 - ((1-methyl azetidin-2-yl)methoxy) benzamide (12.7 mg, 22.6 pmol, 18% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 508.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.86 - 10.61 (m, 1H), 9.62 - 9.45 (m, 1H), 9.31 (s, 1H), 9.11 (br d, J= 4.8 Hz, 1H), 7.96 - 7.82 (m, 1H), 7.75 (s, 1H), 7.67 (br s, 1H), 7.57 (br d, J= 7.3 Hz, 2H), 7.49 - 7.35 (m, 3H), 7.10 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.76 (d, J= 2.5 Hz, 1H), 5.36 (s, 2H), 4.70 - 4.54 (m, 1H), 4.41 - 4.35 (m, 1H), 4.22 (br dd, J= 2.6, 11.2 Hz, 1H), 3.99 (br dd, J= 4.8, 9.0 Hz, 1H), 3.89 - 3.82 (m, 1H), 2.82 - 2.66 (m, 3H), 2.33 (br s, 2H), 1.96 (s, 3H), 1.40 (br s, 2H), 1.30 (br s, 2H). Example 348: (A)-/V-(l-(7-Bromoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 563)

Compound 563

Step 1: 5, 7-Dibromoquinoline (348A-2)

To a solution of 3, 5 -dibromoaniline (10.0 g, 39.8 mmol, 1.0 eq) and sodium 3- nitrobenzenesulfonate (26.9 g, 119 mmol, 3.0 eq) in a mixture of H2SO4 (56 mL) and H2O (72 mL) was added propane-1, 2, 3-triol (14.7 g, 159 mmol, 11.9 mL, 4.0 eq) at 100 °C. The mixture was degassed and purged with N2 three times. The mixture was stirred at 130 °C for 4 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into ice water (200 mL). The aqueous layer was basified to pH 9-10 by using saturated aqueous NH3.H2O and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 5, 7-Dibromoquinoline (25.0 g, 87.1 mmol, 73% yield) was obtained as a white solid. M + H ⁺ = 285.8(LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.05 - 8.98 (m, 1H), 8.52 (d, J= 8.3 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J= 1.7 Hz, 1H), 7.75 (dd, J= 4.2, 8.5 Hz, 1H).

Step 2: 7-Bromoquinoline-5-carbonitrile (348A-3)

To a solution of 5,7-dibromoquinoline (1.00 g, 3.48 mmol, 1.0 eq) in DMF (5.0 mL) were added Py (6.34 g, 80.2 mmol, 6.47 mL, 23 eq) and CuCN (312 mg, 3.48 mmol, 761 pL, 1.0 eq) at 20 °C. The mixture was degassed and purged with N2 three times. The mixture was stirred at 150 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 7-Bromoquinoline-5-carbonitrile (1.00 g, crude) was obtained as a white solid. M + H ⁺ = 233.1 (LCMS).

Step 3: l-(7-Bromoquinolin-5-yl)cyclopropanamine (348A-4)

A mixture of 7-bromoquinoline-5-carbonitrile (500 mg, 2.15 mmol, 1.0 eq) in anhydrous Et2O (50 mL) was degassed and purged with N2 three times. The mixture was stirred with a mechanical stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (915 mg, 3.22 mmol, 950 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 1.57 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 5 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF ₃ .Et2O (609 mg, 4.29 mmol, 529 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (50 mL) and MTBE (25 mL) and extracted with MTBE (25 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). l-(7-Bromoquinolin-5-yl)cyclopropanamine (20.0 mg, 76.0 pmol, 4% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 263.0 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.55 (d, J= 8.6 Hz, 1H), 9.31 (d, J= 5.0 Hz, 1H), 8.55 (s, 1H), 8.37 (d, J= 1.3 Hz, 1H), 8.20 (dd, J= 5.2, 8.7 Hz, 1H), 1.93 - 1.66 (m, 2H), 1.60 - 1.35 (m, 2H).

Step 4: A -/V-(l-(7-Bromoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-2- yl)methoxy)benzamide (Compound 563)

To a solution of l-(7-bromoquinolin-5-yl)cyclopropanamine (20.0 mg, 76.1 pmol, 1.0 eq) and (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (17.9 mg, 76.1 pmol, 1.0 eq) in DMF (3.0 mL) were added DIEA ( 49.1 mg, 380 pmol, 66.2 pL, 5.0 eq) and HATU (57.8 mg, 152 pmol, 2.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). f£J-A-(l-(7-Bromoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (18.0 mg, 34.1 pmol, 45% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 480.0 (LCMS); 'H NMR (400 MHz, DMSO ) 6 10.31 - 10.08 (m, 1H), 9.22 (s, 1H), 9.09 (d, J= 8.3 Hz, 1H), 9.00 - 8.92 (m, 1H), 8.19 (d, J= 1.8 Hz, 1H), 7.97 (d, J= 1.9 Hz, 1H), 7.73 - 7.62 (m, 1H), 7.15 - 7.04 (m, 1H), 6.92 (dd, J= 2.7, 8.2 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 4.71 - 4.49 (m, 1H), 4.36 - 4.17 (m, 2H), 4.00 (br dd, J = 4.9, 9.9 Hz, 1H), 3.85 (br d, J= 3.4 Hz, 1H), 2.82 (d, J = 5.0 Hz, 3H), 2.37 - 2.30 (m, 2H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.28 (br s, 2H).

Example 349: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(7-methylquinolin-5- yl)cyclopropyl)benzamide (Compound 497)

333A-3 ^{Step 1} Step 1: / f/- Butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (349A-1)

To a solution of l-(7-methoxyquinolin-5-yl)cyclopropanamine (300 mg, 1.40 mmol, 1.0 eq) and 5-(2-((/< /7-butoxycarbonyl)amino)propoxy)-2-methylbenzoic acid (390 mg, 1.26 mmol, 0.9 eq) in DMF (5.0 mL) were added HBTU (1.33 g, 3.50 mmol, 2.5 eq) and DIEA (724 mg, 5.60 mmol, 976 pL, 4.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. /c/V-Butyl (l-(3-((l-(7-methoxyquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)propan-2-yl)carbam ate (485 mg, 959 pmol, 68% yield) was obtained as a yellow oil. M + H ⁺ = 506.3 (LCMS).

Step 2: tert-Butyl (l-(3-((l-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (349A-2)

To a solution of tert-butyl (l-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (485 mg, 959 pmol, 1.0 eq) in DCM (10 mL) was added BBr, (3.60 g, 14.4 mmol, 1.39 mL, 15 eq) at -78 °C. The mixture was stirred at -78 °C under a N2 atmosphere for 1 h. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into saturated aqueous NaHCO, (30 mL), then the mixture was concentrated under vacuum to give the crude product tert-butyl (l-(3-((l-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (108 mg) as a yellow oil. M + H ⁺ = 492.2 (LCMS).

Step 3: 5-(l-(5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenz amido) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (349A-3)

To a solution of tert-butyl (l-(3-((l-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)propan-2-yl)carbamate (108 mg, 220 pmol, 1.0 eq) in THF (2.0 mL) was added t-BuOK (36.9 mg, 330 pmol, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 15 min. Then l,l,l-trifluoro-7V-phenyl-7V-((trifluoromethyl)sulfonyl)m ethanesulfonamide (117 mg, 330 pmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 0 °C for 30 min. LCMS indicated that the starting material was completely consumed. The mixture was quenched by saturated aqueous NaHCO, (5.0 mL), and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.46). 5- (l-(5-(2-((tert-Butoxycarbonyl)amino)propoxy)-2-methylbenzam ido)cyclopropyl)quinolin-7- yl trifluoromethanesulfonate (75.0 mg, 120 pmol, 54% yield) was obtained as a colourless oil. M + H ⁺ = 624.2 (LCMS).

Step 4: tert-Butyl (l-(4-methyl-3-((l-(7-methylquinolin-5-yl)cyclopropyl) carbamoyl) phenoxy)propan-2-yl)carbamate (349A-4)

To a solution of 5-(l-(5-(2-((ter/-butoxycarbonyl)amino)propoxy)-2-methylbenz amido) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (75.0 mg, 120 pmol, 1.0 eq) and 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (60.4 mg, 241 pmol, 67.3 pL, 50% purity, 2.0 eq) in DMF (1.5 mL) were added CS2CO3 (129 mg, 397 pmol, 3.3 eq) and Pd(dppf)C12.CH2C12 (9.82 mg, 12.0 pmol, 0.1 eq). The mixture was stirred at 110 °C under a N2 atmosphere for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude product tert-butyl (l-(4-methyl-3-((l-(7-methylquinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (80.0 mg) as a brown liquid. M + H ⁺ = 490.3 (LCMS).

Step 5: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(7-methylquinolin-5-yl)cyc lopropyl) benzamide (Compound 497)

To a solution of tert-butyl (l-(4-methyl-3-((l-(7-methylquinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (80.0 mg, 163 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(2-Aminopropoxy)-2-methyl-A-(l-(7- methylquinolin-5-yl)cyclopropyl)benzamide (36.2 mg, 71.9 pmol, 44% yield, TFA salt) as a white solid. M + H ⁺ = 390.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.31 (br d, J= 7.88 Hz, 1H), 9.18 (s, 1H), 9.03 (br d, J= 3.50 Hz, 1H), 7.98 (br s, 3H), 7.84 (br d, J= 6.13 Hz, 2H), 7.76 (br dd, J= 8.25, 4.13 Hz, 1H), 7.09 (d, J= 8.50 Hz, 1H), 6.90 (dd, J= 8.32, 2.56 Hz, 1H), 6.68 (d, = 2.50 Hz, 1H), 4.03 (dd, J= 10.26, 3.75 Hz, 1H), 3.86 (dd, J= 10.19, 7.07 Hz, 1H), 3.62 - 3.47 (m, 1H), 2.58 (s, 3H), 1.96 (s, 3H), 1.37 (br s, 2H), 1.30 - 1.16 (m, 5H).

Example 350:( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(7-methy lquinolin- 5-yl)cyclopropyl)benzamide (Compound 581)

Compound 581

Step 1: 5-Bromo-7-methylquinoline (350A-1)

To a solution of 5,7-dibromoquinoline (1.50 g, 5.23 mmol, 1.0 eq) and methylboronic acid (313 mg, 5.23 mmol, 1.0 eq) in a mixture of 1,4-dioxane (45 mL) and H2O (11 mL) were added Pd(dppf)C12 (382 mg, 523 pmol, 0.1 eq) and K2CO3 (1.44 g, 10.5 mmol, 2.0 eq). The mixture was degassed and purged with N2 three times, and then stirred at 70 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 5-Bromo-7-methylquinoline (1.00 g, 4.50 mmol, 43% yield) was obtained as a white solid. M + H ⁺ = 222.1 (LCMS).

Step 2: 7-Methylquinoline-5-carbonitrile (350A-2)

To a solution of 5-bromo-7-methylquinoline (1.00 g, 4.50 mmol, 1.0 eq) in DMF (30 mL) were added Zn(CN)2 (1.59 g, 13.5 mmol, 857 pL, 3.0 eq) BrettPhos Pd G3 (816 mg, 900 pmol, 0.2 eq), and BrettPhos (483 mg, 900 pmol, 0.2 eq). The mixture was stirred at 80 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 7- Methylquinoline-5-carbonitrile (600 mg, 3.57 mmol, 79% yield) was obtained as a white solid. M + H ⁺ = 169.2 (LCMS).

Step 3: l-(7-Methylquinolin-5-yl)cyclopropanamine (350A-3)

A mixture of 7-methylquinoline-5-carbonitrile (180 mg, 1.07 mmol, 1.0 eq) in anhydrous Et20 (20 mL) was degassed and purged with N2 three times. The mixture was stirred with a mechanical stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (456 mg, 1.61 mmol, 473 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et20, 784 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (304 mg, 2.14 mmol, 264 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(7- Methylquinolin-5-yl)cyclopropanamine (220 mg, crude) was obtained as a white solid. M + H ⁺ = 199.0 (LCMS).

Step 4: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-methy lquinolin-5- yl)cyclopropyl)benzamide (Compound 581)

A mixture of l-(7-methylquinolin-5-yl)cyclopropanamine (20.0 mg, 101 pmol, 1.0 eq) , S)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (23.7 mg, 101 pmol, 1.0 eq), HATU (76.7 mg, 202 pmol, 2.0 eq), and DIEA (39.1 mg, 303 pmol, 52.7 pL, 3.0 eq) in DMF (2.0 mL) was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (4.0 mL) and extracted with EtOAc (2.0 mL x 2), dried over Na2SO4, filtered and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l- methylazeti din-2 -yl)methoxy)-7V-(l-(7-methylquinolin-5-yl)cy cl opropyl)benzamide (10.0 mg, 21.7 pmol, 22% yield) was obtained as a white solid. M + H ⁺ = 416.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.08 (s, 1H), 9.01 (d, J= 8.4 Hz, 1H), 8.85 (d, J= 4.1 Hz, 1H), 7.72 (d, J = 6.9 Hz, 2H), 7.50 (dd, J = 4.3, 8.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.83 (dd, J = 2.6, 8.4 Hz, 1H), 6.59 (d, J= 2.6 Hz, 1H), 3.86 (d, J= 5.5 Hz, 2H), 3.30 (s, 3H), 3.26 - 3.17 (m, 2H), 2.75 - 2.67 (m, 1H), 2.20 (s, 3H), 1.98 - 1.91 (m, 4H), 1.89 - 1.78 (m, 1H), 1.40 - 1.30 (m,

2H), 1.19 (br s, 2H).

Example 351: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7- (trifluoromethyl)quinolin-5-yl)cyclopropyl)benzamide (Compound 600)

Compound 600

Step 1: 5-Bromo-7-(trifluoromethyl)quinoline (351 A-2)

To a solution of 7-(trifluoromethyl)quinoline (900 mg, 4.56 mmol, 1.0 eq) in H2SO4 (9.0 mL, 98% purity) was added NBS (1.62 g, 9.13 mmol, 2.0 eq) at 70 °C. The mixture was stirred at 70 °C for 3.5 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and then quenched by saturated aqueous NaHCO, (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried overlSfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 5-Bromo-7-(trifluoromethyl)quinoline (735 mg, 2.50 mmol, 93% yield) was obtained as a white solid. M + H ⁺ = 276.0 (LCMS).

Step 2: 7-(Trifluoromethyl)quinoline-5-carbonitrile (351A-3)

To a solution of 5-bromo-7-(trifluoromethyl)quinoline (735 mg, 2.66 mmol, 1.0 eq) in DMF (10 mL) were added Pd(PPh3)4 (307 mg, 266 pmol, 0.1 eq) and Zn(CN)2 (712 mg, 6.07 mmol, 2.3 eq) at 20 °C. The resulting mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature. The mixture was treated with H2O (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 0/1. 7- (Trifluoromethyl)quinoline-5-carbonitrile (528 mg, 2.31 mmol, 86% yield) was obtained as a white solid. M + H ⁺ = 223.1 (LCMS).

Step 3: l-(7-(Trifluoromethyl)quinolin-5-yl)cyclopropanamine (351A-4)

A mixture of 7-(trifluoromethyl)quinoline-5-carbonitrile (50.0 mg, 225 pmol, 1.0 eq) in anhydrous Et2O (10 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (95.9 mg, 337 pmol, 99.6 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 165 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (63.8 mg, 450 pmol, 55.5 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.55). l-(7-(Trifluoromethyl)quinolin-5-yl)cyclopropanamine (10.0 mg, 37.0 pmol, 16% yield) was obtained as a yellow oil. M + H ⁺ = 253.1 (LCMS). Step 4: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(tr ifluoromethyl) quinolin-5-yl)cyclopropyl)benzamide (Compound 600)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (11.3 mg, 41.0 pmol, 1.2 eq, HC1 salt) and l-(7-(trifluoromethyl)quinolin-5-yl)cyclopropanamine (10.0 mg, 34.6 pmol, 1.0 eq, HC1 salt) in DMF (1.0 mL) were added HBTU (32.8 mg, 86.6 pmol, 2.5 eq) and DIEA (13.4 mg, 103 pmol, 18.1 pL, 3.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Phenomenex Gemini C18 column (150 x 40 mm, 10 pm); flow rate: 60 mL/min; gradient: 5% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)- 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(7-(trifluo romethyl)quinolin-5-yl) cyclopropyl)benzamide (6.90 mg, 99.7 pmol, 39% yield) was obtained as a yellow solid. M + H ⁺ = 470.2 (LCMS); 'H NMR (400 MHz, DMSO ) 510.55 - 10.38 (m, 1H), 9.29 (s, 1H), 9.24 (br d, J= 8.6 Hz, 1H), 9.11 (dd, J = 1.4, 4.1 Hz, 1H), 8.34 (s, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.83 (dd, J= 4.3, 8.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 2.7, 8.3 Hz, 1H), 6.72 (d, = 2.6 Hz, 1H), 4.66 - 4.56 (m, 1H), 4.35 - 4.28 (m, 1H), 4.25 - 4.18 (m, 1H), 3.85 - 3.80 (m, 2H), 2.90 - 2.85 (m, 1H), 2.81 (d, J= 4.9 Hz, 3H), 2.44 (br d, J= 5.5 Hz, 1H), 1.94 (s, 3H), 1.42 (br s, 2H), 1.31 (br s, 2H).

Example 352: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(prop -l-en-2-yl) quinolin-5-yl)cyclopropyl)benzamide (Compound 568) Step 2

352A-1

Compound 568

Step 1 : (5)-5-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do)cyclopropyl) quinolin-7-yl trifluoromethanesulfonate (352A-1)

To a solution of (5)-7V-(l-(7-hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l- methylazetidin-2-yl)methoxy)benzamide (450 mg, 1.08 mmol, 1.0 eq) in THF (27 mL) was added Z-BuOK (242 mg, 2.16 mmol, 2.0 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. l,l,l-Trifluoro-7V-phenyl-7V-((trifluoromethyl)sulfonyl)meth anesulfonamide (770 mg, 2.16 mmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over NajSCL filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. (5)-5-(l-(2-Methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl) quinolin-7-yl trifluoromethanesulfonate (370 mg, 673 pmol, 31% yield) was obtained as a yellow solid. M + H ⁺ = 550.2 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.21 (s, 1H), 9.14 (d, J= 8.5 Hz, 1H), 9.05 (dd, J= 1.5, 4.3 Hz, 1H), 8.08 (d, J= 2.5 Hz, 1H), 7.88 (d, J= 2.5 Hz, 1H), 7.74 (dd, J= 4.2, 8.7 Hz, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.85 (dd, J= 2.7, 8.3 Hz, 1H), 6.64 (d, J= 2.8 Hz, 1H), 3.89 (d, J= 5.4 Hz, 2H), 3.29 - 3.25 (m, 1H), 2.84 - 2.73 (m, 1H), 2.24 (s, 3H), 1.99 (s, 1H), 1.98 - 1.94 (m, 1H), 1.92 (s, 3H), 1.90 - 1.81 (m, 1H), 1.44 - 1.38 (m, 2H), 1.30 - 1.25 (m, 2H).

Step 2: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(pr op-l-en-2-yl) quinolin-5-yl)cyclopropyl)benzamide (Compound 568)

To a solution of (8)-5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do) cyclopropyl) quinolin-7-yl trifluoromethanesulfonate (70.0 mg, 127 pmol, 1.0 eq) and 2- isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (23.5 mg, 140 pmol, 1.1 eq) in a mixture of dioxane (5.0 mL) and H2O (1.0 mL) were added NajCO, (31.0 mg, 293 pmol, 2.3 eq) and Pd(dppf)C12 (10.4 mg, 12.7 pmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL) and extracted with DCM (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 15% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(7-(pr op-l-en- 2-yl) quinolin-5-yl) cyclopropyl)benzamide (28.0 mg, 54.0 pmol, 43% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 442.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.65 (br d, J= 8.5 Hz, 1H), 9.33 (s, 1H), 9.21 (br d, J= 4.8 Hz, 1H), 8.31 (s, 1H), 8.19 (s, 1H), 8.03 (dd, J= 5.1, 8.4 Hz, 1H), 7.09 (br d, J= 8.4 Hz, 1H), 6.91 (br dd, = 2.4, 8.4 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 5.87 (s, 1H), 5.51 (s, 1H), 4.70 - 4.56 (m, 1H), 4.38 - 4.27 (m, 1H), 4.26 - 4.15 (m, 1H), 4.08 - 3.95 (m, 1H), 3.91 - 3.77 (m, 1H), 2.81 (s, 3H), 2.69 (s, 1H), 2.34 - 2.31 (m, 1H), 2.27 (s, 3H), 1.96 (s, 3H), 1.44 (br s, 2H), 1.34 (br s, 2H).

Example 353: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(thio phen-2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 551)

Compound 551 Step 1: 5-Bromo-7-(thiophen-2-yl)quinoline (353 A-l)

To a mixture of 5,7-dibromoquinoline (2.00 g, 6.97 mmol, 1.0 eq) and thiophen-2-ylboronic acid (713 mg, 5.58 mmol, 0.8 eq) in DMSO (100 mL) were added KOAc (2.74 g, 27.9 mmol, 4.0 eq), cataCXium A (1.25 g, 3.48 mmol, 0.5 eq) and Pd(0Ac)2 (313 mg, 1.39 mmol, 0.2 eq). The mixture was degassed and purged with N2 for 3 times, then stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (100 mL) and extracted with EtOAc (50 mL x 4). The combined organic layers were washed with brine (50 mL x 2), dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 5-Bromo-7-(thiophen-2-yl)quinoline (220 mg, 758 pmol, 11% yield) was obtained as a yellow solid. M + H ⁺ = 289.9 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.98 (dd, J= 1.5, 4.3 Hz, 1H), 8.48 (d, J= 8.7 Hz, 1H), 8.35 (d, J= 1.6 Hz, 1H), 8.25 (s, 1H), 7.89 (dd, J= 0.9, 3.6 Hz, 1H), 7.77 - 7.63 (m, 2H), 7.23 (dd, J= 3.8, 5.0 Hz, 1H).

Step 2: 7-(Thiophen-2-yl)quinoline-5-carbonitrile (353A-2)

To a mixture of 5-bromo-7-(thiophen-2-yl)quinoline (160 mg, 551 pmol, 1.0 eq) in DMF (8.0 mL) were added Zn(CN)2 (130 mg, 1.10 mmol, 70.0 pL, 2.0 eq), BrettPhos Pd G3 (100 mg, 110 pmol, 0.2 eq), BrettPhos (59.1 mg, 110 pmol, 0.2 eq). The mixture was stirred at 80 °C for 1 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 7- (Thiophen-2-yl)quinoline-5-carbonitrile (100 mg, 422 pmol 89% yield) was obtained as a yellow solid. ^X H NMR (400 MHz, DMSO-tL) 8 9.09 (dd, J= 1.6, 4.2 Hz, 1H), 8.71 (d, J= 1.9 Hz, 1H), 8.54 - 8.42 (m, 2H), 7.95 (dd, J= 0.9, 3.6 Hz, 1H), 7.82 - 7.70 (m, 2H), 7.26 (dd, J = 3.8, 5.0 Hz, 1H).

Step 3: l-(7-(Thiophen-2-yl)quinolin-5-yl)cyclopropanamine (353A-3)

A mixture of 7-(thiophen-2-yl)quinoline-5-carbonitrile (100 mg, 423 pmol, 1.0 eq) in anhydrous Et2O (20 mL) was degassed and purged with N2 three times. The mixture was cooled to -78 °C. To this mixture was added Ti(z-PrO)4 (180 mg, 635 pmol, 187 pL, 1.5 eq) slowly, and then EtMgBr (3 M, 310 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 2 h. BF3.Et2O (120 mg, 846 pmol, 104 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (8.0 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.24). l-(7-(Thiophen-2-yl)quinolin-5-yl)cyclopropanamine (25.0 mg, 93.9 pmol, 22% yield) was obtained as a yellow gum. 'H NMR (400 MHz, CDCL) 8 8.97 (br d, J= 2.7 Hz, 1H), 8.79 (br d, J= 8.2 Hz, 1H), 8.29 (s, 1H), 7.89 (s, 1H), 7.56 (d, J = 4.0 Hz, 1H), 7.49 (br dd, J= 4.1, 8.6 Hz, 1H), 7.42 (d, J= 4.8 Hz, 1H), 7.19 (dd, J= 3.7, 5.0 Hz, 1H), 1.31 - 1.18 (m, 4H).

Step 4: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(th iophen-2-yl)quinolin -5-yl)cyclopropyl)benzamide (Compound 551)

To a solution of (A)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (20.0 mg, 85.0 pmol, 1.0 eq) and l-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropanamine (22.6 mg, 85.0 pmol, 1.0 eq) in DMF (2.0 mL) were added HATU (80.8 mg, 213 pmol, 2.5 eq) and DIEA (33.0 mg, 255 pmol, 44.4 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (8)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)- A-(l-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (8.70 mg, 17.4 pmol, 21% yield) was obtained as a yellow solid. M + H ⁺ = 484.1 (LCMS); 'H NMR (400 MHz, CDCL) 6 9.02 (d, J = 8.6 Hz, 1H), 8.94 (dd, J = 1.4, 4.1 Hz, 1H), 8.29 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.58 (d, J= 3.6 Hz, 1H), 7.47 (dd, J= 4.1, 8.5 Hz, 1H), 7.38 (d, J= 5.0 Hz, 1H), 7.16 (dd, J= 3.8, 4.9 Hz, 1H), 7.04 - 6.97 (m, 1H), 6.82 - 6.76 (m, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.51 - 6.37 (m, 1H), 3.94 - 3.83 (m, 2H), 3.44 (br d, J= 4.1 Hz, 1H), 3.37 - 3.26 (m, 1H), 2.84 (q, J= 7.6 Hz, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 2.08 - 1.98 (m, 2H), 1.67 - 1.64 (m, 2H), 1.46 - 1.41 (m, 2H).

Example 354: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(7-(oxa zol-2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 588)

Compound 588

Step 1 : (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(ox azol-2-yl)quinolin-5- yl)cyclopropyl)benzamide (Compound 588)

To a solution of (8)-5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do) cyclopropyl)quinolin-7-yltrifluoromethanesulfonate (65.0 mg, 118 pmol, 1.0 eq) and 2- (tributylstann yl)oxazole (84.7 mg, 237 pmol, 2.0 eq) in DMF (5.0 mL) was added Pd(PPh ₃ ) ₂ C12 (8.30 mg, 11.8 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 60 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC (Phenomenex luna Cl 8 column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 5% - 35% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(7- (oxazol-2-yl)quinolin-5-yl)cyclo propyl)benzamide (12.1 mg, 24.8 pmol, 21% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 469.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.34 (d, J= 8.5 Hz, 1H), 9.28 (s, 1H), 9.12 (dd, J= 1.4, 4.5 Hz, 1H), 8.62 - 8.52 (m, 2H), 8.37 (s, 1H), 7.85 (dd, J= 4.6, 8.6 Hz, 1H), 7.53 (s, 1H), 7.14 - 7.06 (m, 1H), 6.99 - 6.88 (m, 1H), 6.80 - 6.69 (m, 1H), 4.73 - 4.52 (m, 1H), 4.32 - 4.17 (m, 2H), 4.01 (dt, J= 4.8, 9.6 Hz, 1H), 3.85 (q, J= 9.4 Hz, 1H), 2.82 (s, 3H), 2.40 - 2.26 (m, 2H), 1.94 (s, 3H), 1.45 (br s, 2H), 1.31 (br s, 2H).

Example 355: /V-(l-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin- 2-yl)methoxy)benzamide (Compound 436)

Compound 436

Step 1: tert-Butyl (l-(quinolin-5-yl)cyclopropyl)carbamate (355A-1)

To a solution of l-(quinolin-5-yl)cyclopropanamine (590 mg, 2.71 mmol, 1.0 eq) in DCM (40 mL) were added TEA (549 mg, 5.43 mmol, 755 pL, 2.0 eq) and BOC2O (711 mg, 3.26 mmol, 748 pL, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl (l-(quinolin-5-yl)cyclopropyl)carbamate (590 mg, 2.07 mmol, 76% yield) was obtained as a white solid. M + H ⁺ = 285.1 (LCMS). Step 2: 5-(l-((tert-Butoxycarbonyl)amino)cyclopropyl)quinoline 1-oxide (355A-2)

To a solution of tert-butyl (l-(quinolin-5-yl)cyclopropyl)carbamate (290 mg, 1.02 mmol, 1.0 eq) in DCM (20 mL) was added m-CPBA (311 mg, 1.53 mmol, 85% purity, 1.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with saturated aqueous NaHCOs (20 mL) and extracted with DCM (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 0/1 to 1/5. 5-(l-((tert-Butoxycarbonyl)amino)cyclopropyl)quinoline 1-oxide (240 mg, 799 pmol, 78% yield) was obtained as a white solid. M + H ⁺ = 301.1 (LCMS).

Step 3: l-(2-Chloroquinolin-5-yl)cyclopropanamine (355A-3)

A solution of 5-(l-((tert-butoxycarbonyl)amino)cyclopropyl)quinoline 1-oxide (410 mg, 1.37 mmol, 1.0 eq) in POCL (6.60 g, 43.1 mmol, 4.00 mL, 31 eq) was stirred at 80 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to remove POCL, the residue was diluted with H2O (5.0 mL), basified to pH 7 by using NH3.H2O (25% purity), and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/5. l-(2-Chloroquinolin-5-yl)cyclopropanamine (150 mg, 686 pmol, 50% yield) was obtained as a white solid. M + H ⁺ = 219.0 (LCMS).

Step 4: N-( l-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methyla zetidin-2- yl)methoxy)benzamide (Compound 436)

To a solution of l-(2-chloroquinolin-5-yl)cyclopropanamine (50.0 mg, 229 pmol, 1.0 eq) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (53.8 mg, 229 pmol, 1.0 eq) in DMF (5.0 mL) were added DIEA (88.6 mg, 686 pmol, 119 pL, 3.0 eq) and HBTU (173 mg, 457 pmol, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 7V-(l-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (12.1 mg, 21.7 pmol, 9% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 436.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e)) 8 9.87 (br dd, J= 1.8, 8.0 Hz, 1H), 9.24 - 9.05 (m, 2H), 7.91 (dd, J= 7.7, 14.4 Hz, 2H), 7.82 - 7.74 (m, 1H), 7.69 (d, J= 8.9 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.71 (d, = 2.6 Hz, 1H), 4.61 (br d, J= 4.0 Hz, 1H), 4.33 - 4.16 (m, 2H), 4.07 - 3.98 (m, 1H), 3.91 - 3.85 (m, 1H), 2.84 (d, = 4.8 Hz, 3H), 2.42 - 2.20 (m, 2H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.29 - 1.19 (m, 2H).

Example 356: /V-(l-(2-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-

2-yl)methoxy)benzamide (Compound 529)

Compound 529

Step 1: l-(2-Fluoroquinolin-5-yl)cyclopropanamine (356A-1)

To a solution of tert-butyl (l-(2-chloroquinolin-5-yl)cyclopropyl)carbamate (130 mg, 408 pmol, 1.0 eq) in DMSO (5.0 mL) was added CsF (92.9 mg, 612 pmol, 22.5 pL, 1.5 eq). The mixture was stirred at 140 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.1). l-(2- Fluoroquinolin-5-yl)cyclopropanamine (35.0 mg, 173 pmol, 42% yield) was obtained as a white solid. M + H ⁺ = 203.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.14 - 9.03 (m, 1H), 7.78 - 7.73 (m, 1H), 7.71 (d, J= 7.1 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.40 (dd, J= 2.9, 9.0 Hz, 1H), 1.04 (d, J= 2.3 Hz, 2H), 0.95 - 0.79 (m, 2H).

Step 2: /V-(l-(2-Fluoroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-2- yl)methoxy)benzamide (Compound 529)

To a solution of l-(2-fluoroquinolin-5-yl)cyclopropanamine (20.0 mg, 98.9 pmol, 1.0 eq) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (23.3 mg, 98.9 pmol, 1.0 eq) in DMF (2.0 mL) were added DIEA (38.4 mg, 297 pmol, 51.7 pL, 3.0 eq) and HATU (75.2 mg, 198 pmol, 2.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (2.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3 with NH3.H2O (0.05%), mobile phase B: acetonitrile). A-(l-(2-Fluoroquinolin-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (6.00 mg, 14.5 pmol, 15% yield) was obtained as a yellow solid. M + H ⁺ = 420.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.29 (t, J= 8.8 Hz, 1H), 9.13 (s, 1H), 7.96 - 7.86 (m, 1H), 7.85 - 7.72 (m, 2H), 7.45 (dd, J= 2.6, 9.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 2.8, 8.4 Hz, 1H), 6.63 (d, J= 2.6 Hz, 1H), 3.87 (d, J= 5.4 Hz, 2H), 3.24 (br dd, J= 2.3, 6.2 Hz, 2H), 2.80 - 2.62 (m, 1H), 2.21 (s, 3H), 1.95 (s, 5H), 1.49 - 1.30 (m, 2H), 1.29 - 1.16 (m, 2H).

Example 357 : (A)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(2-met hylquinolin- 5-yl)cyclopropyl)benzamide (Compound 547)

Compound 436

Compound 547

Step 1 : (A)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(2-met hylquinolin-5- yl)cyclopropyl)benzamide (Compound 547)

To a solution of f5)-7V-(l-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin- 2-yl)methoxy)benzamide (80.0 mg, 184 pmol, 1.0 eq) in DMF (4.0 mL) were added 2,4,6- trimethyl-l,3,5,2,4,6-trioxatriborinane (185 mg, 734 pmol, 205 pL, 50% purity in THF, 4.0 eq), CS2CO3 (197 mg, 606 pmol, 3.3 eq) and Pd(dppf)C12 (44.9 mg, 55.1 pmol, 0.3 eq). The mixture was degassed and purged with N2 three times. The mixture was stirred at 110 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). f£J-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(2-me thylquinolin-5- yl)cyclopropyl)benzamide (27.2 mg, 58.9 pmol, 32% yield, FA salt) was obtained as a white solid. M + H ⁺ = 416.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.10 (s, 1H), 8.97 (d, J = 8.6 Hz, 1H), 8.18 (s, 1H), 7.94 - 7.74 (m, 2H), 7.69 - 7.59 (m, 1H), 7.48 (d, J= 8.8 Hz, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6.85 (dd, J = 2.6, 8.4 Hz, 1H), 6.62 (d, J = 2.6 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.43 - 3.31 (m, 2H), 2.87 (br d, J= 7.9 Hz, 1H), 2.67 (s, 3H), 2.29 (s, 3H), 2.08 - 1.97 (m, 1H), 1.97 - 1.93 (m, 3H), 1.91 (s, 1H), 1.36 (s, 2H), 1.19 (br d, J= 1.3 Hz, 2H).

Example 358: (A)-/V-(l-(2-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l- methylazetidin-2-yl)methoxy)benzamide (Compound 545)

Compound 436

Compound 545

Step 1 : A -A-(l-(2-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-me thylazetidin-2- yl)methoxy)benzamide (Compound 545)

To a solution of (A)-A-(l-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin- 2-yl)methoxy)benzamide (70.0 mg, 161 pmol, 1.0 eq) in a mixture of dioxane (7.0 mL) and H2O (7.0 mL) were added KOH (180 mg, 3.21 mmol, 20 eq), Pd2(dba)3 (2.94 mg, 3.21 pmol, 0.02 eq) and LBu Xphos (5.45 mg, 12.8 pmol, 0.08 eq). The mixture was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 15% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (A)-A-(l-(2-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin- 2-yl)methoxy)benzamide (15.0 mg, 35.4 pmol, 22% yield, FA salt) was obtained as a white solid. M + H ⁺ = 418.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.74 (br s, 1H), 9.02 (s, 1H), 8.65 (d, J = 9.9 Hz, 1H), 7.53 - 7.35 (m, 2H), 7.32 - 7.14 (m, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.85 (dd, J= 2.6, 8.3 Hz, 1H), 6.65 (d, J= 2.6 Hz, 1H), 6.54 (d, J= 9.9 Hz, 1H), 3.89 (d, J = 5.4 Hz, 2H), 3.28 - 3.25 (m, 2H), 2.75 (br d, J= 8.1 Hz, 1H), 2.24 (s, 3H), 2.01 (s, 3H), 1.98 - 1.74 (m, 2H), 1.28 (br s, 2H), 1.13 (br s, 2H). Example 359: (A)-/V-(l-(2-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l- methylazetidin-2-yl)methoxy)benzamide (Compound 544)

Compound 436 Compound 544

Step 1 : (A)-A-(l-(2-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin-2- yl)methoxy)benzamide (Compound 544)

To a solution of (A)-A-(l-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin- 2-yl)methoxy)benzamide (70.0 mg, 161 pmol, 1.0 eq) in MeOH (4.0 mL) was added NaOMe (49.5 mg, 916 pmol, 4.0 eq). The mixture was stirred at 70 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (A)-A-(l-(2-Methoxyquinolin-5-yl)cyclopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (14.8 mg, 34.1 pmol, 21% yield, FA salt) was obtained as a white solid. M + H ⁺ = 432.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.07 (s, 1H), 8.97 (d, J= 9.1 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.64 - 7.51 (m, 1H), 7.05 (dd, J = 8.8, 16.3 Hz, 2H), 6.83 (dd, J= 2.6, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.98 (s, 3H), 3.87 (d, J= 5.3 Hz, 1H), 3.28 - 3.11 (m, 3H), 2.73 (br d, J = 8.3 Hz, 1H), 2.22 (s, 3H), 1.95 (s, 4H), 1.90 - 1.77 (m, 1H), 1.48 - 1.26 (m, 2H), 1.24 - 1.03 (m, 2H).

Example 360: (A)-/V-(l-(2-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 548)

Compound 436

Compound 548

Step 1 : A)-/V-(l-(2-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 548)

To a solution of (A)-A-(l-(2-chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin- 2-yl)methoxy)benzamide (70.0 mg, 161 pmol, 1.0 eq) and dimethylamine (2 M in THF, 161 pmol, 2.0 eq) in DMSO (4.0 mL) were added DIEA (41.5 mg, 321 pmol, 55.9 pL, 2.0 eq) and CsF (48.8 mg, 321 pmol, 11.8 pL, 2.0 eq). The mixture was stirred at 120 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). (S)-N-(l-(2- (Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methyl-5-((l-met hylazetidin-2-yl)methoxy) benzamide (22.0 mg, 49.3 pmol, 31% yield, FA salt) was obtained as a white solid. M + H ⁺ = 445.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.02 (s, 1H), 8.77 (d, J= 9.4 Hz, 1H), 8.16 (s, 2H), 7.59 - 7.34 (m, 3H), 7.16 - 6.99 (m, 2H), 6.84 (dd, J = 2.6, 8.3 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H), 3.95 (br d, J= 4.4 Hz, 2H), 3.56 - 3.34 (m, 2H), 3.16 (s, 6H), 3.02 - 2.86 (m, 1H), 2.34 (s, 3H), 2.03 (br s, 1H), 1.98 (s, 3H), 1.96 - 1.78 (m, 1H), 1.31 (s, 2H), 1.12 (br s, 2H).

Example 361: ( )-/V-(l-(2-Methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 555)

Cl CI MeO^ ^/CI Pd ₂ (dba) ₃

T J Tol T J ^DMA step 1 step 2

361A-1 361A-2 361A-3

Compound 555

Step 1: 4-Chloro-2-methoxyquinoline (361 A-2)

To a solution of 2,4-dichloroquinoline (3.00 g, 15.2 mmol, 1.0 eq) in toluene (200 mL) was added NaOMe (3.11 g, 57.6 mmol, 3.8 eq). The mixture was stirred at 120 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (150 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. 4- Chloro-2-methoxyquinoline (2.27 g, 11.7 mmol, 77% yield) was obtained as a white solid. M + H ⁺ = 194.0 (LCMS).

Step 2: 2-Methoxyquinoline-4-carbonitrile (361A-3)

To a solution of 4-chloro-2-methoxyquinoline (1.00 g, 5.16 mmol, 1.0 eq) in DMA (50 mL) were added Zn(CN)2 (1.09 g, 9.30 mmol, 590 pL, 1.8 eq), Pd2(dba)3 (709 mg, 775 pmol, 0.2 eq), Zn (101 mg, 1.55 mmol, 0.3 eq) and XPhos (492 mg, 1.03 mmol, 0.2 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 120 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. The crude product 2-methoxyquinoline-4- carbonitrile (940 mg) was obtained as a yellow solid. M + H ⁺ = 185.1 (LCMS). Step 3: l-(2-Methoxyquinolin-4-yl)cyclopropanamine (361A-4)

A mixture of 2-methoxyquinoline-4-carbonitrile (600 mg, 3.26 mmol, 1.0 eq) in Et20 (60 mL) was degassed and purged with N2 three times. To this mixture was added Ti(z-PrO)4 (1.34 g, 4.88 mmol, 1.44 mL, 1.5 eq) slowly at -78 °C and then EtMgBr (3 M, 2.38 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. Then BF3.Et2O (924 mg, 6.52 mmol, 804 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (I M aqueous) (120 mL) and MTBE (30 mL), and was extracted with MTBE (30 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. l-(2- Methoxyquinolin-4-yl)cyclopropanamine (190 mg, 887 pmol, 27% yield) was obtained as a yellow oil. M + H ⁺ = 215.1 (LCMS).

Step 4: (5)-/V-(l-(2-Methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 555)

To a solution of l-(2-methoxyquinolin-4-yl)cyclopropanamine (65.0 mg, 303 pmol, 1.0 eq) and (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (71.4 mg, 303 pmol, 1.0 eq) in DMF (7.0 mL) were added DIEA (118 mg, 910 pmol, 159 pL, 3.0 eq) and HBTU (127 mg, 334 pmol, 1.1 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 * 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (5)-7V-(l -(2 -Methoxy quinolin-4-yl)cy clopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (4.40 mg, 10.1 pmol, 3% yield) was obtained as a white solid. M + H ⁺ = 332.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.16 (s, 1H), 8.52 (d, J= 8.8 Hz, 1H), 7.80 (d, J= 8.8 Hz, 1H), 7.65 (t, J= 6.9 Hz, 1H), 7.46 (t, J= 7.7 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.84 (dd, J= 2.6, 8.4 Hz, 1H), 6.62 (d, J= 2.8 Hz, 1H), 3.98 (s, 3H), 3.86 (d, J= 5.4 Hz, 2H), 3.24 - 3.11 (m, 2H), 2.73 (br d, J = 2.1 Hz, 1H), 2.22 (s, 3H), 1.95 (s, 5H), 1.33 (s, 2H), 1.26 - 1.18 (m, 2H).

Example 362: N-( l-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-( ( 1 - methylazetidin-2-yl)methoxy)benzamide (Compound 467)

Compound 467

Step 1: 2,4-Dichloro-7-fluoroquinoline (362A-2) To a solution of malonic acid (7.59 g, 72.9 mmol, 7.59 mL, 1.0 eq) in POCL (30 mL) was added 3 -fluoroaniline (8.10 g, 72.9 mmol, 6.98 mL, 1.0 eq) at 20 °C. The mixture was stirred at 100 °C for 7 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, concentrated under vacuum to give a residue. The residue was diluted with EtOAc (20 mL), and then saturated aqueous NaHCO, solution was added to the solution slowly at 0 °C to adjust the pH 8. The resulting mixture was separated, and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/100. 2,4-Dichloro-7-fluoroquinoline (5.17 g, 24.0 mmol, 33% yield) was obtained as a white solid. M + H ⁺ = 216.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.26 - 8.16 (m, 1H), 7.68 (ddd, J= 9.38, 4.44, 2.31 Hz, 1H), 7.52 - 7.39 (m, 2H).

Step 2: 4-Chloro-7-fluoro-2-methoxyquinoline (362A-3)

To a solution of 2,4-dichloro-7-fluoroquinoline (4.77 g, 22.1 mmol, 1.0 eq) in MeOH (50 mL) was added NaOMe (19.9 g, 110 mmol, 30% purity in MeOH, 5.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was treated with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/100. 4-Chloro-7-fhioro-2-methoxyquinoline (3.60 g, 15.7 mmol, 71% yield) was obtained as awhite solid. M + H ⁺ = 212.1 (LCMS).

Step 3: 7-Fluoro-2-methoxyquinoline-4-carbonitrile (362A-4)

To a solution of 4-chloro-7-fluoro-2-methoxyquinoline (1.40 g, 6.62 mmol, 1.0 eq) in DMF (30 mL) were added Zn(CN)2 (1.55 g, 13.2 mmol, 2.0 eq) and Pd(PPh3)4 (764 mg, 662 pmol, 0.1 eq). The mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (90 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 7-Fluoro-2- methoxyquinoline-4-carbonitrile (1.14 g, 4.86 mmol, 73% yield) was obtained as a white solid. M + H ⁺ = 203.1 (LCMS).

Step 4: l-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropanamine (362A-5)

To a solution of 7-fluoro-2-methoxyquinoline-4-carbonitrile (100 mg, 495 pmol, 1.0 eq) in anhydrous Et2O (40 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (211 mg, 742 pmol, 219 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 363 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (140 mg, 989 pmol, 122 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (I M aqueous) (40 mL) and MTBE (40 mL) and extracted with MTBE (40 mL x 2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. l-(7-Fluoro-2- methoxyquinolin-4-yl)cyclopropanamine (150 mg, 520 pmol, 35% yield) was obtained as a yellow oil. M + H ⁺ = 233.3 (LCMS).

Step 5: /V-(l-(7-Fluoro-2-methoxyquinolin-4-yl)cyclopropyl)-2-methyl -5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 467)

To a solution of l-(7-fluoro-2-methoxyquinolin-4-yl)cyclopropanamine (120 mg, 517 pmol, 1.5 eq) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (93.6 mg, 344 pmol, 1.0 eq, HC1 salt) in DMF (2.0 mL) were added HBTU (327 mg, 861 pmol, 2.5 eq) and DIEA (223 mg, 1.72 mmol, 300 pL, 5.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with H2O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were washed with brine (9.0 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 40% - 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3 with NH3.H2O (0.05%), mobile phase B: acetonitrile). A-(l-(7- Fluoro-2-methoxyquinolin-4-yl)cyclopropyl)-2-methyl-5-((l -methyl azetidin-2-yl)methoxy) benzamide (14.7 mg, 32.7 pmol, 10% yield) was obtained as a pale yellow solid. M + H ⁺ = 450.3 (LCMS); ^X H NMR (400 MHz, CD3OD) 6 8.51 - 8.45 (m, 1H), 7.54 - 7.46 (m, 1H), 7.29 - 7.23 (m, 1H), 7.23 - 7.20 (m, 1H), 7.05 (d, J= 8.4 Hz, 1H), 6.87 - 6.83 (m, 1H), 6.65 (d, J = 2.6 Hz, 1H), 4.06 - 4.02 (m, 3H), 3.91 (d, J= 5.4 Hz, 2H), 3.51 - 3.43 (m, 1H), 3.42 - 3.36 (m, 1H), 2.98 - 2.89 (m, 1H), 2.39 - 2.35 (m, 3H), 2.10 - 2.01 (m, 2H), 2.01 - 1.98 (m, 3H), 1.46 - 1.40 (m, 2H), 1.34 - 1.29 (m, 2H). Example 363: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(3-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)phenyl)cyclopropyl)benzamide (Compound 565)

Compound 565

Step 1: 4-(l-Aminocyclopropyl)quinolin-2-ol (363 A-l)

A solution of l-(2-methoxyquinolin-4-yl)cyclopropanamine (180 mg, 840 pmol, 1.0 eq) inHBr (30 mL, 30% purity in water) was stirred at 130 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into NaHCO, aqueous (30 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue was used in the next step without any further purification. 4-(l-Aminocyclopropyl)quinolin-2-ol (120 mg, 600 pmol, 72% yield) was obtained as a yellow solid. M + H ⁺ = 201.1 (LCMS).

Step 2: (S)-\-( l-(2-Hydroxyqiiiiioliii-4-yl)cyclopropyl)-2-inetliyl-5-((l-i nethyl:izetidin-2- yl)methoxy)benzamide (Compound 565)

To a solution of 4-(l-aminocyclopropyl)quinolin-2-ol (110 mg, 549 pmol, 1.0 eq) and (S)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (129 mg, 549 pmol, 1.0 eq) in DMF (6.0 mL) were added DIEA (213 mg, 1.65 mmol, 287 pL, 3.0 eq) and HBTU (229 mg, 604 pmol, 1.1 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-7V-(l-(2-hydroxyquinolin-4-yl)cyclopropyl)-2-methyl-5-(( l- methylazetidin-2-yl)methoxy)benzamide (7.8 mg, 16.8 pmol, 3% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 418.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 89.10 (s, 1H), 8.27 (br d, J= 8.4 Hz, 1H), 7.50 (br t, J= 7.6 Hz, 1H), 7.34 (br d, J= 8.3 Hz, 1H), 7.21 (br t, J = 7.4 Hz, 1H), 7.11 (br d, J= 8.5 Hz, 1H), 6.93 (br dd, J = 2.5, 8.5 Hz, 1H), 6.74 (br d, J= 1.9 Hz, 1H), 6.68 (s, 1H), 4.69 - 4.57 (m, 1H), 4.36 - 4.19 (m, 2H), 4.11 - 3.97 (m, 1H), 3.93 - 3.79 (m, 1H), 2.90 - 2.79 (m, 3H), 2.39 - 2.26 (m, 2H), 1.99 (s, 3H), 1.27 (br s, 2H), 1.18 (br s, 2H).

Example 364: ( )-/V-(l-(7-Fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 542)

Compound 542

Step 1: 4-(l-Aminocyclopropyl)-7-fluoroquinolin-2-ol (364A-1)

To a solution of HBr (30 mL, 30% purity in water) was added l-(7-fluoro-2-methoxyquinolin- 4-yl)cyclopropanamine (320 mg, 1.38 mmol, 1.0 eq). The mixture was stirred at 120 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature and concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 4-(l-Aminocyclopropyl)- 7-fluoroquinolin-2-ol (150 mg, 513 pmol, 37% yield, TFA salt) was obtained as a yellow oil. M + H ⁺ = 219.2 (LCMS). Step 2: (5)-A-(l-(7-Fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 542)

To a solution of 4-(l-aminocyclopropyl)-7-fluoroquinolin-2-ol (120 mg, 550 pmol, 1.0 eq, TFA salt) in DMF (1.0 mL) was added (5)-2-methyl-5-((l-methylazetidin-2- yl)methoxy)benzoic acid (129 mg, 550 pmol, 1.2 eq), followed by HBTU (521 mg, 1.37 mmol, 2.5 eq) and DIEA (210 mg, 1.65 mmol, 2.87 mL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give (5)-A-(l-(7-fluoro-2-hydroxyquinolin-4- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (32.0 mg, 69.8 pmol, 13% yield, HC1 salt) as a white solid. M + H ⁺ = 436.0 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 6 ppm 11.79 (br s, 1H), 9.07 (s, 1H), 8.37 - 8.26 (m, 1H), 7.13 - 7.03 (m, 3H), 6.85 (dd, J= 8.44, 2.52 Hz, 1H), 6.65 - 6.57 (m, 2H), 3.87 (d, J= 5.48 Hz, 2H), 3.26 - 3.19 (m, 2H), 2.75 - 2.67 (m, 1H), 2.22 (s, 3H), 2.00 (s, 3H), 1.98 - 1.79 (m, 2H), 1.29 - 1.23 (m, 2H), 1.19 - 1.13 (m, 2H).

Example 365: (5)-A-(l-(2-Chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 586)

Compound 586 Step 1 : (5)-A-(l-(2-Chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 586)

To a solution of (5)-7V-(l-(7-fluoro-2-hydroxyquinolin-4-yl)cyclopropyl)-2-me thyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (43.0 mg, 98.7 pmol, 1.0 eq) in SOCh (1.7 mL) was added DMF (100 pL). The mixture was stirred at 20 °C for 3.5 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was quenched by saturated aqueous NaHCO, (30 mL) at 0 °C and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (800 x 30 mm, 3 pm); flow rate: 60 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(2-Chloro-7-fluoroquinolin-4- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (2.30 mg, 4.69 pmol, 5% yield) was obtained as a yellow gum. M + H ⁺ = 454.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.35 (s, 1H), 8.74 (dd, J= 6.2, 9.3 Hz, 1H), 7.79 (dd, J= 2.6, 10.1 Hz, 1H), 7.72 - 7.63 (m, 2H), 7.15 - 7.06 (m, 1H), 6.93 (dd, J= 2.6, 8.3 Hz, 1H), 6.81 - 6.68 (m, 1H), 4.70 - 4.58 (m, 1H), 4.37 - 4.28 (m, 1H), 4.27 - 4.18 (m, 1H), 4.05 - 3.97 (m, 1H), 3.91 - 3.85 (m, 1H), 2.86 - 2.80 (m, 3H), 2.40 - 2.27 (m, 2H), 2.00 - 1.90 (m, 3H), 1.41 - 1.31 (m, 4H).

Example 366: A)-/V-(l-(7-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5- ((l- methylazetidin-2-yl)methoxy)benzamide (Compound 538)

Compound 538 366A-5

Step 1: )-A-(3-Bromo-5-methoxybenzylidene)-2,2-dimethoxy ethanamine (366A-2)

To a solution of 3-bromo-5-methoxybenzaldehyde (21.0 g, 97.7 mmol, 1.0 eq) in toluene (220 mL) was added 2,2-dimethoxyethanamine (10.3 g, 97.7 mmol, 10.6 mL, 1.0 eq) at 20 °C. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, concentrated under vacuum to give a crude product (Z)-7V-(3-bromo-5-methoxybenzylidene)- 2,2-dimethoxyethanamine (30.0 g) as a yellow oil. M + H ⁺ = 302.0 (LCMS).

Step 2: 5-Bromo-7-methoxyisoquinoline (366A-3)

To a solution of (Z)-7V-(3-bromo-5-methoxybenzylidene)-2,2-dimethoxyethanamin e (10.0 g, 33.0 mmol, 1.0 eq) in toluene (30 mL) were added TFAA (13.9 g, 66.2 mmol, 9.21 mL, 2.0 eq) and BF3.Et2O (9.39 g, 66.2 mmol, 8.17 mL, 2.0 eq) at 0 °C. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was treated with water (50 mL), the aqueous layer was adjusted to pH 8 by using saturated aqueous NaHCO,. The aqueous layer was then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 5-Bromo-7-methoxyisoquinoline (8.30 g, 34.8 mmol, 35% yield) was obtained as a yellow solid. M + H ⁺ = 238.1 (LCMS).

Step 3: 7-Methoxyisoquinoline-5-carbonitrile (366A-4)

To a solution of 5-bromo-7-methoxyisoquinoline (300 mg, 1.26 mmol, 1.0 eq) in DMF (4.0 mL) were added Zn(CN)2 (370 mg, 3.15 mmol, 2.5 eq) and Pd(PPh3)4 (146 mg, 126 pmol, 0.1 eq). The mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. 7- Methoxyisoquinoline-5-carbonitrile (210 mg, 842 pmol, 67% yield) was obtained as a yellow solid. M + H ⁺ = 185.3 (LCMS).

Step 4: l-(7-Methoxyisoquinolin-5-yl)cyclopropanamine (366A-5)

A mixture of 7-methoxyisoquinoline-5-carbonitrile (50.0 mg, 271 pmol, 1.0 eq) in anhydrous Et2O (10 mL) was degassed and purged with N2 three times. The mixture was stirred at -78 °C. To this mixture was added Ti(z-PrO)4 (116 mg, 407 pmol, 120 pL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 199 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (77.1 mg, 543 pmol, 67.0 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that 29% starting material remained and 50% desired compound was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (60 mL) and MTBE (60 mL) and extracted with MTBE (60 mL x 2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (60 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 100/1. l-(7- Methoxyisoquinolin-5-yl)cyclopropanamine (12.5 mg, 30.5 pmol, 11% yield) was obtained as a yellow oil. M + H ⁺ = 215.3 (LCMS).

Step 5: A)-/V-(l-(7-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5- ((l-methylazetidin- 2-yl)methoxy)benzamide (Compound 538)

To a solution of l-(7-methoxyisoquinolin-5-yl)cyclopropanamine (50.0 mg, 233 pmol, 1.0 eq) and (A)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (54.9 mg, 233 pmol, 1.0 eq) in DMF (1.0 mL) were added HATU (177 mg, 467 pmol, 2.0 eq) and DIEA (90.5 mg, 700 pmol, 122 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 45% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3 with NH3.H2O (0.05%), mobile phase B: acetonitrile). (A)-A-(l-(7-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5- ((l-methylazetidin-2- yl)methoxy)benzamide (11.3 mg, 25.3 pmol, 11% yield) was obtained as a white solid. M + H ⁺ = 432.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.25 - 9.17 (m, 1H), 9.17 - 9.09 (m, 1H), 8.48 - 8.39 (m, 1H), 8.39 - 8.33 (m, 1H), 7.61 (d, J= 2.5 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.61 (d, J= 2.8 Hz, 1H), 3.95 - 3.89 (m, 3H), 3.86 (d, J= 5.4 Hz, 2H), 3.28 - 3.20 (m, 2H), 2.75 - 2.67 (m, 1H), 2.27 - 2.19 (m, 3H),

2.04 - 1.90 (m, 4H), 1.90 - 1.79 (m, 1H), 1.39 - 1.24 (m, 2H), 1.23 - 1.15 (m, 2H).

Example 367: /V-(l-(3-Hydroxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l - methylazetidin-2-yl)methoxy)benzamide (Compound 509)

Compound 509

Step 1: 3-Methoxyisoquinoline-5-carbonitrile (367A-2)

To a solution of 5-bromo-3-methoxyisoquinoline (4.00 g, 16.8 mmol, 1.0 eq) in DMF (40 mL) were added Zn(CN)2 (4.10 g, 35.0 mmol, 2.22 mL, 2.1 eq) and Pd(PPh3)4 (1.94 g, 1.68 mmol, 0.1 eq). The mixture was stirred at 120 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (120 mL x 3), dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 4/10. 3- Methoxyisoquinoline-5-carbonitrile (3.00 g, 16.2 mmol, 96% yield) was obtained as a white solid. M + H ⁺ = 185.1 (LCMS).

Step 2: l-(3-Methoxyisoquinolin-5-yl)cyclopropanamine (367A-3)

A mixture of 3-methoxyisoquinoline-5-carbonitrile (500 mg, 2.71 mmol, 1.0 eq) in anhydrous Et2O (100 mL) was degassed and purged with N2 three times. The mixture was stirred at - 78 °C. To this mixture was added Ti(z-PrO)4 (1.16 g, 4.07 mmol, 1.20 mL, 1.5 eq) slowly, and then EtMgBr (3 M in Et2O, 1.99 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C under a N2 atmosphere. After the addition was completed, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (771 mg, 5.43 mmol, 670 pL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that 12% starting material remained and 40% desired compound was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (100 mL) and MTBE (100 mL) and extracted with MTBE (100 mL x 2). The organic phase was discarded. The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of (DCM/MeOH = 10: l)/petroleum ether from 0/1 to 2/10. l-(3-Methoxyisoquinolin-5-yl)cyclopropanamine (300 mg, 1.29 mmol, 24% yield) was obtained as a yellow oil. M + H ⁺ = 215.2 (LCMS).

Step 3: 5-(l-Aminocyclopropyl)isoquinolin-3-ol (367A-4)

To a solution of l-(3-methoxyisoquinolin-5-yl)cyclopropanamine (200 mg, 933 pmol, 1.0 eq) in DCM (2.0 mL) was added BBn (3.51 g, 14.0 mmol, 1.35 mL, 15 eq) dropwise at -78 °C. The mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS and HPLC indicated that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NaHCCL solution (10 mL) slowly at 0 °C, extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 5-(l- aminocyclopropyl)isoquinolin-3-ol (40.0 mg, 127 pmol, 14% yield, TFA salt) as a red solid. M + H ⁺ = 201.3 (LCMS).

Step 4: /V-(l-(3-Hydroxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin-2- yl)methoxy)benzamide (Compound 509)

To a solution of 5-(l-aminocyclopropyl)isoquinolin-3-ol (35.0 mg, 111 pmol, 1.0 eq, TFA salt) and 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (26.2 mg, 96.4 pmol, 0.9 eq, HC1 salt) in DMF (1.0 mL) were added HBTU (84.5 mg, 223 pmol, 2.0 eq) and DIEA (43.2 mg, 334 pmol, 58.2 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give A-(l-(3-hydroxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2- yl)methoxy)benzamide (10.7 mg, 18.8 pmol, 17% yield, TFA salt) as a yellow solid. M + H ⁺ = 418.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.83 - 8.65 (m, 1H), 8.02 - 7.92 (m, 1H), 7.80 (d, J= 8.5 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.31 - 7.19 (m, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.79 (d, J= 2.8 Hz, 1H), 4.74 - 4.63 (m, 1H), 4.33 - 4.26 (m, 1H), 4.26 - 4.09 (m, 2H), 4.02 - 3.90 (m, 1H), 3.02 - 2.90 (m, 3H), 2.61 - 2.50 (m, 2H), 2.12 - 2.05 (m, 3H), 1.45 - 1.38 (m, 2H), 1.30 - 1.24 (m, 2H).

Example 368: /V-(3-Fluorobenzyl)-l-(l-(quinolin-5-yl)ethyl)piperidine-4-c arboxamide (Compound 549)

368A-4

Compound 549

Step 1: l-(Quinolin-5-yl)ethanol (368A-2)

To a solution of l-(quinolin-5-yl)ethanone (200 mg, 1.17 mmol, 1.0 eq) in MeOH (12 mL) was added NaBHj (66.3 mg, 1.75 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into ice water (15 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.6). l-(Quinolin-5-yl)ethanol (120 mg, 693 pmol, 60% yield) was obtained as a colorless oil. M + H ⁺ = 174.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.94 (dd, J = 1.5, 4.1 Hz, 1H), 8.58 (d, J= 8.8 Hz, 1H), 8.11 - 8.03 (m, 1H), 7.77 - 7.69 (m, 2H), 7.45 (dd, J= 4.1, 8.6 Hz, 1H), 5.72 - 5.53 (m, 1H), 2.06 - 1.99 (m, 1H), 1.70 (d, J= 6.5 Hz, 3H).

Step 2: Ethyl l-(l-(quinolin-5-yl)ethyl)piperidine-4-carboxylate (368A-3)

To a solution of l-(quinolin-5-yl)ethanol (70.0 mg, 404 pmol, 1.0 eq) and DIEA (209 mg, 1.62 mmol, 282 pL, 4.0 eq) in DCM (5.0 mL) was added a mixture of MS2O (70.4 mg, 404 pmol, 1.0 eq) in DCM (500 pL) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. Then ethyl piperidine-4-carboxylate (63.5 mg, 404 pmol, 62.3 pL, 1.0 eq) was added. The mixture was stirred at 20 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.5). Ethyl l-(l-(quinolin-5-yl)ethyl)piperidine-4- carboxylate (100 mg) was obtained as a colorless oil.

Step 3: l-(l-(Quinolin-5-yl)ethyl)piperidine-4-carboxylic acid (368A-4)

To a solution of ethyl l-(l-(quinolin-5-yl)ethyl)piperidine-4-carboxylate (100 mg, 320 pmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and H2O (0.6 mL) was added NaOH (1 M aqueous, 640 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. H2O (5.0 mL) was added and the mixture was washed with MTBE (3.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (I M aqueous). The product was extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product l-(l-(quinolin-5-yl)ethyl)piperidine-4-carboxylic acid (100 mg), which was used in the next step without any further purification. M + H ⁺ = 285.0 (LCMS).

Step 4: /V-(3-Fluorobenzyl)-l-(l-(quinolin-5-yl)ethyl)piperidine-4-c arboxamide (Compound 549)

To a solution of l-(l-(quinolin-5-yl)ethyl)piperidine-4-carboxylic acid (100 mg, 352 pmol, 1.0 eq) and (3-fluorophenyl)methanamine (48.4 mg, 387 pmol, 44.0 pL 1.1 eq) in DMF (5.0 mL) were added DIEA (45.5 mg, 352 pmol, 61.3 pL, 1.0 eq), EDCI (67.4 mg, 352 pmol, 1.0 eq) and HOBt (57.0 mg, 422 pmol, 1.2 eq). The mixture was stirred at 20 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). N-(3 -Fluorobenzyl)- 1-(1- (quinolin-5-yl)ethyl)piperidine-4-carboxamide (19.3 mg, 45.1 pmol, 13% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 392.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 10.76 - 10.57 (m, 1H), 9.23 - 9.10 (m, 2H), 8.57 - 8.46 (m, 1H), 8.38 (br d, J= 7.1 Hz, 1H), 8.26 (br d, J= 8.4 Hz, 1H), 8.04 (br t, J= 7.9 Hz, 1H), 7.85 (br dd, J= 4.2, 8.4 Hz, 1H), 7.45 - 7.26 (m, 1H), 7.16 - 6.93 (m, 3H), 5.55 - 5.34 (m, 1H), 4.26 (br d, J= 5.9 Hz, 2H), 3.95 (br d, J= 12.1 Hz, 1H), 3.20 - 2.77 (m, 3H), 2.41 (br d, J= 4.0 Hz, 1H), 2.20 - 1.97 (m, 2H), 1.91 - 1.75 (m, 5H).

Example 369: /V-(3-Fluorobenzyl)-l-(l-(isoquinolin-5-yl)ethyl)piperidine- 4-carboxamide (Compound 522)

369A-1 369A-2

Compound 522

Step 1: l-(Isoquinolin-5-yl)ethanol (369A-2)

A solution of isoquinoline-5-carbaldehyde (500 mg, 3.18 mmol, 1.0 eq) in THF (10 mL) was degassed and purged with N2 three times. To this mixture was added MeMgBr (3 M in Et20, 1.06 mL, 1.0 eq) dropwise at -78 °C. The mixture was stirred at the same temperature for 30 min under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 1- (Isoquinolin-5-yl)ethanol (238 mg, 1.37 mmol, 43% yield) was obtained as a yellow solid. M + H ⁺ = 174.1 (LCMS).

Step 2: \-(3-I luorobenzyl)-l-( l-(isoquinolin-5-yl)ethyl)piperidine-4-carboxamide (Compound 522)

To a solution of l-(isoquinolin-5-yl)ethanol (127 mg, 733 pmol, 1.0 eq) in DCM (5.0 mL) were added DIEA (379 mg, 2.93 mmol, 511 pL, 4.0 eq) and methyl sulfonyl methanesulfonate (128 mg, 733 pmol, 1.0 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. N-(3- Fluorobenzyl)piperidine-4-carboxamide(200 mg, 733 pmol, 1.0 eq, HC1 salt) was added in portions. The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 40 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile). N-(3 -Fluorob enzyl)-l-(l-(i soquinolin-5- yl)ethyl)piperidine-4-carboxamide (5.60 mg, 14.3 pmol, 2% yield) was obtained as a white solid. M + H ⁺ = 392.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.29 (s, 1H), 8.50 (d, J = 6.1 Hz, 1H), 8.27 (br d, J= 6.0 Hz, 2H), 8.00 (d, J= 8.0 Hz, 1H), 7.78 (d, J= 7.1 Hz, 1H), 7.64 (s, 1H), 7.40 - 7.24 (m, 1H), 7.09 - 6.93 (m, 3H), 4.24 (d, J= 6.0 Hz, 2H), 4.19 - 4.13 (m, 1H), 3.06 - 2.96 (m, 1H), 2.82 - 2.73 (m, 1H), 2.19 - 2.09 (m, 1H), 2.07 - 1.96 (m, 2H), 1.76 - 1.67 (m, 1H), 1.59 (br s, 3H), 1.40 (d, J= 6.6 Hz, 3H).

Example 370: /V-(3-Fluorobenzyl)-l-(l-(3-methoxynaphthalen-l-yl)ethyl)pip eridine-4- carboxamide (Compound 524)

Compound 524

Step 1: l-(l-Ethoxyvinyl)-3-methoxynaphthalene (370A-1)

To a solution of l-bromo-3 -methoxynaphthalene (100 mg, 422 pmol, 1.0 eq) in toluene (2.0 mL) were added tributyl(l-ethoxyvinyl)stannane (305 mg, 844 pmol, 2.0 eq) and Pd(dppf)C12 (30.9 mg, 42.2 pmol, 0.1 eq). The mixture was stirred at 110 °C for 16 h under aN2 atmosphere. LCMS indicated that the starting material remained, and the desired mass was detected. The mixture was allowed to cool to room temperature, poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/10, R/= 0.6). 1-(1 -Ethoxy vinyl)-3 -methoxynaphthalene (82.2 mg, 360 pmol, 85% yield) was obtained as a white solid. M + H ⁺ = 229.2 (LCMS). Step 2: l-(3-Methoxynaphthalen-l-yl)ethanone (370A-2)

To a solution of HCl/EtOAc (4 M, 1.0 mL) was added 1-(1 -ethoxy vinyl)-3- methoxynaphthalene (82.2 mg, 360 pmol, 1.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/10, R/= 0.59). 1 -(3 -Methoxynaphthal en-l-yl)ethanone (40.1 mg, 178 pmol, 50% yield) was obtained as a yellow oil. M + H ⁺ = 201.1 (LCMS).

Step 3: l-(3-Methoxynaphthalen-l-yl)ethanol (370A-3)

To a solution of 1 -(3 -methoxynaphthal en-l-yl)ethanone (100 mg, 499 pmol, 1.0 eq) in EtOH (2.0 mL) was added NaBHj (20.0 mg, 529 pmol, 1.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a crude product 1 -(3 -m ethoxynaphthal en-l-yl)ethanol (110 mg) as a yellow oil. M + H ⁺ - 18 = 185.2 (LCMS).

Step 4: \-(3-I luorobenzyl)-l-( l-(3-methoxynaphthalen-l-yl)ethyl)piperidine-4- carboxamide (Compound 524)

To a solution of l-(3-methoxynaphthalen-l-yl)ethanol (40.0 mg, 198 pmol, 1.0 eq) in DCM (2.0 mL) were added DIEA (102 mg, 791 pmol, 4.0 eq) and methyl sulfonyl methanesulfonate (34.5 mg, 198 pmol, 1.0 eq) dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min, then 7V-(3-fluorobenzyl)piperidine-4-carboxamide (46.7 mg, 198 pmol, 1.0 eq) was added and the mixture was stirred at 40 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 50% - 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B : acetonitrile) . N-(3 -Fluorobenzyl)- 1 -( 1 -(3 -methoxynaphthalen- 1 -yl)ethyl)piperidine-4- carboxamide (2.97 mg, 6.50 pmol, 3% yield) was obtained as a pale yellow gum. M + H ⁺ = 421.2 (LCMS); 'H NMR (400 MHz, DMSO ) 8 8.39 - 8.24 (m, 2H), 7.81 (d, J= 7.9 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.23 - 7.15 (m, 2H), 7.08 - 6.90 (m, 3H), 4.24 (d, J= 6.0 Hz, 2H), 4.09 (br d, J= 6.6 Hz, 1H), 3.86 (s, 3H), 3.07 (br d, J= 10.4 Hz, 1H), 2.78 (br d, J= 11.9 Hz, 1H), 2.20 - 2.09 (m, 1H), 2.00 (br d, J = 11.4 Hz, 2H), 1.77 - 1.67 (m, 1H), 1.65 - 1.56 (m, 2H), 1.55 (br d, J= 3.3 Hz, 1H), 1.37 (d, J= 6.6 Hz, 3H).

Example 371: (l?)-4-Methyl-3-(((l-(naphthalen-l-yl)ethyl)amino)methyl)ani line (Compound 106)

14A-3 Compound 106

Step 1: (l?)-4-Methyl-3-(((l-(naphthalen-l-yl)ethyl)amino)methyl)ani line (Compound 106)

To a solution of (7?)-5-amino-2-methyl-7V-(l-(naphthalen-l-yl)ethyl)benzamide (50.0 mg, 164 pmol, 1.0 eq) in THF (2.0 mL) was added BH3-Me2S (10 M, 164 pL, 10 eq) at 0 °C. The mixture was stirred at 60 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (1.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 50% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (A)-4-Methyl-3-(((l- (naphthalen-l-yl)ethyl)amino)methyl)aniline (18.2 mg, 60.2 pmol, 37% yield) was obtained as a yellow oil. M + H ⁺ = 291.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.19 (br d, J= 7.8 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.78 (br dd, J = 5.4, 6.8 Hz, 2H), 7.59 - 7.45 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.53 (dd, J= 2.0, 7.9 Hz, 1H), 4.73 (q, J= 6.5 Hz, 1H), 3.73 - 3.58 (m, 2H), 2.16 (s, 3H), 1.55 (d, J= 6.5 Hz, 3H). Example 372: /V-(( lZ/-indazol-5-yl)methyl)-l-(naphthalen-l-yl)cyclopropan-l -amine (Compound 178)

372A-1 Compound 178

Step 1: N-(( lH-Indazol-5-yl)methyl)-l-(naphthalen-l-yl)cyclopropan-l -amine (Compound 178)

To a stirred solutin of U/-indazole-5-carbaldehyde (100 mg, 684 pmol, 1.0 eq) and 1- (naphthalen-l-yl)cyclopropan-l -amine (125 mg, 684 pmol, 1.0 eq) in MeOH (5.0 mL) was added NaBHiCN (86.0 mg, 1.37 mmol, 2.0 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 50% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 7V-((17/-Indazol-5-yl)methyl)-l-(naphthalen-l- yl)cyclopropan-l -amine (200 mg, 619 pmol, 90% yield) was obtained as white solid. M + H ⁺ = 314.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 10.34 - 9.65 (m, 1H), 8.55 - 8.39 (m, 1H), 7.98 - 7.90 (m, 2H), 7.85 - 7.78 (m, 1H), 7.61 - 7.43 (m, 5H), 7.38 - 7.31 (m, 1H), 7.23 - 7.17 (m, 1H), 3.77 - 3.61 (m, 2H), 1.35 - 1.16 (m, 2H), 1.12 - 0.94 (m, 2H).

Example 373: \ -(( 1 //-I nd:izol-5-yl)methyl)- \ -met hyl-l-(napht halen- 1-yl (cyclopropane amine (Compound 184)

Step 1

Compound 178 Compound 184 Step 1: X-(( 1 //- Indazol-5-yl )met hyl)- \-nielIiyl- 1 -(napht halen- 1 -yl)cyclopropananiine (Compound 184)

To a stirred solution of A-(l/Z-indazol-5-ylmethyl)-l-(l-naphthyl)cyclopropanamine (140 mg, 447 pmol, 1.0 eq) in MeOH (5.0 mL) was added formaldehyde (72.5 mg, 893 pmol, 66.5 pL, 37% purity in water, 2.0 eq), followed by NaBHsCN (56.1 mg, 893 pmol, 2.0 eq). The mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). A-((l/Z-Indazol-5-yl)methyl)-A-methyl-l- (naphthalen-l-yl)cyclopropanamine (42.2 mg, 127 pmol, 28% yield) was obtained as white solid. M + H ⁺ = 328.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.69 - 8.58 (m, 1H), 8.06 - 7.94 (m, 3H), 7.89 - 7.82 (m, 1H), 7.71 - 7.48 (m, 5H), 7.40 - 7.32 (m, 1H), 4.26 - 4.12 (m, 1H), 4.38 - 3.95 (m, 2H), 2.56 - 2.39 (m, 3H), 1.85 - 1.64 (m, 2H), 1.51 - 1.28 (m, 2H).

Example 374: N, 1, 5-Trim et by l-X-( 1 -( na pli t halen- 1 -y 1 )cy clopropy 1 )- 1 //-indole-6- carboxamide (Compound 208)

Compound 199 Compound 208

Step 1: \ J.5-Trimethyl-\-( l-(naphthalen-l-yl)cyclopropyl)-lH-indole-6-carboxamide (Compound 208)

To a solution of 5-methyl-7V-(l-(naphthalen-l-yl)cyclopropyl)-lZZ-indole-6-ca rboxamide (50.0 mg, 147 pmol, 1.0 eq) in THF (2.0 mL) was added sodium hydride (11.8 mg, 294 pmol, 60% purity, 2.0 eq) at 0 °C, followed by Mel (20.9 mg, 147 pmol, 9.14 pL, 1.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 40% - 80% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). TV, 1,5- Trim ethyl -/f-CI -(naphthal en-l-yl)cy cl opropyl)-U/-indole-6-carboxamide (17.0 mg, 46.1 pmol, 31% yield, HCI salt) was obtained as a white solid. M + H ⁺ = 339.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 9.37 - 9.12 (m, 1H), 8.02 - 7.94 (m, 1H), 7.93 - 7.81 (m, 2H), 7.69 - 7.59 (m, 1H), 7.58 - 7.44 (m, 2H), 7.37 - 7.31 (m, 1H), 7.02 - 6.99 (m, 1H), 6.99 - 6.97 (m, 1H), 6.39 - 6.34 (m, 1H), 3.69 (s, 3H), 2.85 (s, 3H), 2.10 (s, 3H), 1.92 - 1.72 (m, 2H), 1.58 -

1.41 (m, 2H).

Example 375: /V-(3-Fluorobenzyl)-l-(l-(naphthalen-l-yl)cyclopropyl)piperi dine-4- carboxamide (Compound 179)

Step 7

Compound 179

Step 1: Dimethyl 2,2-bis((l,3-dioxolan-2-yl)methyl)malonate (375A-2)

A mixture of dimethyl malonate (5.01 g, 37.9 mmol, 4.35 mL, 1.0 eq) and /-BuOK (5.10 g, 45.5 mmol, 1.2 eq) in DMSO (100 mL) was stirred at 20 °C for 1 h. 2-(Bromomethyl)-l,3- dioxolane (7.60 g, 45.5 mmol, 4.66 mL, 1.2 eq) was added, and the mixture was stirred at 80 °C for 12 h. The solution was cooled to room temperature, Z-BuOK (5.10 g, 45.5 mmol, 1.2 eq) was added, and the mixture was stirred at room temperature for 1 h. 2-(Bromomethyl)-l,3- dioxolane (7.60 g, 45.5 mmol, 4.66 mL, 1.2 eq) was added again, and the solution was stirred at 80 °C for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (100 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/10. Dimethyl 2,2- bis((l,3-dioxolan-2-yl)methyl)malonate (5.00 g, 16.4 mmol, 43% yield) was obtained as a colorless oil. M + H ⁺ = 305.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 5.02 (t, J= 4.8 Hz, 2H), 3.95 - 3.88 (m, 4H), 3.83 - 3.77 (m, 4H), 3.74 - 3.68 (m, 6H), 2.45 (d, J= 4.9 Hz, 4H).

Step 2: Dimethyl 2,2-bis(2-oxoethyl)malonate (375A-3)

To a solution of dimethyl 2,2-bis((l,3-dioxolan-2-yl)methyl)malonate (2.00 g, 6.57 mmol, 1.0 eq) in THF (40 mL) was added HC1 (10% purity in water, 40.0 mL). The mixture was stirred at 20 °C for 12 h. TLC indicated that the starting material was completely consumed. Dimethyl 2,2-bis(2-oxoethyl)malonate was obtained as a mixture (40 mL), which was used in the next step without any further purification.

Step 3: Dimethyl l-(l-(naphthalen-l-yl)cyclopropyl)pyridine-4,4(lH)-dicarboxy late (375A-4)

To a solution of dimethyl 2,2-bis(2-oxoethyl)mal onate (590 mg, 2.73 mmol, 40 mL, 1.0 eq) was added NaHCOs (458 mg, 5.46 mmol, 212 pL, 2.0 eq) to adjust the pH to 7, followed by a solution of l-(naphthalen-l-yl)cyclopropan-l -amine (500 mg, 2.73 mmol, 1.0 eq) in THF (5.0 mL). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was extracted with DCM (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Dimethyl 1- (l-(naphthalen-l-yl)cyclopropyl)pyridine-4,4(U7)-dicarboxyla te (300 mg, 826 pmol, 30% yield) was obtained as a white solid. M + H ⁺ = 364.2 (LCMS).

Step 4: Dimethyl l-(l-(naphthalen-l-yl)cyclopropyl)piperidine-4,4-dicarboxyla te (375A- 5)

To a solution of dimethyl l-(l-(naphthalen-l-yl)cyclopropyl)pyridine-4,4(U7)-dicarboxy late (150 mg, 413 pmol, 1.0 eq) in MeOH (5.0 mL) was added 10% palladium on carbon (100 mg) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 12 h under a H2 (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with MeOH (3.0 mL x 5). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative TLC (petroleum ether/EtOAc = 5/1, R/= 0.4). Dimethyl l-(l-(naphthalen-l- yl)cyclopropyl)piperidine-4,4-dicarboxylate (100 mg, 272 pmol, 66% yield) was obtained as a white solid. M + H ⁺ = 368.2 (LCMS).

Step 5: Methyl l-(l-(naphthalen-l-yl)cyclopropyl)piperidine-4-carboxylate (375A-6)

To a solution of dimethyl 1-(1 -(naphthal en-l-yl)cy cl opropyl)piperidine-4,4-dicarboxylate (100 mg, 272 pmol, 1.0 eq) in DMSO (2.0 mL) were added NaCl (79.5 mg, 1.36 mmol, 5.0 eq) and H2O (24.5 mg, 1.36 mmol, 5.0 eq). The mixture was stirred at 140 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (2.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude methyl l-(l-(naphthalen-l-yl)cyclopropyl)piperidine-4-carboxylate (80.0 mg), which was used in the next step without any further purification. M + H ⁺ = 310.3 (LCMS).

Step 6: l-(l-(Naphthalen-l-yl)cyclopropyl)piperidine-4-carboxylic acid (375A-7)

To a solution of methyl l-(l-(naphthalen-l-yl)cyclopropyl)piperidine-4-carboxylate (40.0 mg, 129 pmol, 1.0 eq) in a mixture of H2O (2.0 mL) and THF (5.0 mL) was added LiOH.LLO (16.3 mg, 388 pmol, 3.0 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (7.0 mL) and washed with MTBE (4.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (1 M aqueous). The product was extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give l-(l-(naphthalen-l- yl)cyclopropyl)piperidine-4-carboxylic acid (30.0 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 296.1 (LCMS).

Step 7: /V-(3-Fluorobenzyl)-l-(l-(naphthalen-l-yl)cyclopropyl)piperi dine-4-carbox amide (Compound 179)

To a solution of 1-(1 -(naphthal en-l-yl)cy cl opropyl)piperidine-4-carboxylic acid (30.0 mg, 102 pmol, 1.0 eq) and (3-fhiorophenyl)methanamine (14.0 mg, 112 pmol, 12.7 pL, 1.1 eq) in DCM (2.0 mL) were added TEA (30.8 mg, 305 pmol, 42 pL, 3.0 eq), EDCI (38.9 mg, 203 pmol, 2.0 eq) and HOBt (27.5 mg, 203 pmol, 2.0 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (2.0 mL) and extracted with DCM (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (150 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). A-(3-Fluorobenzyl)-l-(l-(naphthalen-l- yl)cyclopropyl)piperidine-4-carboxamide (6.31 mg, 12.2 pmol, 12% yield, TFA salt) was obtained as a yellow gum. M + H ⁺ = 403.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.50 (d, = 8.6 Hz, 1H), 8.42 - 8.32 (m, 1H), 8.14 - 8.07 (m, 1H), 8.04 - 7.98 (m, 1H), 7.94 - 7.86 (m, 1H), 7.75 - 7.68 (m, 1H), 7.66 - 7.58 (m, 2H), 7.35 - 7.24 (m, 1H), 7.09 - 7.01 (m, 1H), 7.00 - 6.87 (m, 2H), 4.41 - 4.25 (m, 2H), 4.23 - 3.80 (m, 2H), 3.14 - 2.94 (m, 1H), 2.80 - 2.60 (m, 1H), 2.31 - 2.16 (m, 1H), 2.14 - 1.85 (m, 5H), 1.80 -1.25 (m, 4H).

Example 376: /V-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-2-(naphthale n-l- yl)propanamide (Compound 577)

35A-3 Compound 577

Step 1: /V-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-2-(naphthale n-l-yl) propanamide (Compound 577)

To a stirred solution of 2-(naphthalen-l-yl)propanoic acid (65.0 mg, 325 pmol, 1.0 eq) and 5- (2-(dimethylamino)ethoxy)-2-methylaniline (69.4 mg, 357 pmol, 1.1 eq) in DMF (3.5 mL) was added DIEA (126 mg, 974 pmol, 170 pL, 3.0 eq), followed by HATU (370 mg, 974 pmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired compound was detected. The mixture was poured into H2O (5 mL) and extracted with EtOAc (5.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-2-(naphthalen - 1 -yl) propanamide (36.2 mg, 85.4 pmol, 26% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 377.1 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.91 - 9.73 (m, 1H), 9.52 - 9.43 (m, 1H), 8.37 - 8.28 (m, 1H), 8.00 - 7.93 (m, 1H), 7.89 - 7.82 (m, 1H), 7.63 - 7.48 (m, 4H), 7.15 - 7.08 (m, 2H), 6.77 - 6.68 (m, 1H), 4.83 - 4.69 (m, 1H), 4.24 (t, J= 4.8 Hz, 2H), 3.46 (q, J= 4.9 Hz, 2H), 2.82 (d, J= 4.6 Hz, 6H), 2.04 (s, 3H), 1.60 (d, J= 7.0 Hz, 3H). Example 377: /V-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-l-(naphthale n-l- yl)cyclopropane-l-carboxamide (Compound 580)

Compound 580

Step 1: /V,/V-Dimethyl-2-(4-methyl-3-nitrophenoxy)ethan-l-amine (377A-2)

To a mixture of 4-methyl-3 -nitrophenol (1.50 g, 9.80 mmol, 1.0 eq) and 2- (dimethylamino)ethanol (873 mg, 9.80 mmol, 98.9 pL, 1.0 eq) in toluene (80 mL) were added TMAD (5.06 g, 29.4 mmol, 3.0 eq) and PPhs (7.71 g, 29.4 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 100 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (80 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. A,A-Dimethyl-2-(4-methyl-3-nitrophenoxy)ethan-l- amine (1.80 g, 8.03 mmol, 82% yield) was obtained as a brown solid. M + H ⁺ = 225.1 (LCMS).

Step 2: 5-(2-(Dimethylamino)ethoxy)-2-methylaniline (377A-3)

To a mixture of A,A-dimethyl-2-(4-methyl-3-nitrophenoxy)ethan-l -amine (1.00 g, 4.46 mmol, 1.0 eq) in a mixture of MeOH (15 mL) and H2O (3.0 mL) were added iron powder (1.25 g, 22.3 mmol, 5.0 eq) and NH4CI (1.19 g, 22.3 mmol, 5.0 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 100 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was triturated with EtOAc (2.0 mL). 5-(2-(Dimethylamino)ethoxy)-2-methylaniline (500 mg, crude) was obtained as a brown solid, which was used in the next step without any further purification. M + K ⁺ = 219.1 (LCMS).

Step 3: l-(Naphthalen-l-yl)cyclopropane-l-carbonitrile (377A-5)

To a solution of 2-(l-naphthyl)acetonitrile (1.67 g, 9.99 mmol, 1.0 eq) in DMF (10 mL) was added NaH (1.20 g, 30.0 mmol, 60% purity, 3.0 eq) at -30 °C under a N2 atmosphere. The resulting mixture was stirred at the same temperature for 1 h, then a solution of 1,2- dibromoethane (3.75 g, 20.0 mmol, 1.5 mL, 2.0 eq) in DMF (10 mL) was added dropwise. The resulting mixture was warmed slowly to 25 °C and stirred at the same temperature for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was quenched with saturated aqueous NH4CI (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/8. 1 -(Naphthal en-1- yl)cyclopropane-l -carbonitrile (1.00 g, 5.17 mmol, 52% yield) was obtained as a white solid. M + H ⁺ = 194.1 (LCMS). Step 4: l-(Naphthalen-l-yl)cyclopropane-l-carboxylic acid (377A-6)

To a solution of (400 mg, 2.07 mmol, 1.0 eq) in ethane- 1,2-diol (5.0 mL) was added KOH (1.16 g, 20.7 mmol, 10 eq). The resulting mixture was stirred at 190 °C for 3 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (7.0 mL), and washed with MTBE (4.0 mL x 2). The aqueous layer was acidified to pH 5 with HC1 (I M aqueous). The product was extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give the crude 1 -(naphthal en-l-yl)cy cl opropane-1 -carboxylic acid (300 mg, 1.41 mmol, 68% yield) as a brown solid, which was used in the next step without any further purification. 'H NMR (400 MHz, DMSO-tL) 8 8.09 (d, J= 8.3 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.59 - 7.41 (m, 4H), 1.75 - 1.55 (m, 2H), 1.31 - 1.14 (m, 2H).

Step 5: l-(Naphthalen-l-yl)cyclopropane-l-carbonyl chloride (377A-7)

To a solution of 1 -(naphthal en-l-yl)cy cl opropane-1 -carboxylic acid (100 mg, 471 pmol, 1.0 eq) in SOCI2 (224 mg, 1.88 mmol, 137 pL, 4.0 eq) was added DMF (3.44 mg, 47.0 pmol, 3.63 pL, 0.1 eq). The resulting mixture was stirred at 90 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a crude 1- (naphthalen-l-yl)cy cl opropane-1 -carbonyl chloride (100 mg) as a brown oil, which was used in the next step without any further purification. M + H ⁺ = 227.1 (LCMS, quenched by MeOH for testing).

Step 6: /V-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-l-(naphthale n-l- yl)cyclopropane-l-carboxamide (Compound 580)

To a mixture of 5-(2-(dimethylamino)ethoxy)-2-methylaniline (75.8 mg, 390 pmol, 1.0 eq) in THF (2.0 mL) was added TEA (79.0 mg, 780 pmol, 110 pL, 2.0 eq), then a solution of 1- (naphthalen-l-yl)cyclopropanecarbonyl chloride (90.0 mg, 390 pmol, 1.0 eq) in THF (1.0 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(5-(2-(Dimethylamino)ethoxy)-2-methylphenyl)-l- (naphthal en-l-yl)cy cl opropane-1 -carboxamide (11.3 mg, 28.7 pmol, 7% yield, HC1 salt) was obtained as a brown solid. M + H ⁺ = 389.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 8 9.66 (s, 1H), 8.19 (d, J= 8.4 Hz, 1H), 8.00 (br d, J= 16.1 Hz, 2H), 7.73 (d, J= 6.5 Hz, 1H), 7.54 - 7.65 (m, 4H), 7.29 (d, J= 2.5 Hz, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.62 (dd, J= 2.6, 8.3 Hz, 1H), 4.16 - 4.23 (m, 2H), 3.46 (br d, J= 5.1 Hz, 2H), 2.83 (s, 6H), 1.74 (br d, J= 2.3 Hz, 2H), 1.21

- 1.30 (m, 2H), 1.34 - 1.40 (m, 3H).

Example 378: (5-(Azetidin-3-ylamino)-2-methylphenyl)(5-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)isoindolin-2-yl)methanone (Compound 111)

378A-5 Compound 111 Step 1: te/7- Butyl 5-(5-formylthiophen-2-yl)isoindoline-2-carboxylate (378A-2)

To a stirred solution of tert-butyl 5-bromoisoindoline-2-carboxylate (200 mg, 671 pmol, 1.0 eq) in DMSO (10 mL) were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene- 2-carbaldehyde (192 mg, 805 pmol, 1.2 eq), Pd(OAc)2 (15.1 mg, 67.1 pmol, 0.1 eq), cataCxium A (48.1 mg, 134.15 pmol, 0.2 eq), and KOAc (198 mg, 2.01 mmol, 3.0 eq). The mixture was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, treated with H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was triturated from TBME (5 mL) and filtered. The cake was dried under vacuum to give tert-butyl 5-(5-formyl-2- thienyl)isoindoline-2-carboxylate (150 mg, 455 pmol, 68% yield) as an off-white solid.

Step 2: te/7- Butyl 5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)isoindoline-2-carb oxylate (378A-3)

To a stirred solution of tert-butyl 5-(5-formyl-2-thienyl)isoindoline-2-carboxylate (120 mg, 364 pmol, 1.0 eq) and pyrrolidine (51.8 mg, 729 pmol, 2.0 eq) in MeOH (15 mL) was added NaBEECN (68.7 mg, 1.09 mmol, 3.0 eq) under a N2 atmosphere. The mixture was stirred at 20 °C for 12 h. TLC indicated that the starting material was completely consumed. The mixture was poured into water (20 mL) and extracted with DCM (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue. The residue was treated with TBME (5.0 mL) and a precipitate was formed. The mixture was filtered and the cake was dried under vacuum to give the crude tert-butyl 5-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)isoindoline-2-carboxylate (150 mg, crude) as a yellow solid.

Step 3: 5-(5-(Pyrrolidin-l-ylmethyl)thiophen-2-yl)isoindoline (378A-4)

To a stirred solutin of tert-butyl 5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)isoindoline-2- carboxylate (170 mg, 442 pmol, 1.0 eq) in EtOAc (10 mL) was added HClZEtOAc (4 M, 11 mL). The mixture was stirred at 20 °C for 2 h. TLC indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give the crude 5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)isoindoline (180 mg, HC1 Salt) as a yellow gum, which was used in the next step without any further purification. Step 4: tc/7- Butyl 3-((4-methyl-3-(5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)is oindoline- 2-carbonyl)phenyl)amino)azetidine-l-carboxylate (378A-5)

To a stirred solution of 5-(( l -(/c/7-butoxycarbonyl)azeti din-3 -yl)amino)-2-methylbenzoic acid (172 mg, 561 pmol, 1.0 eq) and 5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)isoindoline (180 mg, 561 pmol, 1.0 eq, HC1 Salt) in DCM (10 mL) were added TEA (170 mg, 1.68 mmol, 234 pL, 3.0 eq), EDCI (129 mg, 673 pmol, 1.2 eq) and HOBt (91.0 mg, 673 pmol, 1.2 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue, which was triturated with TMBE (5 mL) and filtered. The cake was dried under vacuum to give the crude Zc/V-butyl 3- ((4-methyl-3-(5-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)isoi ndoline-2-carbonyl)phenyl) amino)azetidine-l -carboxylate (300 mg, 524 pmol, 93% yield) as a yellow solid.

Step 5: (5-(Azetidin-3-ylamino)-2-methylphenyl)(5-(5-(pyrrolidin-l-y lmethyl)thiophen- 2-yl)isoindolin-2-yl)methanone (Compound 111)

To a stirred solution of Zc/V-butyl 3-((4-methyl-3-(5-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)isoindoline-2-carbonyl)phenyl)amino)azetidine-l-carboxyla te (150 mg, 262 pmol, 1.0 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated in vacuum at 25 °C to give a residue, which was purified by preparative HPLC (Phenomenex Luna column (80 x 40 mm, 3 pm); flow rate: 40 mL/min; gradient: 10% - 34% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5-(Azetidin-3-ylamino)-2-methylphenyl)(5-(5-(pyrrolidin-l-y lmethyl) thiophen-2-yl)isoindolin-2-yl)methanone (72.8 mg, 135.85 pmol, 52% yield, HC1 salt) was obtained as yellow gum. M + H ⁺ = 473.1 (LCMS); ¹ H NMR (400 MHz, CD ₃ OD) 8 7.76 - 7.51 (m, 2H), 7.48 - 7.25 (m, 3H), 7.24 - 7.18 (m, 1H), 6.85 - 6.80 (m, 1H), 6.76 - 6.72 (m, 1H), 5.03 - 4.96 (m, 2H), 4.69 - 4.55 (m, 5H), 4.47 - 4.36 (m, 2H), 4.14 - 4.03 (m, 2H), 3.64 - 3.57 (m, 2H), 3.29 - 3.19 (m, 2H), 2.27 - 2.13 (m, 5H), 2.10 - 1.99 (m, 2H). Example 379: 5-(Azetidin-3-ylamino)-2-methyl-/V-(4-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)benzyl)benzamide (Compound 116)

Step 1: te/7- Butyl 4-(5-formylthiophen-2-yl)benzylcarbamate (379A-2)

To a stirred solution of tert-butyl 4-bromobenzylcarbamate (200 mg, 699 pmol, 1.0 eq) in DMSO (10 mL) were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2- carbaldehyde (109 mg, 699 pmol, 1.0 eq), cataCxium A (50.1 mg, 140 pmol, 0.2 eq), Pd(OAc)2 (15.7 mg, 69.9 pmol, 0.1 eq), and KOAc (206 mg, 2.10 mmol, 3.0 eq) under a N2 atmosphere.

The mixture was stirred at 80 °C for 6 h. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. Zc/V-Butyl 4-(5-formylthiophen-2-yl)benzylcarbamate (200 mg, 630 pmol, 90% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCh) 8 9.90 (s, 1H), 7.75 (d, J = 3.9 Hz, 1H), 7.65 (d, J= 8.3 Hz, 2H), 7.40 (d, J= 3.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 4.91 (br s, 1H), 4.36 (br d, J= 5.4 Hz, 2H), 1.48 (s, 9H).

Step 2: tert-Butyl 4-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)benzylcarbamate (379A-3)

To a stirred solution of tert-butyl 4-(5-formylthiophen-2-yl)benzylcarbamate (200 mg, 630 pmol, 1.0 eq) in MeOH (20 mL) was added pyrrolidine (89.6 mg, 1.26 mmol, 105 pL, 2.0 eq), followed by NaBHiCN (119 mg, 1.89 mmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h. TLC indicated that the starting material was completely consumed. The mixture was poured into water (20 mL) and extracted with DCM (15 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude tert-butyl 4-(5- (pyrrolidin-l-ylmethyl)thiophen-2-yl)benzylcarbamate (250 mg, crude) as a yellow solid, which was used in the next step without any further purification.

Step 3: (4-(5-(Pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)methanamin e (379A-4)

To a stirred solution of tert-butyl 4-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)benzylcarbamate (250 mg, 671 pmol, 1.0 eq) in EtOAc (15 mL) was added HCl/EtOAc (4 M, 17 mL). The mixture was stirred at 20 °C for 2 h. TLC indicated that the starting material was completely consumed. The mixture was concentrated in vacuum at 25 °C to give the crude (4-(5- (pyrrolidin-l-ylmethyl)thiophen-2-yl)phenyl)methanamine (250 mg, crude HC1 salt) as a yellow gum, which was used in the next step without any further purification.

Step 4: te/7- Butyl 3-((4-methyl-3-((4-(5-(pyrrolidin-l-ylmethyl)thiophen-2-yl)b enzyl) carbamoyl)phenyl)amino)azetidine-l-carboxylate (379A-5)

To a stirred solution of 5-((l-(ter/-butoxycarbonyl)azeti din-3 -yl)amino)-2-methylbenzoic acid (200 mg, 653 pmol, 1.0 eq) and (4-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)phenyl)methanamine (202 mg, 653 pmol, 1.0 eq, HC1 salt) in DCM (10 mL) were added HOBt (106 mg, 783 pmol, 1.2 eq), EDCI (150 mg, 783 pmol, 1.2 eq) and TEA (198 mg, 1.96 mmol, 273 pL, 3.0 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert-Butyl 3-((4-methyl-3-((4-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)benzyl)carbamoyl)phenyl) amino)azetidine-l -carboxylate (250 mg, 446 pmol, 68% yield) was obtained as a yellow solid.

Step 5: 5-(Azetidin-3-ylamino)-2-methyl-A-(4-(5-(pyrrolidin-l-ylmeth yl)thiophen-2- yl)benzyl)benzamide (Compound 116)

To a stirred solution of tert-butyl 3-((4-methyl-3-((4-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)benzyl)carbamoyl)phenyl) amino)azetidine-l -carboxylate (200 mg, 357 pmol, 1.0 eq) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated in vacuum at 25 °C to give a residue, which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 5-(Azetidin-3- ylamino)-2-methyl-A-(4-(5-(pyrrolidin-l-ylmethyl)thiophen-2- yl)benzyl)benzamide (44.6 mg, 76.1 pmol, 21% yield, TFA salt) was obtained as a yellow gum. M + H ⁺ = 461.1 (LCMS); ¹ HNMR (400 MHz, CD ₃ OD) 8 7.68 - 7.62 (m, 2H), 7.44 (d, J= 8.3 Hz, 2H), 7.40 (d, J= 3.8 Hz, 1H), 7.30 (d, J= 3.8 Hz, 1H), 7.05 (d, J= 7.8 Hz, 1H), 6.61 - 6.57 (m, 2H), 4.62 (s, 2H), 4.57 - 4.45 (m, 3H), 4.41 - 4.33 (m, 2H), 3.95 (dd, J= 6.8, 11.3 Hz, 2H), 3.59 (br s, 2H), 3.26 (br s, 2H), 2.25 (s, 5H), 2.10 - 1.95 (m, 2H).

Example 380: tert-Butyl (l?)-3-((3-((l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl)carbam oyl)- 4-methylphenyl)amino)azetidine-l-carboxylate (Compound 161)

380A-1 Step 1 380A-2 Step 2

380A-5 Step 5 Compound 161

Step 1: tert-Butyl (l?)-4-(l-(2-methyl-5-nitrobenzamido)ethyl)piperidine-l-carb oxylate

(380A-2)

To a solution of tert-butyl (7?)-4-(l-aminoethyl)piperidine-l -carboxylate (500 mg, 2.19 mmol, 1.0 eq) and 2-methyl-5-nitrobenzoic acid (397 mg, 2.19 mmol, 0.53 mL, 1.0 eq) in DCM (10 mL) were added TEA (444 mg, 4.38 mmol, 610 pL, 2.0 eq), EDCI (504 mg, 2.63 mmol, 1.2 eq) and HOBt (355 mg, 2.63 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into FLO (15 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude tert-butyl (7?)-4-(l-(2-methyl-5-nitrobenzamido)ethyl)piperidine-l- carboxylate (950 mg) as a colorless oil. M - 56 + H ⁺ = 336.3 (LCMS).

Step 2: (l?)-2-Methyl-5-nitro-/V-(l-(piperidin-4-yl)ethyl)benzamide (380A-3)

To a stirred solution of tert-butyl ( ’)-4-( l -(2-methyl-5-nitrobenzamido)ethyl)piperidine- l - carboxylate (800 mg, 2.04 mmol, 1.0 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude (7?)-2-methyl-5-nitro-7V-(l-(piperidin-4-yl)ethyl)benzamide (800 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 292.1 (LCMS). Step 3: (l?)-A ^z -(l-(l-(Ethylsulfonyl)piperidin-4-yl)ethyl)-2-methyl-5 -nitrobenzamide (380A-4)

To a solution of (7?)-2-methyl-5-nitro-7V-(l-(piperidin-4-yl)ethyl)benzamide (500 mg, 1.72 mmol, 1.0 eq) in DCM (30 mL) were added TEA (521 mg, 5.15 mmol, 717 pL, 3.0 eq) and ethanesulfonyl chloride (265 mg, 2.06 mmol, 1.2 eq). The mixture was stirred at 0 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. (R)-A-(l-(l-(Ethylsulfonyl)piperidin-4- yl)ethyl)-2-methyl-5-nitrobenzamide (500 mg, 1.30 mmol, 76% yield) was obtained as a colorless oil. M + H ⁺ = 384.1 (LCMS).

Step 4: (l?)-5-Amino-/V-(l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl)-2 -methylbenzamide (380A-5)

To a solution of (7?)-7V-(l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl)-2-methyl- 5-nitrobenzamide (500 mg, 1.30 mmol, 1.0 eq) in a mixture of MeOH (10 mL) and H2O (2.5 mL) were added iron powder (365 mg, 6.52 mmol, 5.0 eq) and NH4CI (349 mg, 6.52 mmol, 5.0 eq). The mixture was stirred at 80 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude (R)-5-amino-A-(l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl)-2-m ethylbenzamide (26.8 mg, 83.0 pmol, 29% yield) as a white solid. M + H ⁺ = 354.2 (LCMS).

Step 5: terf-Butyl (l?)-3-((3-((l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl)carbam oyl)-4- methylphenyl)amino)azetidine-l-carboxylate (Compound 161)

To a solution of (7?)-5-amino-7V-(l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl)-2 -methylbenzamide (50.0 mg, 141 pmol, 1.0 eq) and tert-butyl 3 -oxoazetidine- 1 -carboxylate (24.3 mg, 141 pmol, 1.0 eq) in MeOH (4.0 mL) was added NaBHiCN (10.7 mg, 170 pmol, 1.2 eq). The resulting mixture was stirred at 25 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (70 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 30% - 70% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give tert-butyl (A)-3-((3-((l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl) carbamoyl) -4-methylphenyl)amino)azetidine-l -carboxylate (2.09 mg, 4.11 pmol, 3% yield) as a white solid. M + Na ⁺ = 531.2 (LCMS); ¹ H NMR (400 MHz, CD ₃ OD) 8 7.04 (d, J= 8.4 Hz, 1H), 6.53 (d, J= 2.5 Hz, 1H), 6.48 (dd, J= 2.4, 8.2 Hz, 1H), 5.49 (br d, J= 8.9 Hz, 1H), 4.34 - 4.25 (m, 2H), 4.24 - 4.14 (m, 2H), 3.92 - 3.84 (m, 2H), 3.72 (dd, J= 4.4, 8.9 Hz, 2H), 2.96 (q, J= 7.5 Hz, 2H), 2.85 - 2.73 (m, 2H), 2.31 (s, 3H), 1.89 - 1.76 (m, 2H), 1.51 - 1.40 (m, 13H), 1.37 (t, J= 7.4 Hz, 3H), 1.22 (d, J= 6.8 Hz, 3H).

Example 381: (l?)-5-(Azetidin-3-ylamino)-/V-(l-(l-(ethylsulfonyl)piperidi n-4-yl)ethyl)-2- methylbenzamide (Compound 166)

Compound 161 Compound 166

Step 1 : (l?)-5-(Azetidin-3-ylamino)-/V-(l-(l-(ethylsulfonyl)piperidi n-4-yl)ethyl)-2- methylbenzamide (Compound 166)

To a stirred solution of tert-butyl (A)-3-((3-((l-(l-(ethylsulfonyl)piperidin-4-yl)ethyl) carbamoyl)-4-methylphenyl)amino)azetidine-l -carboxylate (150 mg, 295 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HClZEtOAc (4 M, 300 pL). The mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 °C to give a residue which was treated with small amount of NH3.H2O to pH 7 and purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (A)-5-(Azetidin-3-ylamino)-A-(l-(l-(ethylsulfonyl)piperidin- 4-yl)ethyl)-2- methylbenzamide (30.0 mg, 71.6 pmol, 24% yield) was obtained as a white solid. M + H ⁺ = 409.1 (LCMS); 'H NMR (400 MHz, CD3OD) 8 7.00 (d, J= 8.1 Hz, 1H), 6.60 - 6.49 (m, 2H), 4.38 (t, J= 7.1 Hz, 1H), 4.05 - 3.92 (m, 2H), 4.12 - 3.90 (m, 1H), 3.80 (br d, J= 12.5 Hz, 2H), 3.61 (br t, J= 8.1 Hz, 2H), 3.03 (q, J= 13 Hz, 2H), 2.89 - 2.74 (m, 2H), 2.24 (s, 3H), 1.95 - 1.80 (m, 2H), 1.59 (dt, J= 3.2, 7.4 Hz, 1H), 1.47 - 1.27 (m, 5H), 1.21 (d, J= 6.8 Hz, 3H). Example 382: /V-(2-Methoxy-l-(naphthalen-l-yl)ethyl)-2-methyl-5-nitrobenz amide

(Compound 108)

Compound 108

Step 1: 2-Amino-2-(naphthalen-l-yl)ethanol (382A-2)

To a solution of 2-amino-2-(naphthalen-l-yl)acetic acid (400 mg, 1.99 mmol, 1.0 eq) in THF (32 mL) was added LiAlHj (755 mg, 19.9 mmol, 10 eq) in portions at 0 °C. The mixture was stirred at 65 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was cooled to 0 °C, quenched by addition of 0.8 mL of H2O, followed by 0.8 mL of 10% aqueous NaOH. The suspension was stirred at room temperature for 5 min, then filtered through a pad of celite. The combined filtrates were dried over ISfeSCU, filtered, and concentrated under vacuum to give the crude 2- amino-2-(naphthalen-l-yl)ethanol (400 mg) as an orange solid, which was used in the next step without any further purification. M + H ⁺ = 188.3 (LCMS).

Step 2: tert-Butyl (2-hydroxy-l-(naphthalen-l-yl)ethyl)carbamate (382A-3)

To a solution of 2-amino-2-(naphthalen-l-yl)ethanol (200 mg, 1.07 mmol, 1.0 eq) in THF (1.0 mL) was added BOC2O (233 mg, 1.07 mmol, 246 pL, 1.0 eq). The resulting mixture was stirred at 20 °C for 13 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give a residue which was triturated with EtOAc (2.0 mL) and filtered. The solid cake was dried in vacuum to give tert-butyl (2-hydroxy-l -(naphthal en-l-yl)ethyl)carbamate (300 mg, 1.04 mmol, 98% yield) as a white solid. M + H ⁺ = 288.3 (LCMS).

Step 3: tert-Butyl (2-methoxy-l-(naphthalen-l-yl)ethyl)carbamate (382A-4)

To a solution of tert-butyl (2-hydroxy-l -(naphthal en-l-yl)ethyl)carbamate (100 mg, 348 pmol, 1.0 eq) in THF (1.0 mL) was added sodium hydride (16.7 mg, 418 pmol, 60% purity, 1.2 eq) and Mel (54.3 mg, 383 pmol, 23.8 pL, 1.1 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (petroleum ether/EtOAc = 3/1, R/= 0.6). tert-Butyl (2-methoxy-l -(naphthal en-l-yl)ethyl)carbamate (60.0 mg, 199 pmol, 57% yield) was obtained as a white solid. M + H ⁺ = 302.3 (LCMS).

Step 4: 2-Methoxy-l-(naphthalen-l-yl)ethan-l-amine (382A-5)

To a solution of tert-butyl (2-methoxy-l -(naphthal en-l-yl)ethyl)carbamate (50.0 mg, 166 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (333 pL). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum to give the crude 2-methoxy- 1 -(naphthal en-l-yl)ethan-l -amine (30.0 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 202.2 (LCMS).

Step 5: /V-(2-Methoxy-l-(naphthalen-l-yl)ethyl)-2-methyl-5-nitrobenz amide (Compound 108)

To a solution of 2-methyl-5-nitrobenzoic acid (29.7 mg, 164 pmol, 1.1 eq) and 2-methoxy-l- (naphthalen-l-yl)ethan-l -amine (30.0 mg, 149 pmol, 1.0 eq, TFA salt) in DCM (2.0 mL) was added TEA (30.2 mg, 298 pmol, 41.5 pL, 2.0 eq) and T3P (94.9 mg, 149 pmol, 88.7 pL, 50% purity in EtOAc, 1.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 40% - 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-(2-Methoxy-l-(naphthalen-l-yl)ethyl)-2-methyl- 5 -nitrobenzamide (10.0 mg, 27.1 pmol, 18% yield) was obtained as an off-white solid. M + H ⁺ = 365.1 (LCMS); ^X H NMR (400 MHz, CDCh) 6 8.28 (d, J= 2.3 Hz, 1H), 8.22 (d, J= 8.5 Hz, 1H), 8.17 (dd, J= 2.4, 8.4 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.85 (d, J= 8.1 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.57 - 7.46 (m, 2H), 7.40 (d, J= 8.5 Hz, 1H), 6.52 (br d, J= 7.6 Hz, 1H), 6.31 - 6.10 (m, 1H), 4.07 - 3.85 (m, 2H), 3.46 (s, 3H), 2.55 (s, 3H).

Example 383: 5-Amino-/V-(2-methoxy-l-(naphthalen-l-yl)ethyl)-2-methylbenz amide

(Compound 118)

Compound 108 Compound 118

Step 1: 5-Amino-/V-(2-methoxy-l-(naphthalen-l-yl)ethyl)-2-methylbenz amide (Compound 118)

To a solution of 7V-(2-methoxy-l -(naphthal en-l-yl)ethyl)-2-methyl-5 -nitrobenzamide (50.0 mg, 137 pmol, 1.0 eq) inEtOAc (5.0 mL) was added 10% palladium on carbon (50.0 mg) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 3 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with EtOAc (2.0 mL x 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-Amino-7V-(2-methoxy-l-(naphthalen-l-yl)ethyl)-2- methylbenzamide (13.1 mg, 37.0 pmol, 27% yield) was obtained as a white solid. M+ H ⁺ = 335.2 (LCMS); ^X H NMR (400 MHz, CDCh) 8 8.24 - 8.16 (m, 1H), 7.92 - 7.84 (m, 1H), 7.79 (d, J= 8.3 Hz, 1H), 7.59 - 7.37 (m, 4H), 6.94 (d, J= 8.3 Hz, 1H), 6.85 (br d, J= 1.6 Hz, 1H), 6.74 (br d, J= 8.0 Hz, 1H), 6.70 (br s, 1H), 6.21 - 6.12 (m, 1H), 3.94 - 3.79 (m, 2H), 3.38 (s, 3H), 2.28 (s, 3H). Example 384: 2-Methyl-/V-(naphthalen-l-yl(tetrahydro-2H-pyran-4-yl)methyl )-5- nitrobenzamide (Compound 105)

Compound 105

Step 1: Naphthalen-l-yl(tetrahydro-2H-pyran-4-yl)methanone (384A-1)

To a solution of 1 -bromonaphthalene (430 mg, 2.08 mmol, 289 pL, 1.2 eq) in THF (10 mL) was added w-BuLi (2.5 M in hexane, 831 pL, 1.2 eq) dropwise at -78 °C under a N2 atmosphere. The mixture was stirred at the same temperature for 50 min. A solution of 7V-methoxy-7V- methyltetrahydro-2J7-pyran-4-carboxamide (300 mg, 1.73 mmol, 1.0 eq) in THF (10 mL) was added dropwise at the same temperature. The resulting mixture was stirred at -78 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to warm to room temperature, poured into H2O (10 mL) and extracted with EtOAc (2.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Naphthal en- l -yl(tetrahydro-27/-pyran-4-yl)methanone (200 mg, 832 pmol, 48% yield) was obtained as a colorless oil. M + H ⁺ = 241.3 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.29 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.94 - 7.86 (m, 1H), 7.75 (d, J= 7.1 Hz, 1H), 7.63 - 7.47 (m, 3H), 4.05 (td, J = 3.4, 11.6 Hz, 2H), 3.59 - 3.38 (m, 3H), 1.98 - 1.79 (m, 4H). Step 2: Naphthalen-l-yl(tetrahydro-2H-pyran-4-yl)methanamine (384A-2)

To a solution of naphthalen- l -yl(tetrahydro-27/-pyran-4-yl)methanone (150 mg, 624 pmol, 1.0 eq) in MeOH (2.0 mL) were added NH ₃ /MeOH (20 M, 5.0 mL) and Ti(z-PrO) ₄ (887 mg, 3.12 mmol, 921 pL, 5.0 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. After that, the mixture was cooled to 0 °C and NaBH ₄ (118 mg, 3.12 mmol, 5.0 eq) was added. The resulting mixture was stirred at 0 °C for 1 h, and then stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (1.0 mL x 5). The combined organic layers were dried over Na2SO ₄ , filtered, and concentrated under vacuum to give the crude naphthalen-l-yl(tetrahydro-2J/-pyran-4-yl)methanamine(150 mg) as a brown oil, which was used in the next step without any further purification. M - 17+ H ⁺ = 225.3 (LCMS).

Step 3: 2-Methyl-/V-(naphthalen-l-yl(tetrahydro-2Z/-pyran-4-yl)methy l)-5-nitroben zamide (Compound 105)

To a solution of naphthalen-l-yl(tetrahydro-2J/-pyran-4-yl)methanamine(100 mg, 414 pmol, 1.0 eq) and 2-methyl-5-nitro-benzoic acid (75.1 mg, 414 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (126 mg, 1.24 mmol, 173 pL, 3.0 eq) and T3P (527 mg, 829 pmol, 493 pL, 50% in EtOAc, 2.0 eq) at 0 °C. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (6.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO ₄ , filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 40% - 75% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile). 2-Methyl-M(naphthalen- l -yl(tetrahydro-27/-pyran-4- yl)methyl)-5-nitrobenzamide (13.7 mg, 32.9 pmol, 8% yield) was obtained as an off-white solid. M + H ⁺ = 405.1 (LCMS); ^X H NMR (400 MHz, CDCh) 8 8.31 (d, J = 8.5 Hz, 1H), 8.19

- 8.09 (m, 2H), 7.92 (d, J = 8.1 Hz, 1H), 7.85 (dd, J = 3.1, 6.1 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.59 - 7.53 (m, 1H), 7.52 - 7.46 (m, 2H), 7.36 (d, J = 8.9 Hz, 1H), 6.23 - 6.09 (m, 1H), 5.95 (t, J= 9.1 Hz, 1H), 4.17 - 3.86 (m, 2H), 3.50 - 3.28 (m, 2H), 2.45 (s, 3H), 2.35 (br s, 1H), 1.94

- 1.69 (m, 2H), 1.59 - 1.40 (m, 2H). Example 385: 5-Amino-2-methyl-/V-(naphthalen-l-yl(tetrahydro-2H-pyran-4- yl)methyl)benzamide (Compound 109)

Compound 105 Compound 109

Step 1: 5-Amino-2-metliyl- \-(n:iplith:ilen-l-yl(tetr:ihydro-2//-pyr:in-4-yl)methyl) benzamide (Compound 109)

To a solution of 2-methyl-7V-(naphthalen-l-yl(tetrahydro-2J/-pyran-4-yl)methy l)-5- nitrobenzamide (80.0 mg, 198 pmol, 1.0 eq) in EtOAc (5.0 mL) and MeOH (5.0 mL) was added 10% palladium on carbon (80.0 mg) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 5 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with EtOAc (5.0 mL x 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (150* 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 25% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). 5-Amino-2-methyl- 7V-(naphthalen-l-yl(tetrahydro-2J/-pyran-4-yl)methyl)benzami de (25.8 mg, 68.5 pmol, 35% yield) was obtained as a white solid. M + H ⁺ = 375.1 (LCMS); ^T H NMR (400 MHz, CDCL) 8 8.31 (d, J = 8.4 Hz, 1H), 7.90 (d, J= 8.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.63 - 7.41 (m, 4H), 6.96 (d, J = 8.8 Hz, 1H), 6.68 - 6.59 (m, 2H), 6.14 - 5.87 (m, 2H), 4.07 (br dd, J = 2.4, 11.7 Hz, 1H), 3.92 (br d, J = 11.0 Hz, 1H), 3.58 (br s, 2H), 3.44 - 3.28 (m, 2H), 2.39 - 2.14 (m, 4H), 1.88 - 1.67 (m, 2H), 1.62 - 1.44 (m, 2H). Example 386: 5-Amino-2-methyl-/V-(naphthalen-l-ylsulfonyl) benzamide (Compound 242)

386A-3

Compound 242

Step 1: Naphthalene-l-sulfonamide (386A-2)

To a solution of naphthalene- 1 -sulfonyl chloride (500 mg, 2.21 mmol, 1.0 eq) in acetone (10 mL) was added NH3.H2O (12 mL, 25% purity) at 0 °C. The mixture was stirred at 0 °C for 15 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 ml) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude naphthalene-l-sulfonamide (400 mg, 1.93 mmol, 88% yield) as a white solid. M + H ⁺ = 208.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.63 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 13 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.73 - 7.60 (m, 5H).

Step 2: 2-Methyl-/V-(naphthalen-l-ylsulfonyl)-5-nitrobenzamide (386A-3)

To a solution of naphthalene-l-sulfonamide (100 mg, 483 pmol, 1.0 eq) and 2-methyl-5-nitro- benzoic acid (87.4 mg, 483 pmol, 1.0 eq) in DCM (4.0 mL) were added DMAP (88.4 mg, 724 pmol, 1.5 eq) and EDCI (185 mg, 965 pmol, 2.0 eq). The mixture was stirred at 25 °C for 20 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (4.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 2-methyl-7V-(naphthalen-l-ylsulfonyl)-5- nitrobenzamide (170 mg, 459 pmol, 95% yield) as a white solid. M + H ⁺ =371.2 (LCMS). Step 3: 5-Amino-2-methyl-/V-(naphthalen-l-ylsulfonyl) benzamide (Compound 242)

To a solution of 2-methyl-7V-(naphthalen-l-ylsulfonyl)-5-nitrobenzamide (100 mg, 270 pmol, 1.0 eq) in a mixture of MeOH (10 mL) and H2O (2.5 mL) was added iron powder (75.4 mg, 1.35 mmol, 5.0 eq), followed by NH4CI (72.2 mg, 1.35 mmol, 5.0 eq). The mixture was stirred at 80 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- Amino-2-methyl-N-(naphthalen-l-ylsulfonyl)benzamide (16.0 mg, 41.4 pmol, 15% yield, HC1 salt) was obtained as a white solid. M + H+ = 341.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 8.63 (d, J= 8.4 Hz, 1H), 8.37 (dd, J= 7.5, 14.9 Hz, 2H), 8.16 (d, J= 7.9 Hz, 1H), 7.81-7.66 (m, 3H), 7.24 -6.96 (m, 3H), 1.85 (s, 3H).

Example 387: (l?)-5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzenesu lfonamide

(Compound 138)

Compound 138

Step 1: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-nitrobenzenesu lfonamide (387A-2)

To a solution of 2-methyl-5-nitrobenzenesulfonyl chloride (300 mg, 1.27 mmol, 1.0 eq) and (R)-l-(naphthalen-l-yl)ethan-l -amine (218 mg, 1.27 mmol, 204 pL, 1.0 eq) in DCM (5.0 mL) was added TEA (155 mg, 1.53 mmol, 213 pL, 1.2 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (5.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give (7?)-2-methyl-7V-(l-(naphthalen-l-yl)ethyl)-5-nitrobenzenesu lfonamide (400 mg) as a pale yellow solid, which was used in the next step without any further purification. (M + 18) ⁺ = 388.2 (LCMS).

Step 2: (l?)-5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)ethyl)benzenesu lfonamide (Compound 138)

To a solution of (7?)-2-methyl-7V-(l-(naphthalen-l-yl)ethyl)-5-nitrobenzenesu lfonamide (200 mg, 540 pmol, 1.0 eq) in MeOH (2.5 mL) and H2O (0.5 mL) were added iron powder (151 mg, 2.70 mmol, 5.0 eq) and NH4CI (144 mg, 2.70 mmol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (6.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (80* 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (R)-5-Amino-2-methyl-7V-(l- (naphthalen-l-yl)ethyl)benzenesulfonamide (93.8 mg, 200 pmol, 37% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 341.0 (LCMS); ¹ H NMR (400 MHz, CDCh) 6 7.97 - 7.89 (m, 1H), 7.79 - 7.73 (m, 1H), 7.65 (d, J= 8.1 Hz, 1H), 7.58 (d, J= 1.6 Hz, 1H), 7.47 (d, J = 13 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.34 - 7.28 (m, 1H), 7.13 - 7.07 (m, 2H), 5.25 (q, J = 6.9 Hz, 1H), 2.56 - 2.30 (m, 3H), 1.57 (d, J= 6.9 Hz, 3H).

Example 388: 5-Amino-2-methyl-/V-(l-(naphthalen-l-yl)cyclopropyl)-4-(phen ylethynyl) benzamide (Compound 217)

Step 1

Compound 216 Compound 217

Step 1 : 5-Amino-2-met hyl- \-( 1 -( napht halen- 1 -yl)cyclopropyl )-4-(phenylet by nyl ) benzamide (Compound 217)

A mixture of 5-amino-4-iodo-2-methyl-7V-(l -(naphthal en-l-yl)cy cl opropyl)benzamide (100 mg, 226 pmol, 1.0 eq), TEA (45.8 mg, 452 pmol, 62.9 pL, 2.0 eq), Pd(PPh ₃ ) ₂ C12 (4.76 mg, 6.78 pmol, 0.03 eq), Cui (431 pg, 2.26 pmol, 0.01 eq) and ethynylbenzene (34.6 mg, 339 pmol, 37.2 pL, 1.5 eq) in toluene (5.0 mL) and H2O (2.5 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 70 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna Cl 8 column (80 x 40 mm, 3 pm); flow rate: 25 mL/min; gradient: 43% - 83% B over 7 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5- Amino-2-methyl-A-( 1 -(naphthal en- 1 -yl)cyclopropyl)-4-

(phenylethynyl)benzamide (50.0 mg, 110 pmol, 48% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 417.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.47 (d, J= 8.5 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.81 (d, J= 8.3 Hz, 1H), 7.62 - 7.47 (m, 5H), 7.37 - 7.31 (m, 3H), 7.11 (s, 1H), 6.51 (s, 1H), 6.47 (s, 1H), 2.08 (s, 3H), 1.57 (br d, J= 1.8 Hz, 2H), 1.42 - 1.38 (m, 2H). Example 389: ( )-/V-(l-(7-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 624)

389A-4

Compound 624

Step 1: 5-Bromo-7-chloroquinoline (389A-2)

To a solution of 3-bromo-5-chloroaniline (10.0 g, 48.4 mmol, 1.0 eq) and sodium 3- nitrobenzenesulfonate (21.8 g, 96.9 mmol, 2.0 eq) in H2SO4 (125 g, 1.25 mol, 68.1 mL, 98% purity, 26 eq) and H2O (29 mL) was added glycerol (17.8 g, 194 mmol, 14.5 mL, 4.0 eq) at 100 °C. The mixture was stirred at 125 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/20 to 1/5. A mixture of 7-bromo-5-chloroquinoline and 5-bromo-7-chloroquinoline (8.00 g, 33.0 mmol, 64% yield) was obtained as a white solid, which was hard to be separated from each other. M + H ⁺ = 241.9 (LCMS).

Step 2: 7-Chloroquinoline-5-carbonitrile (389A-3)

To a solution of 7-bromo-5-chloroquinoline and 5-bromo-7-chloroquinoline (1.00 g, 4.12 mmol, 1.0 eq) in DMF (10 mL) were added Zn(CN)2 (242 mg, 2.06 mmol, 131 pL, 0.5 eq) and Pd(PPh3)4 (477 mg, 412 pmol, 0.1 eq). The mixture was stirred at 120 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried overNa2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/10. 7-Chloroquinoline-5-carbonitrile (150 mg, 795 pmol, 19% yield) was obtained as a white solid. M + H ⁺ = 189.0 (LCMS).

Step 3: l-(7-Chloroquinolin-5-yl)cyclopropan-l-amine (389A-4)

A mixture of 7-chloroquinoline-5-carbonitrile (1.30 g, 6.89 mmol, 1.0 eq) in anhydrous Et2O (100 mL) was degassed and purged with N2 three times. The mixture was stirred with a mechanical stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (2.94 g, 10.3 mmol, 3.05 mL, 1.5 eq) slowly, and then EtMgBr (2 M in Et2O, 7.58 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -73 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (1.96 g, 13.8 mmol, 1.70 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (100 mL) and extracted with MTBE (50 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 5% - 25% B over 10 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give l-(7-chloroquinolin-5-yl)cyclopropan-l -amine (4.00 mg, 18.3 pmol, , HC1 salt) as a white solid. ^X H NMR (400 MHz, DMSO ) 8 9.04 (dd, J= 1.5, 4.1 Hz, 1H), 8.77 (br s, 1H), 8.20 (d, J= 1.9 Hz, 1H), 7.87 (d, J= 2.1 Hz, 1H), 7.74 (dd, J= 4.3, 8.6 Hz, 1H), 1.60 (s, 2H), 1.31 (s, 2H).

Step 4: (5)-/V-(l-(7-Chloroquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin-2- yl)methoxy)benzamide (Compound 624)

To a solution of (S)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (5.38 mg, 22.9 pmol, 1.0 eq) inDMF (15 mL) was added l-(7-chloroquinolin-5-yl)cyclopropan-l -amine (5.00 mg, 22.9 pmol, 1.0 eq), followed by HATU (17.4 mg, 45.7 pmol, 2.0 eq) and DIEA (14.8 mg, 114 pmol, 19.9 pL, 5.0 eq). The resulting mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (1.0 mL) and extracted with EtOAc (1.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-Chloroquinolin-5-yl)cyclopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (2.00 mg, 4.36 pmol, 19% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 436.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.77 - 10.14 (m, 1H), 9.28 (s, 1H), 9.21 (br d, J= 8.6 Hz, 1H), 9.04 (d, J= 4.0 Hz, 1H), 8.09 (d, J= 1.5 Hz, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.75 (dd, J= 4.4, 8.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.98 - 6.87 (m, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.68 - 4.55 (m, 1H), 4.33 (br dd, J = 7.8, 11.3 Hz, 1H), 4.26 - 4.18 (m, 1H), 3.99 (br dd, J= 4.6, 10.0 Hz, 1H), 3.88 - 3.83 (m, 1H), 2.81 (d, = 5.0 Hz, 3H), 2.38 - 2.27 (m, 2H), 1.95 (s, 3H), 1.38 (br s, 2H), 1.30 (br s, 2H).

Example 390: ( )-/V-(l-(7-Aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 729) ep

Compound 729

Step 1: te/7- Butyl (5)-(5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzam ido) cyclopropyl)quinolin-7-yl)carbamate (390A-1)

To a mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (250 mg, 455 pmol, 1.0 eq) and tert-butyl carbamate (63.9 mg, 546 pmol, 1.2 eq) in t-AmylOH (13 mL) were added CS2CO3 (296 mg, 910 pmol, 2.0 eq) and Xphos Pd G3 (38.5 mg, 45.5 pmol, 0.1 eq). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (12 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl (5)-(5-(l-(2-methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl)quinolin-7-yl)carbamate (170 mg, 329 pmol, 72% yield) was obtained as a yellow oil. M + H ⁺ = 517.3 (LCMS). Step 2: (5)-/V-(l-(7-Aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl) methoxy)benzamide (Compound 729)

To a solution of tert-butyl (5)-(5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzam ido) cyclopropyl)quinolin-7-yl)carbamate (170 mg, 329 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (5)-A-(l-(7-aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-m ethylaze tidin-2-yl)methoxy)benzamide (5.10 mg, 8.10 pmol, 3% yield) as a yellow solid. M + H ⁺ = 417.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.00 (s, 1H), 8.74 (d, J= 7.4 Hz, 1H), 8.58 (dd, J= 1.6, 4.2 Hz, 1H), 7.32 (d, J= 2.3 Hz, 1H), 7.11 (dd, J= 4.3, 8.4 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.86 - 6.81 (m, 2H), 6.61 (d, J= 2.6 Hz, 1H), 5.75 (d, J= 6.4 Hz, 2H), 3.87 (d, J = 5.5 Hz, 2H), 3.27 - 3.21 (m, 2H), 2.77 - 2.67 (m, 1H), 2.22 (s, 3H), 1.99 - 1.97 (m, 3H), 1.96 - 1.90 (m, 1H), 1.89 - 1.82 (m, 1H), 1.32 - 1.27 (m, 2H), 1.13 - 1.08 (m, 2H).

Example 391: ( )-/V-(l-(7-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-methy l-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 627)

Step 3

391A-3

Compound 627

Step 1: 5-(l-Aminocyclopropyl)quinolin-7-ol (391 A-l) To a solution of l-(7-methoxyquinolin-5-yl)cyclopropan-l-amine (1.50 g, 5.98 mmol, 1.0 eq) in DCM (50 mL) was added a solution of BBr, (22.5 g, 90.0 mmol, 8.7 mL, 15 eq) in DCM (20 mL) dropwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred at the same temperature for 2 h, then warmed to 20 °C and stirred for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with MeOH (20 mL) at 0 °C and treated with NH3.H2O to adjust the pH 8. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1, followed by DCM/MeOH from 100/1 to 10/1. 5-(l-Aminocyclopropyl)quinolin-7-ol (1.73 g, 8.64 mmol, 72% yield) was obtained as a yellow solid. M + H ⁺ = 201.3 (LCMS); 'H NMR (400 MHz,

DMSO-tL) 8 10.51 - 10.23 (m, 1H), 8.90 - 8.78 (m, 1H), 8.62 (d, J= 8.5 Hz, 1H), 7.43 (dd, J = 4.3, 8.5 Hz, 1H), 7.38 (d, J= 2.4 Hz, 1H), 7.32 (d, J= 2.3 Hz, 1H), 4.09 (q, J= 5.1 Hz, 2H), 1.55 - 1.48 (m, 2H), 1.28 - 1.15 (m, 2H). Step 2: 5-(l-Aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (391A-2)

To a solution of 5-(l-aminocyclopropyl)quinolin-7-ol (1.40 g, 6.99 mmol, 1.0 eq) in THF (50 mL) was added Z-BuOK (1.57 g, 14.0 mmol, 2.0 eq) at 0 °C under a N2 atmosphere. The mixture was stirred at 0 °C for 15 min. l,l,l-Trifluoro-7V-phenyl-7V-(trifluoromethylsulfonyl)methan e sulfonamide (5.00 g, 14.0 mmol, 2.0 eq) was added in portions. The resulting reaction mixture was stirred at 20 °C for 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-(l- Aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (1.25 g, 3.76 mmol, 54% yield) was obtained as a yellow oil. M + H ⁺ = 333.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.05 (dd, J = 1.6, 4.1 Hz, 1H), 8.96 (d, J= 8.5 Hz, 1H), 8.05 (d, J= 2.5 Hz, 1H), 7.74 (dd, J= 4.3, 8.6 Hz, 1H), 7.67 (d, J= 2.6 Hz, 1H), 4.20 - 3.98 (m, 2H), 3.17 (s, 3H), 1.22 - 1.15 (m, 2H), 1.04 - 0.95 (m, 2H).

Step 3: tert-Butyl (S)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (391A-3)

To a solution of 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (517 mg, 1.56 mmol, 1.0 eq) and (S)-5-((l-(tert-butoxycarbonyl)azeti din-2 -yl)methoxy)-2-methylbenzoic acid (500 mg, 1.56 mmol, 1.0 eq) in DMF (13 mL) were added DIEA (603 mg, 4.67 mmol, 813 pL, 3.0 eq) and HATU (1.48 g, 3.89 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAC (30 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. /c/V-Butyl (S)- 2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)quinol in-5-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine -1 -carboxylate (840 mg, 1.32 mmol, 85% yield) was obtained as a yellow gum. M + H ⁺ = 636.4 (LCMS).

Step 4: tert-Butyl (S)-2-((3-(( 1 -(7-((/cr/-biitoxyc:irboiiyl):iiniiio)quinolin-5-yl)cyclopro pyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-l-carboxylate (391A-4)

To a mixture of Zc/V-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (200 mg, 315 pmol, 1.0 eq) and /c/V-butyl carbamate (44.2 mg, 378 pmol, 1.2 eq) in Z-AmylOH (10 mL) were added CS2CO3 (205 mg, 629 pmol, 2.0 eq) and XPhos Pd G3 (26.6 mg, 31.5 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times, and the mixture was stirred at 80 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. /c/V-Butyl (A -2-((3-(( l -(7-((/c/7-butoxycarbonyl) amino)quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)m ethyl)azetidine-l- carboxylate (130 mg, 216 pmol, 69% yield) was obtained as a colorless oil. M + H ⁺ = 603.4 (LCMS); 'H NMR (400 MHz, CDCh) 8 9.02 (d, J= 8.4 Hz, 1H), 8.87 (dd, J= 1.6, 4.2 Hz, 1H), 8.04 (br d, J= 2.4 Hz, 2H), 7.39 (dd, J= 4.3, 8.5 Hz, 1H), 7.02 (d, J= 8.5 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.75 (d, J= 2.6 Hz, 1H), 6.65 (br s, 1H), 4.44 (br d, J= 7.2 Hz, 1H), 4.23 - 4.16 (m, 1H), 4.02 (dd, J= 2.6, 10.4 Hz, 1H), 3.86 (br t, J= 7.5 Hz, 2H), 2.35 - 2.17 (m, 2H), 2.14 (s, 3H), 1.61 (br s, 9H), 1.41 - 1.38 (m, 2H), 1.34 (br s, 9H), 1.30 - 1.24 (m, 2H).

Step 5: (5)-/V-(l-(7-Aminoquinolin-5-yl)cyclopropyl)-5-(azetidin-2-y lmethoxy)-2- methylbenzamide (391A-5)

To a solution of Zc/V-butyl (8)-2-((3-((l-(7-((tert-butoxycarbonyl)amino)quinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (130 mg, 132 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude product (5)-A-(l-(7-aminoquinolin-5-yl)cyclopropyl)-5-(azetidin-2-yl methoxy)-2- methylbenzamide (170 mg, TFA salt) as a yellow oil. M + H ⁺ = 403.2 (LCMS).

Step 6: (5)-/V-(l-(7-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 627)

To a solution of (5)-A-(l-(7-aminoquinolin-5-yl)cyclopropyl)-5-(azetidin-2-yl methoxy)-2- methylbenzamide (150 mg, 290 pmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (40.4 pL) followed by formaldehyde (236 mg, 2.90 mmol, 216 pL, 37% purity in water, 10 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaftfLCN (91.3 mg, 1.45 mmol, 5.0 eq) was added. The reaction mixture was stirred at 25 °C for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-(Dimethylamino)quinolin-5-yl)cyclopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (52.9 mg, 117 pmol, 40% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 445.2 (LCMS). 'H NMR (400 MHz, DMSO-tL) 8 10.86 - 10.77 (m, 1H), 9.43 (br d, J= 8.0 Hz, 1H), 9.26 (s, 1H), 8.86 (dd, J = 1.1, 5.5 Hz, 1H), 7.73 (d, J= 2.4 Hz, 1H), 7.59 (dd, J= 5.6, 8.2 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 7.00 (d, J= 2.1 Hz, 1H), 6.93 (dd, = 2.7, 8.5 Hz, 1H), 6.82 - 6.73 (m, 1H), 4.71 - 4.57 (m, 1H), 4.43 - 4.34 (m, 1H), 4.22 (dd, = 3.3, 11.4 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.91 - 3.79 (m, 1H), 3.21 (s, 6H), 2.81 (d, J= 3.9 Hz, 3H), 2.36 - 2.26 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.33 (br s, 2H).

Example 392: ( )-/V-(l-(2-(Dimethylamino)-7-fluoroquinolin-4-yl)cyclopropyl )-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 611)

Compound 611

Step 1 : (5)-A-(l-(2-(Dimethylamino)-7-fluoroquinolin-4-yl)cyclopropy l)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 611)

To a solution of (5)-7V-(l-(2-chloro-7-fluoroquinolin-4-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 176 pmol, 1.0 eq), dimethylamine (2 M in THF, 176 pL, 2.0 eq) in DMSO (1.0 mL) were added DIEA (45.5 mg, 352 pmol, 61.4 pL, 2.0 eq) and CsF (53.5 mg, 352 pmol, 2.0 eq) at 20 °C. The mixture was stirred at 120 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was purified by preparative HPLC (Phenomenex Luna C18 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(2-(Dimethylamino)-7-fluoroquinolin-4- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (5.50 mg, 10.5 pmol, 6% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 463.2 (LCMS); ^T H NMR (400 MHz, D SO ) 6 13.12 - 12.61 (m, 1H), 11.03 - 10.89 (m, 1H), 9.38 (s, 1H), 8.60 (dd, J = 6.0, 9.1 Hz, 1H), 8.26 - 8.10 (m, 1H), 7.52 - 7.43 (m, 1H), 7.37 (s, 1H), 7.12 (d, J= 8.5 Hz, 1H), 6.94 (dd, J= 2.7, 8.4 Hz, 1H), 6.75 (d, J= 2.6 Hz, 1H), 4.63 (br s, 1H), 4.41 (dd, J= 8.1, 11.1 Hz, 1H), 4.22 (dd, J= 3.1, 11.1 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.46 (s, 6H), 2.54 (s, 3H), 2.42 - 2.25 (m, 2H), 1.99 (s, 3H), 1.40 (s, 4H).

Example 393: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(prop ylamino) quinolin-5-yl)cyclopropyl)benzamide (Compound 743)

Step 1

Compound 729 Compound 743

Step 1 : (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(pr opylamino)quinolin- 5-yl)cyclopropyl)benzamide (Compound 743)

To a solution of (5)-A-(l-(7-aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-m ethylazetidin- 2-yl)methoxy)benzamide (60.0 mg, 144 pmol, 1.0 eq) in MeOH (3.0 mL) was added TEA (20.0 pL), followed by propionaldehyde (8.37 mg, 144 pmol, 10.5 pL, 10 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. NaBHiCN (45.3 mg, 720 pmol, 5.0 eq) was added. The resulting mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 * 30 mm, 3 pin); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(7- (propylamino)quinolin-5-yl)cyclopropyl)benzamide (1.9 mg, 3.84 pmol, 3% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 459.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.23 - 10.14 (m, 1H), 9.31 - 9.22 (m, 1H), 9.17 (s, 1H), 8.77 (br d, J= 6.1 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.54 - 7.47 (m, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.93 (dd, J= 2.7, 8.3 Hz, 1H), 6.76 (d, J= 2.9 Hz, 1H), 6.72 (br s, 1H), 4.67 - 4.57 (m, 1H), 4.33 - 4.20 (m, 2H), 4.07 - 3.96 (m, 1H), 3.91 - 3.82 (m, 1H), 3.19 - 3.13 (m, 2H), 2.87 - 2.79 (m, 3H), 2.37 - 2.28 (m, 2H), 1.97 (s, 3H), 1.71 - 1.63 (m, 2H), 1.40 - 1.33 (m, 2H), 1.23 - 1.17 (m, 2H), 1.00 (t, J= 7.4 Hz, 3H).

Example 394: (5)-/V-(l-(7-Acetamidoquinolin-5-yl)cyclopropyl)-2-methyl-5- ((l- methylazetidin-2-yl)methoxy)benzamide (Compound 744)

Compound 729 Compound 744

Step 1: (5)-/V-(l-(7-Acetamidoquinolin-5-yl)cyclopropyl)-2-methyl-5- ((l-methylazetidin- 2-yl)methoxy)benzamide (Compound 744)

To a solution of (5)-A-(l-(7-aminoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-m ethylazetidin- 2-yl)methoxy)benzamide (50 mg, 120 pmol, 1.0 eq) in DCM (5 mL) were added TEA (48.6 mg, 480 pmol, 66.8 pL, 4.0 eq) and AC2O (24.5 mg, 240 pmol, 22.5 pL, 2.0 eq) at 0 °C. The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (8)-A-(l-(7-Acetamidoquinolin-5-yl)cyclopropyl)-2-methyl-5-( (l -methyl azetidin-2-yl)methoxy)benzamide (4.50 mg, 7.86 pmol, 7% yield) was obtained as a white solid. M + H ⁺ = 459.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.00 (s, 1H), 8.74 (d, J= 7.4 Hz, 1H), 8.58 (dd, J= 1.6, 4.2 Hz, 1H), 7.32 (d, J= 2.3 Hz, 1H), 7.11 (dd, J= 4.3, 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.86 - 6.81 (m, 2H), 6.61 (d, J= 2.6 Hz, 1H), 5.75 (d, J= 6.4 Hz, 2H), 3.87 (d, J= 5.5 Hz, 2H), 3.27 - 3.21 (m, 2H), 2.77 - 2.67 (m, 1H), 2.22 (s, 3H), 1.99 - 1.97 (m, 3H), 1.96 - 1.90 (m, 1H), 1.89 - 1.82 (m, 1H), 1.32 - 1.27 (m, 2H), 1.13 - 1.08 (m, 2H)

Example 395: (.S)-2-Methyl-5-((l-methyl:izetidin-2-yl)methoxy)- \-( l-(7- (methylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (Compound 786)

Compound 786

Step 1: te/7- Butyl (5)-2-((4-methyl-3-((l-(7-(methylsulfonamido)quinolin-5-yl) cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxylate (395A-1)

To a mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (250 mg, 393 pmol, 1.0 eq) and methanesulfonamide (46.3 mg, 472 pmol, 1.2 eq) in /-AmylOH (10 mL) were added CS2CO3 (256 mg, 787 pmol, 2.0 eq) and XPhos Pd G3 (33.3 mg, 39.3 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times, then the mixture was stirred at 80 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert-Butyl (5)-2-((4-methyl-3-((l-(7- (methylsulfonamido)quinolin-5-yl)cyclopropyl)carbamoyl)pheno xy)methyl)azetidine-l- carboxylate (210 mg, crude) was obtained as a yellow oil. M + H ⁺ = 581.4 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 6 10.29 - 10.05 (m, 1H), 9.11 (d, J= 19.6 Hz, 1H), 9.00 - 8.87 (m, 1H), 8.86 - 8.71 (m, 1H), 7.84 - 7.68 (m, 1H), 7.51 - 7.44 (m, 1H), 7.35 - 7.14 (m, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.88 (dd, J= 2.4, 8.4 Hz, 1H), 6.66 (d, J= 1.8 Hz, 1H), 4.38 (br dd, J= 2.9, 7.6 Hz, 1H), 4.14 (dd, J= 4.7, 10.3 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.73 (br s, 2H), 3.30 - 3.28 (m, 6H), 2.30 - 2.22 (m, 1H), 2.20 - 2.15 (m, 9H), 2.11 - 2.03 (m, 1H), 1.23 (s, 2H), 1.16 (br d, J = 7.0 Hz, 2H).

Step 2: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(methylsulfonam ido)quinolin-5- yl) cyclopropyl)benzamide (395A-2)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(methylsulfonamido)quinolin-5-yl)c yclo propyl)carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (200 mg, 344 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude product S)- 5-(azetidin-2-ylmethoxy)-2-methyl-A-(l-(7-(methylsulfonamido )quinolin-5- yl)cyclopropyl)benzamide (200 mg, TFA salt) as a yellow oil. M + H ⁺ = 481.3 (LCMS).

Step 3: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(me thylsulfonamido) quinolin-5-yl)cyclopropyl)benzamide (Compound 786)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-2-methyl-A-(l-(7-(methylsulfona mido)quino lin-5-yl)cyclopropyl)benzamide (200 mg, 336 pmol, 1.0 eq) in MeOH (6.0 mL) was added TEA (47 pL), followed by formaldehyde (20.2 mg, 673 pmol, 19.0 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (63.4 mg, 1.01 mmol, 3.0 eq) was added. The reaction mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna Cl 8 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). The compound was further purified by SFC separation (DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 pm); flow rate: 30 mL/min; gradient: 20% B over 17 min; mobile phase A: heptane, mobile phase B: z-PrOH (0.1%NH3.H2O)). (5)-2-Methyl-5-((l- methylazetidin-2-yl)methoxy)-A-(l-(7-(methylsulfonamido)quin olin-5-yl)cyclopropyl) benzamide (10.8 mg, 21.8 pmol, 7% yield) was obtained as a yellow solid. M + H ⁺ = 495.4 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.11 (s, 1H), 8.96 (br d, J= 8.1 Hz, 1H), 8.87 - 8.79 (m, 1H), 7.79 (d, J= 2.0 Hz, 1H), 7.67 (s, 1H), 7.45 (dd, J = 4.2, 8.4 Hz, 1H), 7.03 (d, J

= 8.5 Hz, 1H), 6.83 (dd, J= 2.5, 8.4 Hz, 1H), 6.61 (d, J= 2.5 Hz, 1H), 3.86 (d, J= 5.4 Hz, 2H), 3.25 - 3.21 (m, 2H), 3.10 (s, 3H), 2.76 - 2.67 (m, 1H), 2.21 (s, 3H), 1.98 - 1.81 (m, 5H), 1.36 (br s, 2H), 1.16 (br s, 2H).

Example 396: 2-Methyl-5-((5)-l-((5)-l-methylazetidin-2-yl)ethoxy)-/V-(l-( 7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 757)

Compound 757

Step 1: tert- Butyl (5)-2-(methoxy(methyl)carbamoyl)azetidine-l-carboxylate (396A-2)

To a solution of CS')- l -(tert-butoxycarbonyl)azetidine-2-carboxylic acid (4.00 g, 11.8 mmol, 1.0 eq) and 7V,O-dimethylhydroxylamine hydrochloride (2.33 g, 23.8 mmol, 1.2 eq) in DMF (40 mL) were added EDCI (4.57 g, 11.8 mmol, 1.0 eq), HOBt (3.22 g, 23.8 mmol, 1.2 eq) and NMM (2.41 g, 23.8 mmol, 2.62 mL, 1.2 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was diluted with EtOAc (160 mL), then the solution was washed with HC1 (1 M, 100 mL x 1), NaOH (2 M, 100 mL x 2) and brine (100 mL x 3). The organic layers was dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl fS')- 2-(methoxy(methyl)carbamoyl)azetidine-l -carboxylate (2.95 g, 12.1 mmol, 60% yield) as a yellow solid. M - 100 + H ⁺ = 145.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 5.03 (br dd, J = 5.4, 8.5 Hz, 1H), 4.04 (dt, J= 6.4, 8.4 Hz, 1H), 3.86 (dt, J= 5.6, 8.4 Hz, 1H), 3.70 (s, 3H), 3.21 (s, 3H), 2.46 (dtd, J= 6.3, 9.0, 11.2 Hz, 1H), 2.18 - 2.04 (m, 1H), 1.42 (s, 9H).

Step 2: tert-Butyl (5)-2-acetylazetidine-l-carboxylate (396A-3)

To a solution of tert-butyl CS')-2-(methoxy(methyl)carbamoyl)azetidine- l -carboxylate (2.95 g, 12.1 mmol, 1.0 eq) in THF (30 mL) were added MeMgBr (3 M in THF, 6.04 mL, 1.5 eq) at - 78 °C. The mixture was stirred at 20 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was quenched with NH4CI (30 mL), the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 3/7. /crt-Butyl (8)-2-acetylazetidine-l -carboxylate (2.50 g) was obtained as a pale-yellow oil. M + Na ⁺ = 222.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 4.60 (dd, J= 6.1, 9.5 Hz, 1H), 3.96 - 3.84 (m, 2H), 2.52 - 2.40 (m, 1H), 2.27 (s, 3H), 2.13 (tdd, J= 6.4, 8.7, 11.6 Hz, 1H), 1.44 (s, 9H).

Step 3: tert-Butyl (5)-2-((5)-l-hydroxyethyl)azetidine-l-carboxylate (396A-4) and tertbutyl (5)-2-((l?)-l-hydroxyethyl)azetidine-l-carboxylate (396A-4A)

To a solution of tert-butyl (5)-2-acetylazetidine-l -carboxylate (2.51 g, 12.6 mmol, 1.0 eq) in MeOH (30 mL) was added NaBHj (571 mg, 15.1 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was quenched with NH4CI (30 mL), then extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. tert-Butyl S)- 2-(fS')- l -hydroxyethyl )azetidine- l -carboxylate (897 mg, 4.46 mmol, 35% yield) was obtained as a colourless oil. M + Na ⁺ = 224.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 4.09 - 4.03 (m, 1H), 3.93 - 3.80 (m, 2H), 3.74 (dt, J= 4.6, 8.9 Hz, 1H), 2.16 (dt, J= 4.3, 7.8 Hz, 1H), 1.92 - 1.81 (m, 1H), 1.45 (s, 9H), 1.06 (d, J = 6.3 Hz, 3H). te/7-Butyl (S)-2-((A)-l- hydroxyethyl)azetidine-l -carboxylate (921 mg, 4.58 mmol, 36% yield) was obtained as a colourless oil. M + Na ⁺ = 224.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 4.33 (br s, 1H), 3.96 (br dd, J= 2.1, 6.4 Hz, 1H), 3.85 (q, J= 8.1 Hz, 1H), 3.77 - 3.67 (m, 1H), 2.09 (q, = 7.7 Hz, 2H), 1.45 (s, 9H), 1.15 (d, J = 6.5 Hz, 3H).

Step 4: tert-Butyl (5)-2-((5)-l-(3-(methoxycarbonyl)-4-methylphenoxy)ethyl)azet idine-l- carboxylate (396A-5)

To a solution of tert-butyl (5)-2-((A)-l-hydroxyethyl)azetidine-l -carboxylate (897 mg, 4.46 mmol, 1.0 eq) and methyl 5-hydroxy-2-methylbenzoate (740 mg, 4.45 mmol, 1.0 eq) in toluene (10 mL) were added TMAD (2.30 g, 13.3 mmol, 3.0 eq) and PPI13 (3.50 g, 13.3 mmol, 3.0 eq) at 20 °C. The mixture was stirred at 100 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction was allowed to cool to room temperature. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/50. tert-Butyl (8)-2-((8)-l -(3 -(m ethoxy carbonyl)-4- methylphenoxy)ethyl)azetidine-l -carboxylate (1.04 g, 2.98 mmol, 66% yield) was obtained as a colourless oil. M + H ⁺ = 350.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 7.51 (d, J= 2.6 Hz, 1H), 7.16 - 7.08 (m, 1H), 7.03 (dd, J= 2.3, 8.3 Hz, 1H), 4.84 (br d, J= 1.5 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.88 (s, 3H), 3.82 (br t, J= 7.5 Hz, 2H), 2.51 (s, 3H), 2.45 - 2.32 (m, 1H), 2.29 - 2.15 (m, 1H), 1.36 (s, 9H), 1.20 (d, J = 6.4 Hz, 3H).

Step 5: 5-((5)-l-((5)-l-(tert-Butoxycarbonyl)azetidin-2-yl)ethoxy)-2 -methylbenzoic acid (396A-6)

To a solution of tert-butyl (5)-2-((5)- 1 -(3 -(methoxy carbonyl)-4- methylphenoxy)ethyl)azetidine-l -carboxylate (1.04 g, 2.98 mmol, 1.0 eq) in MeOH (3.0 mL) and THF (12 mL) was added NaOH (2 M, 5.95 mL, 4.0 eq) at 20 °C. The mixture was stirred at 70 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction was allowed to cool to room temperature. The mixture was concentrated under vacuum. The residue was diluted with H2O (5.0 mL) and the mixture was extracted with EtOAc (5.0 mL x 1). The organic layer was discarded. The aqueous layer was acidified to pH 5 by using HC1 (1 M aqueous), then extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried overNa2SO4, filtered, and concentrated under vacuum to give 5-((8)-l-((S)-l-(tert-butoxycarbonyl)azetidin-2-yl)ethoxy)-2 -methylbenzoic acid (994 mg, 2.87 mmol, 96% yield) as a yellow oil. M - 100 + H ⁺ = 280.1 (LCMS).

Step 6: tert-Butyl (5)-2-((5)-l-(4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl) oxy) quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)ethyl)azetidine- l-carboxylate (396A-7)

To a solution of 5-((8)-l -(($)- l-(tert-butoxycarbonyl)azeti din-2 -yl)ethoxy)-2-methylbenzoic acid (75.0 mg, 223 pmol, 1.0 eq) and 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (74.3 mg, 223 pmol, 1.0 eq) in DMF (1.0 mL) were added DIEA (86.7 mg, 670 pmol, 116 pL, 3.0 eq) and HBTU (169 mg, 447 pmol, 2.0 eq) at 20 °C. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The residue was diluted with H2O (5.0 mL), the aqueous layer was extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.65). tert-Butyl CS')-2-(fS')- l -(4-methyl- 3-(( l -(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropy l) carbamoyl)phenoxy)ethyl)azetidine-l -carboxylate (104 mg, 160 pmol, 71% yield) as a yellow oil. Step 7: tert-Butyl (5)-2-((5)-l-(4-methyl-3-((l-(7-vinylquinolin-5-yl)cycloprop yl) carbamoyl)phenoxy)ethyl)azetidine-l-carboxylate (396A-8)

To a solution of tert-butyl (A -2-((A')- l -(4-methyl-3-(( l -(7- (((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)cyclopropyl)ca rbamoyl)phenoxy)ethyl) azetidine- 1 -carboxylate (104 mg, 160 pmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2- dioxaborolane (49.3 mg, 320 pmol, 2.0 eq) in a mixture of dioxane (2.0 mL) and H2O (0.2 mL) were added Pd(dppf)C12.CH2C12 (13.1 mg, 16.0 pmol, 0.1 eq) andlSfeCCh (39.0 mg, 368 pmol, 2.3 eq) at 20 °C. The mixture was stirred at 80 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and was diluted with H2O (5.0 mL). The aqueous layer was extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.59). tert- Butyl (5)-2-((5)-l-(4-methyl-3-((l-(7-vinylquinolin-5-yl)cycloprop yl)carbamoyl)phenoxy) ethyl)azetidine-l -carboxylate (56.0 mg, 106 pmol, 66% yield) was obtained as a pale yellow liquid.

Step 8: 5-((5)-l-((5)-Azetidin-2-yl)ethoxy)-2-methyl-/V-(l-(7-vinylq uinolin-5- yl)cyclopropyl)benzamide (396A-9)

To a solution of tert-butyl (5)-2-((5)-l-(4-methyl-3-((l-(7-vinylquinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)ethyl)azetidine-l-carboxyla te (56.0 mg, 106 pmol, 1.0 eq) in DCM (1.5 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL, 63 eq) at 20 °C. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give 5-(fS')- l -(fS')-azetidin-2-yl)ethoxy)-2-methyl-/' -( l -(7-vinylquinolin-5- yl)cyclopropyl)benzamide (60.0 mg, crude, TFA salt) as a brown liquid, which was used in the next step without any further purification. M + H ⁺ = 428.2 (LCMS).

Step 9: 2-Methyl-5-((5)-l-((5)-l-methylazetidin-2-yl)ethoxy)-A-(l-(7 -vinylquinolin-5- yl)cyclopropyl)benzamide (Compound 757)

To a solution of 5-((5)-l-((5 -azetidin-2-yl)ethoxy)-2-methyl-7V-(l-(7-vinylquinolin-5- yl)cyclopropyl)benzamide (60.0 mg, 111 pmol, 1.0 eq, TFA salt) in MeOH (1.5 mL) was added TEA (15.0 pL), followed by formaldehyde (18.0 mg, 221 pmol, 6.34 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (20.9 mg, 332 pmol, 3.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). LCMS indicated that the purity was 68%, then the residue was further purified by preparative HPLC (Phenomenex Gemini C18 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-( S')-l- (CS’)- I -methylazetidin-2-yl)ethoxy)-A-(l -(7-vinylquinolin-5-yl)cyclopropyl)benzamide (8.30 mg, 17.0 pmol, 15% yield, HC1 salt) was obtained as a colorless gum. M + H ⁺ = 442.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.97 - 9.83 (m, 1H), 9.49 (br d, J= 8.5 Hz, 1H), 9.30 (s, 1H), 9.12 (d, J= 3.9 Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.89 (dd, J= 4.8, 8.3 Hz, 1H), 7.13 - 7.00 (m, 2H), 6.93 (dd, J= 2.6, 8.4 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.19 (d, J= 17.6 Hz, 1H), 5.62 (d, J= 11.0 Hz, 1H), 4.85 - 4.77 (m, 1H), 4.50 - 4.39 (m, 1H), 4.04 - 3.97 (m, 1H), 3.81 (br dd, J= 5.9, 9.4 Hz, 1H), 2.81 (d, J= 4.9 Hz, 3H), 2.46 - 2.34 (m, 2H), 2.01 - 1.95 (m, 3H), 1.42 (br s, 2H), 1.33 (br d, J= 5.0 Hz, 2H), 1.15 - 1.08 (m, 3H).

Example 397 : ( )-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-/V-(l-(7-vinylquinolin -5-yl) cyclopropyl)benzamide (Compound 713)

Step 2 Step 3

397A-2

Compound 713

Step 1: tert-Butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carbox ylate (397A-1)

To a solution of 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (350 mg, 1.05 mmol, 1.0 eq) and CS')-5-(( l -(/c77-butoxycarbonyl)pyrrolidin-2-yl)methoxy)-2-methylbenzo ic acid (353 mg, 1.05 mmol, 1.0 eq) in DMF (10 mL) were added DIEA (408 mg, 3.16 mmol, 3.0 eq) and HATU (1.00 g, 2.63 mmol, 2.5 eq). The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl(5)-2-((4-methyl-3-((l-(7-(((trifluoro methyl)sulfonyl)oxy)quinolin-5-yl)cyclopropy)carbamoyl)pheno xy)methyl)pyrolidine-l- carboxylate (520 mg, 800 pmol, 75% yield) was obtained as a white solid. M + H ⁺ = 650.3 (LCMS).

Step 2: tert-Butyl (5)-2-((4-methyl-3-((l-(7-vinylquinolin-5-yl) cyclopropyl) carbamoyl) phenoxy) methyl) pyrrolidine-l-carboxylate (397A-2)

To a stirred solution of Zc/V-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl) oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrro lidine-l-carboxylate (250 mg, 385 pmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (65.2 mg, 423 pmol, 1.1 eq) in a mixture of dioxane (15 mL) and H2O (3.0 mL) were added Pd(dppf)C12 (31.4 mg, 38.5 pmol, 0.1 eq), ISfeCCL (93.8 mg, 885 pmol, 2.3 eq). The mixture was degassed, purged with N2 three times, and stirred at 80 °C for 4 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. tert-Butyl (5)- 2-((4-methyl-3-((l-(7-vinylquinolin-5-yl)cyclopropyl)carbamo yl) phenoxy)methyl) pyrrolidine- 1 -carboxylate (156 mg, 296 pmol, 76% yield) was obtained as a white solid. M - 56 + H ⁺ = 472.3 (LCMS).

Step 3: (5)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-/V-(l-(7-vinylquinol in-5-yl)cyclopropyl) benzamide (Compound 713)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-vinylquinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)pyrrolidine-l-carbox ylate (46.0 mg, 87.1 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (770 mg, 6.75 mmol, 500 pL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-2-Methyl-5-(pyrrolidin-2-ylmethoxy)-A-(l- (7-vinylquinolin-5-yl)cyclopropyl)benzamide (34.1 mg, 63.0 pmol, 72% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 428.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 9.18 - 9.09 (m, 3H), 8.96 (dd, J= 1.5, 4.4 Hz, 1H), 8.73 - 8.51 (m, 1H), 8.08 (d, J= 1.5 Hz, 1H), 7.97 (s, 1H), 7.64 (dd, J= 4.3, 8.5 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.05 - 6.96 (m, 1H), 6.89 (dd, J = 2.8, 8.4 Hz, 1H), 6.66 (d, = 2.8 Hz, 1H), 6.11 (d, J= 17.6 Hz, 1H), 5.51 (d, J= 11.0 Hz, 1H), 4.15 (dd, J= 3.6, 10.6 Hz, 1H), 3.98 (dd, J = 8.4, 10.5 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.23 - 3.14 (m, 2H), 2.19 - 2.02 (m, 1H), 1.99 - 1.96 (m, 3H), 1.95 - 1.83 (m, 2H), 1.74 - 1.62 (m, 1H), 1.37 (br s, 2H), 1.29 (br s, 2H).

Example 398: 2-Methyl-5-((tetrahydro-lH-pyrrolizin-7a(5FT)-yl)methoxy)-A- (l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 748)

Step 4

Compound 748

Step 1: Methyl 2-methyl-5-((tetr:ihydro-l//-pyrrolizin-7:i(5//)-yl)methoxy) benzo:ite (398A-1) and methyl 5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoate (398 A-2)

To a solution of methyl 5-hydroxy-2-methylbenzoate (2.00 g, 12.0 mmol, 1.0 eq) and (tetrahydro- l/Z-pyrrolizin-7a(5J7)-yl)m ethanol (1.70 g, 12.0 mmol, 1.0 eq) in toluene (20 mL) was added TMAD (3.11 g, 18.0 mmol, 1.5 eq). The mixture was stirred at 100 °C under a N2 atmosphere for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. Methyl 2-methyl-5-((tetrahydro- IT/-pyrrolizin- 7a(5J7)-yl)methoxy)benzoate and methyl 5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2- methylbenzoate (3.50 g, 7.38 mmol, 61% yield) were obtained as a mixture of a white solid.

M + H ⁺ = 290.2 (LCMS). Step 2: 2- Iethyl- -((tetr:ihydro-l//-pyrrolizin-7:i( //)-yl)methoxy)benzoic acid (398A- 3) and 5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoic acid (398A-4)

To a mixture of methyl 2-methyl-5-((tetrahydro-l/Z-pyrrolizin-7a(5J7)-yl)methoxy)be nzoate and methyl 5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoate (2.68 g, 5.56 mmol, 1.0 eq) in a mixture of MeOH (4.0 mL) and THF (12 mL) was added NaOH (11.1 mL, 2 M aqueous, 4.0 eq). The mixture was stirred at 70 °C for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile) to give 2-methyl-5-((tetrahydro-17T- pyrrolizin-7a(5J7)-yl)methoxy)benzoic acid and 5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2- methylbenzoic acid (300 mg, 1.09 mmol, 19% yield) as a mixture of a white solid. M + H ⁺ = 276.2 (LCMS).

Step 3: 5-( l-(2-Methyl- -((tetr:ihydro-l//-pyrrolizin-7:i( //)-yl)inethoxy)benzainido) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (398A-5) and 5-(l-(5-((l- azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzamido)cycloprop yl)quinolin-7-yl trifluoromethanesulfonate (398A-6)

To a mixture of 2-methyl-5-((tetrahydro- I T/-pyrrolizin-7a(57/)-yl)methoxy)benzoic acid and 5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzoic acid (130 mg, 472 pmol, 1.0 eq) in DMF (2.0 mL) were added 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (156 mg, 472 pmol, 1.0 eq), HATU (269 mg, 708 pmol, 1.5 eq) and DIEA (183 mg, 1.42 mmol, 247 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 40% - 70% B over 8 min; mobile phase A: 0.1% aqueous NH4HCO3, mobile phase B: acetonitrile). 5-(l-(2-Methyl-5- ((tetrahydro- l7/-pyrrolizin-7a(57/-yl)methoxy)benzamido)cyclopropyl)quino lin-7-yl trifluoromethanesulfonate (25.0 mg, 38.5 pmol, 8% yield) was obtained as a white solid. M + H ⁺ = 590.2 (LCMS). 5-(l-(5-((l-Azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzami do) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (30.0 mg, 38.5 pmol, 10% yield) was obtained as a white solid. M + H ⁺ = 590.2 (LCMS). Step 4: 2-Methyl-5-((tetr:ihydro-l//-pyrrolizin-7a(5//)-yl)niethoxy) -\-( l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 748)

To a solution of 5-(l-(2-methyl-5-((tetrahydro-U/-pyrrolizin-7a(5J/-yl)methox y) benzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (25.0 mg, 42.4 pmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (13.0 mg, 84.8 pmol, 2.0 eq) in a mixture of dioxane (1.0 mL) and H2O (100 pL) were added ISfeCCh (10.3 mg, 97.5 pmol, 2.3 eq) and Pd(dppf)C12.CH2C12 (3.46 mg, 4.24 pmol, 0.10 eq). The resulting mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 2-methyl-5-((tetrahydro- 17/-pyrrolizin-7a(5J7)-yl)methoxy)-A-(l-(7-vinylquinolin-5-y l)cyclopropyl)benzamide (10.9 mg, 21.6 pmol, 51% yield, HC1 salt) as a white solid. 'H NMR (400 MHz, DMSO-t/e) 8 10.32 - 10.11 (m, 1H), 9.32 (td, J= 2.6, 4.9 Hz, 1H), 9.20 (s, 1H), 9.05 (br d, J= 4.0 Hz, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.77 (br d, J= 9.4 Hz, 1H), 7.12 - 6.99 (m, 2H), 6.90 (dd, J= 2.7, 8.1 Hz, 1H), 6.72 (d, J= 2.4 Hz, 1H), 6.18 (s, 1H), 5.57 (d, J= 10.7 Hz, 1H), 4.07 (s, 2H), 3.47 - 3.41 (m, 2H), 3.21 - 3.13 (m, 2H), 2.11 - 2.03 (m, 4H), 1.98 - 1.91 (m, 7H), 1.40 (br s, 2H), 1.32 (br s, 2H).

Example 399: 5-(l-Azabicyclo[3.3.1]nonan-5-yloxy)-2-methyl-/V-(l-(7-vinyl quinolin-5- yl)cyclopropyl)benzamide (Compound 749) Step 1: 5-((l-Azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methyl-/V-(l-(7-vin ylquinolin-5- yl)cyclopropyl)benzamide (Compound 749)

To a solution of 5-(l-(5-((l-azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methylbenzami do) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (19.5 mg, 33.1 pmol, 1.0 eq) and 4, 4,5,5- tetramethyl-2-vinyl-l,3,2-dioxaborolane (10.2 mg, 66.2 pmol, 2.0 eq) in a mixture of dioxane (1.0 mL) and H2O (100 pL) were added ISfeCCh (8.00 mg, 76.2 pmol, 2.3 eq) and Pd(dppf)C12.CH2C12 (2.71 mg, 3.31 pmol, 0.10 eq). The resulting mixture was stirred at 80 °C for 12 h under a N2 atmospher. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give 5-((l- azabicyclo[3.3.1]nonan-5-yl)oxy)-2-methyl-7V-(l-(7-vinylquin olin-5-yl)cyclopropyl) benzamide (5.80 mg, 11.4 pmol, 34% yield, HC1 salt) as a white solid. 'H NMR (400 MHz, DMSO-t/e) 8 10.68 (br s, 1H), 9.36 - 9.17 (m, 2H), 9.10 - 8.98 (m, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.77 (br dd, J = 3.1, 4.7 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 10.9, 17.7 Hz, 1H), 6.92 (dd, J = 2.6, 8.2 Hz, 1H), 6.67 (d, J= 2.5 Hz, 1H), 6.15 (d, J = 17.4 Hz, 1H), 5.56 (d, J= 11.0 Hz, 1H), 3.23 - 3.11 (m, 6H), 2.24 - 2.11 (m, 2H), 2.02 - 1.99 (m, 3H), 1.99 - 1.93 (m, 2H), 1.87 - 1.77 (m, 4H), 1.40 (br s, 2H), 1.31 (br s, 2H).

Example 400: ( )-4-Fluoro-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l -(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 800)

Compound 800 Step 1: Methyl 2-bromo-4-fluoro-5-methoxybenzoate (400A-2)

To a solution of 2-bromo-4-fluoro-5-methoxybenzoic acid (1.20 g, 4.82 mmol, 1.0 eq) in acetonitrile (30 mL) were added CH3I (1.73 g, 9.64 mmol, 600 pL, 2.0 eq) and DBU (1.25 g, 8.19 mmol, 1.23 mL 1.7 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Methyl 2-bromo-4-fluoro-5-methoxybenzoate (1.25 g, 4.75 mmol, 99% yield) was obtained as a white solid. M + H ⁺ = 263.1 (LCMS). Step 2: Methyl 4-fluoro-5-methoxy-2-methylbenzoate (400A-3)

A solution of methyl 2-bromo-4-fluoro-5-methoxybenzoate (1.25 g, 4.76 mmol, 1.0 eq) in a mixture of dioxane (60 mL) and H2O (12 mL) was degassed and purged with N2 three times. To this mixture were added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2.38 g, 9.50 mmol, 2.66 mL, 50% purity, 2.0 eq), K2CO3 (1.97 g, 14.3 mmol, 3.0 eq), and Pd(dppf)C12 (348 mg, 2.53 mmol, 475 pL, 0.1 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (60 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Methyl 4-fluoro-5-methoxy-2- methylbenzoate (722 mg, 3.64 mmol, 77% yield) was obtained as a white solid.

Step 3: Methyl 4-fluoro-5-hydroxy-2-methylbenzoate (400A-4)

To a solution of methyl 4-fluoro-5-methoxy-2-methylbenzoate (722 mg, 3.64 mmol, 1.0 eq) in DCM (40 mL) was added BBn (13.7 g, 54.6 mmol, 6.92 mL, 15 eq). The mixture was stirred at -78 °C for 1 h under aN2 atmosphere, then at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue. The reaction mixture was poured into MeOH (2.0 ml) and basified to pH 8 with NH3 H2O. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. Methyl 4- fhioro-5-hydroxy-2-methylbenzoate (500 mg, 2.71 mol, 75% yield) was obtained as a yellow solid. M + H ⁺ = 185.2 (LCMS).

Step 4: tert-Butyl ( )-2-((2-fluoro-5-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine-l-carboxylate (400A-5)

To a solution of methyl 4-fluoro-5 -hydroxy -2 -methylbenzoate (490 mg, 2.66 mmol, 1.0 eq) and tert-butyl fS')-2-(hydroxymethyl)azetidine- l -carboxylate (498 mg, 2.66 mmol, 1.0 eq) in toluene (30 mL) were added TMAD (1.37 g, 7.98 mmol, 3.0 eq) and PPI13 (2.09 g, 7.98 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl (5)-2-((2-fluoro-5-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine-l-carboxylate (820 mg, 2.32 mmol, 87% yield) was obtained as a white oil. M - 56 + H ⁺ = 298.2 (LCMS).

Step 5: (5)-5-((l-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-4-fluo ro-2-methylbenzoic acid (400A-6)

To a solution of tert-butyl (5)-2-((2-fluoro-5-(methoxycarbonyl)-4-methylphenoxy)methyl) azetidine- 1 -carboxylate (820 mg, 2.32 mmol, 1.0 eq) in a mixture of MeOH (36 mL) and THF (18 mL) was added NaOH (2 M aqueous, 4.6 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL), and washed with MTBE (15 mL x 2). The aqueous layer was acidified to pH 6 with HC1 (1 M aqueous) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude (5)-5-((l- (/c/7-butoxycarbonyl)azetidin-2-yl)methoxy)-4-fluoro-2-methy lbenzoic acid (787 mg, 2.32 mmol, 100% yield) as a brown oil. M - 56 + H ⁺ = 284.1 (LCMS).

Step 6: tert-Butyl (5)-2-((2-fluoro-4-methyl-5-((l-(7-(((trifluoromethyl)sulfon yl)oxy)quin olin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-c arboxylate (400A-7)

To a solution of CS')-5-(( l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-4-fluoro-2- methylbenzoic acid (306 mg, 903 pmol, 1.0 eq) and 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 903 pmol, 1.0 eq) in DMF (30 mL) were added DIEA (350 mg, 2.71 mmol, 472 pL, 3.0 eq) and HATU (858 mg, 2.26 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (30 mL) and extracted with EtOAc (12 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl (5)-2-((2-fluoro-4-methyl-5-((l-(7-(((trifluoromethyl)sulfon yl)oxy)quinolin-5- yl)cyclopropyl) carbamoyl)phenoxy) methyl)azetidine-l -carboxylate (571 mg, 874 pmol, 97% yield) was obtained as a brown oil. M - 56 + H ⁺ = 598.2 (LCMS).

Step 7: tert-Butyl (5)-2-((2-fluoro-4-methyl-5-((l-(7-vinylquinolin-5-yl)cyclop ropyl)carba moyl)phenoxy)methyl)azetidine-l-carboxylate (400A-8)

To a solution of tert-butyl (5)-2-((2-fluoro-4-methyl-5-((l-(7-(((trifluoromethyl)sulfon yl) oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azeti dine-l -carboxylate (571 mg, 874 pmol, 184 pL 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (135 mg, 874 pmol, 1.0 eq) in a mixture of dioxane (30 mL) and H2O (6.0 mL) were added Pd(dppf)C12.CH2C12 (71.3 mg, 87.3 pmol, 0.1 eq) and ISfeCCh (213 mg, 2.01 mmol, 2.3 eq). The mixture was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. /c V-Butyl (5)-2-((2-fluoro-4-methyl-5-((l-(7- vinylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine- 1 -carboxylate (280 mg, 527 pmol, 60% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 476.4 (LCMS).

Step 8: ( )-5-(Azetidin-2-ylmethoxy)-4-fluoro-2-methyl-/V-(l-(7-vinylq uinolin-5-yl)cyclo propyl)benzamide (400A-9)

To a solution of /c/7-butyl (5)-2-((2-fluoro-4-methyl-5-((l-(7-vinylquinolin-5-yl)cyclop ropyl) carbamoyl)phenoxy) methyl)azetidine-l -carboxylate (280 mg, 527 pmol, 1.0 eq) in DCM (10 mL) was added TFA (4.93 g, 43.3 mmol, 3.2 mL, 82 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude (S)-5- (azetidin-2-ylmethoxy)-4-fluoro-2-methyl-7V-(l-(7-vinylquino lin-5-yl)cyclopropyl)benzamide (500 mg) as a yellow oil. M+ H ⁺ = 432.3 (LCMS).

Step 9: ( )-4-Fluoro-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l -(7-vinylquinolin- 5-yl)cyclopropyl)benzamide (Compound 800)

To a solution of (A)-5-(azetidin-2-ylmethoxy)-4-fluoro-2-methyl-A-(l-(7-vinyl quinolin-5- yl)cyclopropyl)benzamide (500 mg, 1.07 mmol, 1.0 eq, TFA salt) in MeOH (10 mL) was added TEA (0.1 pL), followed by formaldehyde (173 mg, 2.14 mmol, 159 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH, then NaBHiCN (134 mg, 2.14 mmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 60 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-4-Fluoro-2-methyl-5-((l- methylazeti din-2 -yl)methoxy)-7V-(l-(7-vinylquinolin-5-yl)cycloprop yl)benzamide (54.0 mg, 107 pmol, 10% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 446.4 (LCMS); 'H NMR (400 MHz, DMSO4) 8 10.78 (br d, J= 3.3 Hz, 1H), 9.56 - 9.42 (m, 1H), 9.39 - 9.28

(m, 1H), 9.11 (br d, J = 4.5 Hz, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 7.95 - 7.80 (m, 1H), 7.16 - 6.92 (m, 3H), 6.19 (d, J= 17.6 Hz, 1H), 5.61 (d, J= 11.0 Hz, 1H), 4.70 - 4.63 (m, 1H), 4.45 - 4.32 (m, 2H), 4.01 - 3.98 (m, 1H), 3.89 - 3.85 (m, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.42 - 2.23 (m, 2H), 1.99 (s, 3H), 1.43 (br s, 2H), 1.34 (br s, 2H). Example 401: (3)-4-Amino-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-( l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 726)

401A-4 401A-5

Compound 726

Step 1: tert-Butyl (5)-2-((5-bromo-4-methyl-2-nitrophenoxy)methyl)azetidine-l- carboxylate (401A-1)

To a solution of l-bromo-5-fluoro-2-methyl-4-nitrobenzene (500 mg, 2.14 mmol, 1.0 eq) in DMF (20 mL) were added CS2CO3 (766 mg, 2.35 mmol, 1.1 eq) and tert-butyl S)-2- (hydroxymethyl)azetidine-l -carboxylate (400 mg, 2.14 mmol, 1.0 eq). The resulting mixture was stirred at 60 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl fS')-2-((5-bromo-4-methyl-2- nitrophenoxy)methyl)azetidine-l -carboxylate (760 mg, 1.89 mmol, 89% yield) was obtained as a yellow solid. M - 56 + H ⁺ = 345.1 (LCMS).

Step 2: tert-Butyl (S)-2-((5-(methoxycarbonyl)-4-methyl-2-nitrophenoxy)methyl) azetidine-l-carboxylate (401A-2)

To a solution of tert-butyl CS')-2-((5-bromo-4-methyl-2-nitrophenoxy)methyl)azetidine- l - carboxylate (600 mg, 1.50 mmol, 1.0 eq) in MeOH (50 mL) were added Pd(PPh3)2C12 (105 mg, 150 pmol, 0.1 eq) and TEA (6.05 g, 59.8 mmol, 8.33 mL, 40 eq). The mixture was degassed and purged with CO three times, then stirred at 70 °C for 16 h under a CO (50 psi) atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl (5)-2-((5-(methoxycarbonyl)-4-methyl-2- nitrophenoxy)methyl)azetidine-l -carboxylate (164 mg, 431 pmol, 14% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 325.2 (LCMS).

Step 3: (5)-5-((l-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth yl-4-nitrobenzoic acid (345A-3)

To a solution of tert-butyl fS')-2-((5-(methoxycarbonyl)-4-methyl-2-nitrophenoxy)methyl) azetidine- 1 -carboxylate (164 mg, 431 pmol, 1.0 eq) in MeOH (11 mL) and THF (5.5 mL) was added NaOH (2 M aqueous, 1.0 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL), and washed with MTBE (5.0 mL x 2). The aqueous layer was acidified to pH 6 with HC1 (1 M aqueous). The product was extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the product (S)-5-((l-(tert- butoxycarbonyl)azetidin-2-yl)methoxy)-2-methyl-4-nitrobenzoi c acid (110 mg, 300 pmol, 70% yield) as a brown oil. M - 56 + H ⁺ = 311.2 (LCMS).

Step 4: tert-Butyl (5)-2-((4-methyl-2-nitro-5-((l-(7-(((trifluoromethyl)sulfony l)oxy) quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine -l-carboxylate (401A-3)

To a solution of (5)-5-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth yl-4- nitrobenzoic acid (90.0 mg, 246 pmol, 1.0 eq) and 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (73.5 mg, 221 pmol, 0.9 eq) in DMF (6.0 mL) were added EDCI (70.6 mg, 369 pmol, 1.5 eq), HOBt (49.8 mg, 369 pmol, 1.5 eq) and TEA (49.7 mg, 491 pmol, 68.4 pL, 2.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.46). The crude product tert-butyl fS')-2-((4-methyl- 2-nitro-5-((l-(7-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)cyclopsropyl)carbamoyl) phenoxy)methyl)azetidine-l -carboxylate (180 mg) was obtained as a yellow oil. M - 56 + H ⁺ = 625.3 (LCMS).

Step 5: tert-Butyl (5)-2-((4-methyl-2-nitro-5-((l-(7-vinylquinolin-5-yl)cyclopr opyl) carbamoyl)phenoxy)methyl)azetidine-l-carboxylate (401A-4)

To a solution of tert-butyl (5)-2-((4-methyl-2-nitro-5-((l-(7-(((trifluoromethyl)sulfony l)oxy) quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine -l -carboxylate (170 mg, 250 pmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (38.5 mg, 250 pmol, 42.4 pL, 1.0 eq) in a mixture of dioxane (8.5 mL) and H2O (1.7 mL) were added Pd(dppf)C12.CH2C12 (20.4 mg, 25.0 pmol, 0.1 eq) and ISfeCCh (60.9 mg, 574 pmol, 2.3 eq). The resulting mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/0, Rf = 0.23). Zc/V-Butyl fS')-2-((4- methyl-2-nitro-5-((l-(7-vinylquinolin-5-yl)cyclopropyl)carba moyl)phenoxy)methyl)azetidine -1 -carboxylate (115 mg, 206 pmol, 82% yield) was obtained as a yellow solid. M + H ⁺ = 559.4 (LCMS).

Step 6: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-4-nitro-/V-(l-(7-vinylqu inolin-5- yl)cyclopropyl)benzamide (401A-5)

To a solution of /c/7-butyl (5)-2-((4-methyl-2-nitro-5-((l-(7-vinylquinolin-5-yl)cyclopr opyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (115 mg, 206 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.93 g, 16.9 mmol, 1.3 mL, 82 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give the crude (5)-5-(azetidin-2-ylmethoxy)-2-methyl-4- nitro-A-(l-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (240 mg, TFA salt) as a yellow solid. M + H ⁺ = 459.3 (LCMS).

Step 7 : ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-4-nitro-/V-(l- (7-vinylquinolin- 5-yl)cyclopropyl)benzamide (401A-6)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-2-methyl-4-nitro-A-(l-(7-vinylq uinolin-5- yl)cyclopropyl)benzamide (240 mg, 419 pmol, 1.0 eq, TFA salt) in MeOH (12 mL) was added TEA (2.4 mL), followed by formaldehyde (68.0 mg, 838 pmol, 62.4 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. Then NaBHiCN (52.7 mg, 838 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.21). (S)-2-Methyl-5-((l- methylazetidin-2-yl)methoxy)-4-nitro-A-(l-(7-vinylquinolin-5 -yl)cyclopropyl) benzamide (50.0 mg, 106 pmol, 25% yield) was obtained as a yellow oil. M + H ⁺ = 473.3 (LCMS).

Step 8: ( )-4-Amino-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l- (7-vinylquinolin- 5-yl)cyclopropyl)benzamide (Compound 726)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-4-nitro-7V-( l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (50.0 mg, 106 mol, 1.0 eq) inMeOH (2.5 mL) and H2O (0.5 mL) were added NH4CI (28.3 mg, 529 pmol, 5.0 eq) and iron powder (29.6 mg, 529 prnol, 5.0 eq). The mixture was stirred at 80 °C for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (7.0 mL), and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna C18 (100 x 30 mm, 5 pm); flow rate: 60 mL/min; gradient: 1% - 23% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-4-Amino-2-methyl-5-((l-methylazetidin-2- yl)methoxy)-7V-(l-(7-vinylquinolin-5-yl)cyclopropyl)benzamid e (12.6 mg, 22.5 pmol, 21% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 443.3 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.16 (br d, J= 8.7 Hz, 1H), 9.00 - 8.88 (m, 1H), 8.74 (s, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.62 (dd, J= 4.4, 8.4 Hz, 1H), 7.00 (dd, J = 10.9, 17.7 Hz, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 6.09 (d, J= 17.2 Hz, 1H), 5.50 (d, J= 10.9 Hz, 1H), 4.70 - 4.54 (m, 1H), 4.15 (br d, J = 3.1 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.92 - 3.82 (m, 2H), 2.87 (s, 3H), 2.39 - 2.30 (m, 2H), 2.00 (s, 3H), 1.35 (br s, 2H), 1.30 - 1.22 (m, 2H).

Example 402: ( )-4-Acetamido-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V -(l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 746)

Compound 726 Compound 746

Step 1: (5)-4-Acetamido-2-methyl-5-((l-methylazetidin-2-yl)methoxy)- /V-(l-(7 -vinylquin olin-5-yl)cyclopropyl)benzamide (Compound 746)

To a solution of (8)-4-amino-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-( l-(7-vinyl quinolin-5-yl)cyclopropyl)benzamide (70.0 mg, 158 pmol, 1.0 eq) in DCM (5.0 mL) were added TEA (64.0 mg, 633 pmol, 88.1 pL, 4.0 eq) and AC2O (32.3 mg, 316 pmol, 29.6 pL, 2.0 eq). The mixture was stirred at 20 °C for 3 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (8 -4-Acetamido-2- methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(7-vinylquino lin-5-yl)cyclopropyl) benzamide (8.60 mg, 16.5 pmol, 10% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 485.4 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 10.73 - 10.51 (m, 1H), 9.44 (s, 1H), 9.38 - 9.28 (m, 1H), 9.23 - 9.03 (m, 2H), 8.15 (s, 1H), 8.02 (s, 1H), 7.78 (br dd, J= 3.8, 8.0 Hz, 1H), 7.62 (s, 1H), 7.04 (dd, J= 10.8, 17.6 Hz, 1H), 6.82 (s, 1H), 6.16 (d, J= 17.7 Hz, 1H), 5.57 (d, J= 10.8 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.27 (d, J= 4.4 Hz, 1H), 4.06 - 4.00 (m, 1H), 3.85 (br dd, J= 6.7, 9.1 Hz, 2H), 2.83 (d, J= 5.1 Hz, 3H), 2.42 - 2.33 (m, 2H), 2.15 - 2.06 (m, 3H), 1.99 - 1.95 (m, 3H), 1.44 - 1.37 (m, 2H), 1.31 (br s, 2H).

Example 403: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-vinyl -l,2,3,4- tetrahydroquinolin-5-yl)cyclopropyl)benzamide (Compound 785)

Step 4

403A-3 Compound 785 Step 1: (S)-V-( l-(7-Methoxy- 1.2.3.4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (403 A-l)

To a solution of (5)-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l-methyl azetidin-2-yl)methoxy)benzamide (250 mg, 579 pmol, 1.0 eq) in THF (35 mL) was added 10% palladium on carbon (750 mg) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 16 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The suspension was filtered through a pad of Celite and the filter cake was washed with THF (10 mL x 5). The combined filtrates were concentrated under vacuum to give (5)-7V-(l-(7-methoxy-l,2,3,4-tetrahydroquinolin-5-yl)cyclopr opyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy) benzamide (500 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 436.1 (LCMS).

Step 2: (5)-/V-(l-(7-Hydroxy-l,2,3,4-tetrahydroquinolin-5-yl)cyclopr opyl)-2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (403 A-2)

To a solution of (5)-7V-(l-(7-Methoxy-l,2,3,4-tetrahydroquinolin-5-yl)cyclopr opyl)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (500 mg) in DCM (20 mL) was added BBr, (1.5 mL, 15 eq) dropwise at -78 °C under a N2 atmosphere. The mixture was stirred at 25 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue. The residue was diluted with MeOH (5.0 mL) and adjusted to pH 8 with DIEA. The resulting mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 1/0 to 10/1. (5)-7V-(l-(7-Hydroxy-

1.2.3.4-tetrahydroquinolin-5-yl)cyclopropyl)-2-methyl-5-( (l-methylazetidin-2-yl)methoxy) benzamide (270 mg, 640 pmol, 70% yield) was obtained as a yellow oil. M + H ⁺ = 422.4 (LCMS).

Step 3: (5)-5-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do)cyclopropyl)-

1.2.3.4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (403 A-3)

To a solution of (5)-7V-(l-(7-hydroxy-l,2,3,4-tetrahydroquinolin-5-yl)cyclopr opyl)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (200 mg, 474 pmol, 1.0 eq) in THF (7.0 mL) was added LBuOK (53.0 mg, 474 pmol, 1 eq) at 0 °C. The mixture was stirred at this temperature for 30 min. To this mixture was added 1,1,1-trifhioro-A-phenyl-TV- ((trifluoromethyl)sulfonyl) methanesulfonamide (170 mg, 474 pmol, 1.0 eq). Then the mixture was stirred at 25 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/= 0.7). (5)-5-(l-(2-Methyl-5-((l-methylazetidin-2- yl)methoxy)benzamido)cyclopropyl)-l,2,3,4-tetrahydroquinolin -7-yl trifluoromethanesulfonate (100 mg, 181 pmol, 38% yield) was obtained as a white solid. M + H ⁺ = 554.2 (LCMS).

Step 4: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-vin yl-l,2,3,4-tetra hydroquinolin-5-yl)cyclopropyl)benzamide (Compound 785)

To a solution of (5)-5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do) cyclopropyl)-l,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (40.0 mg, 72.3 pmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (11.1 mg, 72.3 pmol, 12.3 pL, 1.0 eq) in a mixture of dioxane (1.0 mL) and H2O (0.1 mL) were added NazCOs (23.0 mg, 217 pmol, 3.0 eq) and Pd(dppf)C12.CH2C12 (5.90 mg, 7.23 pmol, 0.1 eq) under a N2 atmosphere. The resulting mixture was stirred at 80 °C for 5 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (2.0 mL), and extracted with EtOAc (2.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylazeti din-2 -yl)methoxy)-A-(l -(7 -vinyl- 1,2,3, 4-tetrahydroquinolin- 5-yl)cyclopropyl) benzamide (6.50 mg, 11.9 pmol, 17% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 432.4 (LCMS); flT NMR (400 MHz, DMSO-tL) 8 9.88 (br dd, J= 3.8, 6.7 Hz, 1H), 8.71 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.99 - 6.91 (m, 2H), 6.78 (d, J= 2.8 Hz, 1H), 6.61 - 6.49 (m, 2H), 5.60 (br d, J= 17.4 Hz, 1H), 5.13 (br d, J= 10.9 Hz, 1H), 4.69 - 4.58 (m, 1H), 4.28 - 4.22 (m, 2H), 4.04 (br dd, J= 4.4, 9.4 Hz, 1H), 3.89 - 3.85 (m, 1H), 3.19 (br d, J= 4.1 Hz, 2H), 2.93 (br t, J= 6.1 Hz, 2H), 2.87 (d, J = 4.9 Hz, 3H), 2.42 - 2.31 (m, 3H), 2.12 (s, 3H), 1.86 - 1.80 (m, 2H), 1.14 - 1.09 (m, 2H), 1.04 (br d, J= 2.6 Hz, 2H). Example 404: ( )-2-Methyl-/V-(l-(l-methyl-7-vinyl-l,2,3,4-tetrahydroquinoli n-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 796)

Compound 785 Compound 796

Step 1: (5)-2-Methyl-/V-(l-(l-methyl-7-vinyl-l,2,3,4-tetrahydroquino lin-5-yl)cyclo propyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 796)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(7-vin yl-l, 2,3,4- tetrahydroquinolin-5-yl)cyclopropyl)benzamide (20.0 mg, 46.3 pmol, 1.0 eq) in MeOH (2.0 mL) was added TEA (50.0 pL), followed by formaldehyde (3.76 mg, 46.3 pmol, 3.5 pL, 37% purity in water, 1.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (2.91 mg, 46.4 pmol, 1.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (2.0 mL) and extracted with DCM (1.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 20% - 50% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-2-Methyl-A-(l-(l-methyl-7-vinyl- 1,2, 3, 4-tetrahydroquinolin-5-yl)cyclopropyl)-5-((l -methyl azetidin-2-yl)methoxy)benzamide (3.00 mg, 5.36 pmol, 12% yield, TFA salt). M + H ⁺ = 446.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 6 10.05 - 9.84 (m, 1H), 8.72 (s, 1H), 7.16 - 7.10 (m, 1H), 7.01 (s, 1H), 6.97 - 6.90 (m, 1H), 6.79 - 6.74 (m, 1H), 6.67 - 6.55 (m, 2H), 5.70 (d, J= 17.6 Hz, 1H), 5.14 (d, J= 11.0 Hz, 1H), 4.70 - 4.57 (m, 1H), 4.33 - 4.22 (m, 2H), 4.09 - 4.00 (m, 1H), 3.94 - 3.83 (m, 1H), 3.18 (t, J= 5.7 Hz, 2H), 2.95 (br t, J= 6.4 Hz, 2H), 2.89 - 2.81 (m, 6H), 2.41 - 2.30 (m, 2H), 2.12 (s, 3H), 1.89 (quin, J= 5.9 Hz, 2H), 1.12 (br s, 2H), 1.03 (br s, 2H). Example 405: (3)-2-Methyl-5-(2-(methylamino)propoxy)-/V-(l-(7-(prop-l-en- 2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 660)

Compound 660

Step 1: (S)-M ethyl 5-(2-((tert-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (405A- 1) To a solution of methyl 5 -hydroxy-2-m ethylbenzoate (5.00 g, 30.1 mmol, 1.0 eq) and tert-butyl

(5)-(l-hydroxypropan-2-yl)carbamate (5.27 g, 30.1 mmol, 1.0 eq) in toluene (200 mL) were added TMAD (15.5 g, 90.3 mmol, 3.0 eq) and PPhi (23.7 g, 90.3 mmol, 3.0 eq). The mixture was stirred at 100 °C for 12 h under a N2 atmosphere. LCMS indicated that the 31% of the starting material remained and 23% of the desired product was detected. The mixture was allowed to cool to room temperature, then concentrated under vacuum to give a residue which was treated with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/19. (5)-Methyl 5-(2-((/c/7-butoxycarbonyl)amino)propoxy)-2-methylbenzoate (6.00 g, 18.5 mmol, 30% yield) was obtained as a white solid. M - 100 + H ⁺ = 224.1 (LCMS).

Step 2: (S)-M ethyl 5-(2-((terCbutoxycarbonyl)(methyl)amino)propoxy)-2- methylbenzoate (405A-2)

To a solution of methyl (S)-5-(2-((te/7-butoxycarbonyl)amino)propoxy)-2-methylbenzoa te (3.00 g, 9.28 mmol, 1.0 eq) in THF (100 mL) were added NaH (556 mg, 13.9 mmol, 60% purity, 1.5 eq) and Mel (3.95 g, 27.8 mmol, 3.0 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the 27% of the starting material remained and 24% of the desired product was detected. The mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/4. (S)-Methyl 5-(2-((/c77- butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoate (3.00 g, 8.90 mmol, 95% yield) was obtained as a white solid. M - 56 + H ⁺ = 282.2 (LCMS).

Step 3: (5)-5-(2-((tert-Butoxycarbonyl)(methyl)amino)propoxy)-2-meth ylbenzoic acid (405A-3)

To a solution of methyl CS')-5-(2-((/c77-butoxycarbonyl)(methyl)amino)propoxy)-2- methylbenzoate (3.00 g, 8.89 mmol, 1.0 eq) in THF (10 mL), H2O (5.0 mL) and MeOH (7.5 mL) was added LiOH.H2O (621 mg, 14.8 mmol, 3.0 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed. THF and MeOH were concentrated under vacuum. The aqueous layer was adjusted to pH 5 with HC1 (1 M aqueous), then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give CS')-5-(2-((/c77- butoxycarbonyl)(methyl)amino)propoxy)-2-methylbenzoic acid (1.67 g, 5.01 mmol, 99% yield) as a white solid. M - 56 + H ⁺ = 268.2 (LCMS). Step 4: (5)-5-(l-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)propoxy)- 2- methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (405A-4)

To a solution of 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 902 pmol, 1.0 eq) and (5)-5-(2-((tert-butoxycarbonyl)(methyl)amino)propoxy)-2-meth ylbenzoic acid (291 mg, 902 pmol, 1.0 eq) in DMF (4.0 mL) were added HATU (514 mg, 1.35 mmol, 1.5 eq) and DIEA (350 mg, 2.71 mmol, 3.0 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. (5)-5-(l-(5-(2-((terLButoxycarbonyl)(methyl)amino)propoxy)-2 - methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 409 pmol, 45% yield) was obtained as a white solid. M + H ⁺ = 638.3 (LCMS).

Step 5: (5)-Methyl(l-(4-methyl-3-((l-(7-(prop-l-en-2-yl)quinolin-5-y l)cyclopropyl) carbamoyl)phenoxy)propan-2-yl)carbamate (405A-5)

To a solution of CS')-5-( l -(5-(2-((/c/7-butoxycarbonyl)(rnethyl)amino)propoxy)-2- methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (130 mg, 203 pmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (49.7 mg, 468 pmol, 2.9 eq) in a mixture of dioxane (1.0 mL) and H2O (100 pL) were added ISfeCCL (8.00 mg, 76.2 pmol, 2.3 eq) and Pd(dppf)C12.CH2C12 (16.6 mg, 20.3 pmol, 0.1 eq). The resulting mixture was stirred at 80 °C for 4 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature, then treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give (5)-methyl(l-(4-methyl-3-((l-(7-(prop-l-en-2-yl)quinolin-5-y l)cyclopropyl)carbamoyl) phenoxy )propan-2-yl)carbamate (130 mg, crude) as a yellow oil. M + H ⁺ = 530.4 (LCMS).

Step 6: (5)-2-Methyl-5-(2-(methylamino)propoxy)-/V-(l-(7-(prop-l-en- 2-yl)quinolin-5- yl)cyclopropyl)benzamide (Compound 660)

To a solution of (5)-methyl(l-(4-methyl-3-((l-(7-(prop-l-en-2-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)propan-2-yl)carbamate (130 mg, 472 pmol, 1.0 eq) in EtOAc (500 pL) was added HCl/EtOAc (4 M, 1.5 mL). The resulting mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini Cl 8 column (80 * 30 mm, 3 m); flow rate: 60 mL/min; gradient: 5% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-(2-(methylamino)propoxy)-A-(l-(7-(prop-l-en-2 -yl)quinolin-5-yl) cyclopropyl)benzamide (25.5 mg, 54.5 pmol, 22% yield) was obtained as a white solid. M + H ⁺ = 430.3 (LCMS); flT NMR (400 MHz, DMSO ) 8 9.68 - 9.40 (m, 1H), 9.29 (s, 1H), 9.17 (br s, 1H), 9.14 - 8.75 (m, 2H), 8.26 (s, 1H), 8.18 (br s, 1H), 7.95 (br d, J= 4.3 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 5.83 (s, 1H), 5.48 (s, 1H), 4.13 (dd, J = 4.0, 10.5 Hz, 1H), 4.06 - 4.01 (m, 1H), 3.44 (br s, 1H), 2.57 - 2.53 (m, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.46 - 1.38 (m, 2H), 1.38 - 1.31 (m, 2H), 1.27 (d, J= 6.7 Hz, 3H).

Example 406: (5)-/V-(l-(7-Acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((l - methylazetidin-2-yl)methoxy)benzamide (Compound 638)

406A-1 Compound 638

Step 1 : (5)-/V-(l-(7-(l-Ethoxyvinyl)quinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (406A-1)

To a solution of (8)-5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (300 mg, 546 pmol, 1.0 eq) in DMF (6.0 mL) were added tributyl (1 -ethoxy vinyl)stannane (394 mg, 1.09 mmol, 369 pL, 2.0 eq) and Pd(PPh3)2Ch (38.3 mg, 54.6 pmol, 0.1 eq). The mixture was stirred at 60 °C for 15 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give (S)-A-(l-(7-(l- ethoxyvinyl) quinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-y l)methoxy) benzamide (300 mg) as a brown oil, which was used in the next step without further purification. M + H ⁺ = 472.3 (LCMS).

Step 2: (5)-/V-(l-(7-Acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin-2- yl)methoxy)benzamide (Compound 638)

A mixture of (5)-7V-(l-(7-(l-ethoxyvinyl)quinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (300 mg, 636 mol, 1.0 eq) and HCl/EtOAc (4 M, 4.0 mL, 25 eq) was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-7V-(l-(7-Acetylquinolin-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (52.4 mg, 105 pmol, 17% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 444.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 5 9.31 - 9.21 (m, 2H), 9.11 (dd, J= 1.4, 4.3 Hz, 1H), 8.62 (d, J= 0.7 Hz, 1H), 8.35 (d, J= 1.4 Hz, 1H), 7.83 (dd, J= 4.3, 8.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.95 - 6.87 (m, 1H), 6.75 - 6.68 (m, 1H), 4.66 - 4.54 (m, 1H), 4.30 - 4.18 (m, 2H), 4.01 (dt, J= 5.1, 9.6 Hz, 1H), 3.85 (q, J= 9.4 Hz, 1H), 2.82 (s, 3H), 2.76 (s, 3H), 2.39 - 2.28 (m, 2H), 1.93 (s, 3H), 1.42 (br s, 2H), 1.30 - 1.23 (m, 2H).

Example 407: N-( l-(7-( l-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((»S) -l- methylazetidin-2-yl)methoxy)benzamide (Compound 676)

Compound 638 Compound 676

Step 1 : -( 1 -( 7-( 1 - Hydroxyet hyl )quinolin-5-yl )cyclopropyl )-2-met hyl-5-(((.S)- 1 - methylazetidin-2-yl)methoxy)benzamide (Compound 676)

To a solution of (5)-7V-(l-(7-acetylquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methylazetidin- 2-yl)methoxy)benzamide (110 mg, 248 pmol, 1.0 eq) in EtOH (10 mL) was added NaBH4 (18.8 mg, 496 pmol, 2.0 eq) at 0 °C. Then the mixture was stirred at 20 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into with NH4CI aqueous (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(7-(l- Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl-5-(((5)-l-m ethylazetidin-2-yl)methoxy) benzamide (27.0 mg, 55.5 pmol, 22% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 446.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 10.13 - 9.93 (m, 1H), 9.34 - 9.18 (m, 1H), 8.45 - 8.32 (m, 1H), 8.29 - 8.22 (m, 1H), 8.21 - 8.14 (m, 1H), 7.19 - 7.09 (m, 1H), 7.04 - 6.95 (m, 1H), 6.92 - 6.82 (m, 1H), 5.18 (q, J= 6.5 Hz, 1H), 4.77 - 4.68 (m, 1H), 4.38 - 4.15 (m, 3H), 3.98 (q, J= 9.5 Hz, 1H), 2.96 (s, 3H), 2.62 - 2.51 (m, 2H), 2.03 (s, 3H), 1.67 - 1.55 (m,

5H), 1.48 - 1.43 (m, 2H).

Example 408: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-ethynylquinolin-5-yl)cyc lopropyl)-2- methylbenzamide (Compound 697)

Compound 697

Step 1: l-(7-((Trimethylsilyl)ethynyl)quinolin-5-yl)cyclopropan-l-am ine (408A-1)

To a solution of 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 602 pmol, 1.0 eq) in acetonitrile (10 mL) were added TEA (82.7 mg, 1.81 mmol, 251 pL, 3.0 eq), ethynyltrimethyl silane (118 mg, 1.20 mmol, 167 pL, 2.0 eq), Cui (11.5 mg, 60.2 pmol, 0.1 eq) and Pd(PPh3)4 (69.6 mg, 60.2 pmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. l-(7- ((Trimethylsilyl)ethynyl)quinolin-5-yl)cyclopropan-l -amine (115 mg, 410 pmol, 68% yield) was obtained as a white solid.

Step 2: l-(7-Ethynylquinolin-5-yl)cyclopropan-l-amine (408A-2)

To a solution of l-(7-((trimethylsilyl)ethynyl)quinolin-5-yl)cyclopropan-l -amine (100 mg, 357 pmol, 1.0 eq) in MeOH (2.0 mL) was added CS2CO3 (232 mg, 713 pmol, 2.0 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (1.0 mL) and extracted with DCM (1.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude l-(7-ethynylquinolin-5- yl)cyclopropan-l -amine (100 mg) as a white solid.

Step 3: tert-Butyl (5)-2-((3-((l-(7-ethynylquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxy)methyl)azetidine-l-carboxylate (408A-3)

To a solution of l-(7-ethynylquinolin-5-yl)cyclopropan-l -amine (100 mg, 480 pmol, 1.0 eq) and (5)-5-((l-(terLbutoxycarbonyl)azetidin-2-yl)methoxy)-2-methy lbenzoic acid (154 mg, 480 pmol, 1.0 eq) in DMF (2.0 mL) were added DIEA (186 mg, 1.44 mmol, 251 pL, 3.0 eq) and HATU (456 mg, 1.20 mmol, 2.5 eq). The resulting mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (10 mL) and extracted with EtOAc (2.0 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/= 0.4). Zc/V-Butyl (5)-2-((3-((l-(7-ethynylquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxy)methyl)azetidine-l -carboxylate (90.0 mg, 176 pmol, 37% yield) was obtained as a white solid.

Step 4: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-ethynylquinolin-5-yl)c yclopropyl)-2- methylbenzamide (Compound 697)

To a solution of /c/7-butyl (S)-2-((3-((l-(7-ethynylquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxy )methyl)azetidine-l -carboxylate (90.0 mg, 176 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (361 mg, 3.17 mmol, 234 pL, 18 eq). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 °C to give a residue which was purified by preparative HPLC (Phenomenex C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-5-(Azetidin-2-ylmethoxy)-A-(l-(7-ethynylquinolin-5-yl)cy clopropyl)-2- methylbenzamide (21.8 mg, 41.5 pmol, 24% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 412.1 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.16 (s, 1H), 9.07 (d, J= 8.8 Hz, 1H), 8.97 (dd, J= 1.5, 4.1 Hz, 1H), 8.89 - 8.70 (m, 2H), 8.06 (s, 1H), 7.87 (d, J= 1.6 Hz, 1H), 7.65 (dd, J = 4.2, 8.6 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.72 - 4.57 (m, 1H), 4.46 (s, 1H), 4.29 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 4.02 - 3.88 (m, 1H), 3.87 - 3.79 (m, 1H), 2.47 - 2.41 (m, 1H), 2.38 - 2.29 (m, 1H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.30 - 1.21 (m, 2H).

Example 409: ( )-/V-(l-(7-Ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 620)

Step 1: (5)-/V-(l-(7-Ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 620)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (192 mg, 816 pmol, 1.0 eq) and l-(7-ethynyl-5-quinolyl)cyclopropanamine (170 mg, 816 pmol, 1.0 eq) in DMF (3.0 mL) were added DIEA ( 316 mg, 2.45 mmol, 427 pL, 3.0 eq) and HATU (776 mg, 2.04 mmol, 2.5 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was filtered. The filtrate obtained was purified by preparative HPLC (Xbridge BEH C18 (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 30% - 50% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). The residue obtained was diluted with a mixture of acetonitrile (1.0 mL), H2O (4.0 mL), and HC1 (1 M aqueous, 133 pL). The resulting mixture was lyophilized to give (5)-7V-(l-(7-ethynylquinolin-5-yl)cyclopropyl)-2- methyl-5-((l-methylaze tidin-2-yl)methoxy)benzamide (51.4 mg, 103 pmol, 13% yield, HC1 salt) as a white solid. M + H ⁺ = 426.1 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 10.78 - 10.35 (m, 1H), 9.21 (s, 1H), 9.07 (d, J = 8.5 Hz, 1H), 8.96 (dd, J = 1.3, 4.1 Hz, 1H), 8.05 (s, 1H), 7.86 (d, J= 1.5 Hz, 1H), 7.63 (dd, J= 4.2, 8.6 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (br d, J = 7.1 Hz, 1H), 6.72 (br s, 1H), 4.60 (br d, J= 7.4 Hz, 1H), 4.46 (s, 1H), 4.37 - 4.28 (m, 1H), 4.26 - 4.17 (m, 1H), 4.04 - 3.95 (m, 1H), 3.92 - 3.79 (m, 1H), 2.81 (br s, 3H), 2.40 - 2.26 (m, 2H), 1.94 (s, 3H), 1.37 (br s, 2H), 1.25 (br s, 2H).

Example 410: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(5,6,7,8-tetrahydronap hthalen-l- yl)ethyl)benzamide (Compound 696)

410A-1 Compound 696

Step 1: te/7- Butyl (5)-2-((4-methyl-3-((l-(7-(prop-l-yn-l-yl)quinolin-5-yl)cycl opropyl) carbamoyl)phenoxy)methyl)azetidine-l-carboxylate (410A-1)

To a mixture of tert-butyl (8)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (100 mg, 157 pmol, 1.0 eq) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-U/- pyrazole (68.7 mg, 330 pmol, 2.1 eq) in a mixture of H2O (1.0 mL) and dioxane (6.0 mL) were added TEA (6.37 mg, 62.9 pmol, 7.0 pL, 0.3 eq), KF (27.4 mg, 472 pmol, 3.0 eq), Pd(dppf)C12.CH ₂ C12 (38.5 mg, 47.2 pmol, 0.3 eq) and Cui (4.49 mg, 23.6 pmol, 0.15 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H ₂ O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/2. tert- Butyl (5)-2-((3-((l-(7-((tert-butoxycarbonyl)amino)quinolin-5-yl)c yclopro pyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (80.0 mg, 152 pmol, 48% yield) was obtained as a yellow solid. M + H ⁺ = 526.3 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 9.13 (s, 1H), 9.02 (d, J= 8.0 Hz, 1H), 8.91 (dd, J= 1.6, 4.2 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J= 1.6 Hz, 1H), 7.58 (dd, J= 4.2, 8.6 Hz, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6.88 (dd, J= 2.8, 8.4 Hz, 1H), 6.66 (d, = 2.6 Hz, 1H), 4.42 - 4.34 (m, 1H), 4.14 (dd, J= 4.8, 10.3 Hz, 1H), 4.00 - 3.96 (m, 1H), 3.77 - 3.69 (m, 2H), 2.33 - 2.25 (m, 1H), 2.13 (s, 3H), 2.10 - 2.03 (m, 1H), 1.93 (s, 3H), 1.39 - 1.25 (m, 13H).

Step 2: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(prop-l-yn-l- yl)quinolin-5-yl) cyclopropyl)benzamide (Compound 696)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(l-methyl-U/-pyrazol-3-yl)quinolin -5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (80.0 mg, 152 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (800 pL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-A-(l-(7-(prop-l-yn-l- yl)quinolin-5-yl)cyclopropyl)benzamide (19.9 mg, 46.7 pmol, 31% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 426.1 (LCMS); 'H NMR (400 MHz, DMSO ) 5 9.15 (s, 1H), 9.05 (d, J= 8.4 Hz, 1H), 8.94 (dd, J= 1.5, 4.1 Hz, 1H), 8.90 - 8.74 (m, 2H), 7.93 (s, 1H), 7.82 (d, J= 1.6 Hz, 1H), 7.61 (dd, J= 4.2, 8.6 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.26 - 4.20 (m, 1H), 4.16 - 4.11 (m, 1H), 3.93 (br s, 2H), 2.46 - 2.30 (m, 2H), 2.14 (s, 3H), 1.95 (s, 3H), 1.35 (br s, 2H), 1.23 (br s, 2H). Example 411: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(3,3, 3- trifluoroprop-l-yn-l-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 803)

Compound 803

Step 1 : A-(l-(7-(l-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl- 5-(((5)-l- methylazetidin-2-yl)methoxy)benzamide (Compound 803)

To a solution of Cui (3.58 mg, 18.8 pmol, 0.2 eq), 1,10-phenanthroline (6.78 mg, 37.6 pmol, 0.4 eq), K2CO3 (26.0 mg, 188 pmol, 2.0 eq) and 3, 3 -dimethyl- 1 -(trifluoromethyl)- 1,3 -dihydro- 113 -benzof d\ [l,2]iodaox ole (31.0 mg, 94.0 pmol, 1.0 eq) in DCM (3.0 mL) was added dropwise a solution of (5)-A-(l-(7-ethynylquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methyl azetidin-2-yl)methoxy)benzamide (40.0 mg, 94.0 pmol, 1.0 eq) in DCM (1.0 mL).The mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(7-(l-Hydroxyethyl)quinolin-5-yl)cyclopropyl)-2-methyl- 5-(((5)-l- methylazetidin-2-yl)methoxy) benzamide (18.1 mg, 33.8 pmol, 36% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 494.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.76 - 10.43 (m, 1H), 9.27 (s, 1H), 9.15 (d, J = 8.8 Hz, 1H), 9.06 (d, J = 4.1 Hz, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.76 (dd, J = 4.2, 8.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.97 - 6.89 (m, 1H), 6.78 - 6.71 (m, 1H), 4.68 - 4.56 (m, 1H), 4.33 (dd, J= 7.8, 11.3 Hz, 1H), 4.25 - 4.17 (m, 1H), 4.06 - 3.94 (m, 1H), 3.90 - 3.79 (m, 1H), 2.81 (d, J= 5.0 Hz, 3H), 2.40 - 2.28 (m, 2H), 1.93 (s, 3H), 1.43 - 1.35 (m, 2H), 1.30 (br s, 2H).

Example 412: 1 -(7-cyanoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l -methyl azetidin-2-yl)methoxy)benzamide (Compound 738)

Compound 738

Step 1: tert- Butyl (S)-2-((3-((l-(7-cyanoquinolin-5-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)methyl)azetidine-l-carboxylate (412A-1)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (200 mg, 315 pmol, 1.0 eq) in DMF (10 mL) were added Zn(CN)2 (111 mg, 944 pmol, 3.0 eq), BrettPhosPdGs (28.5 mg, 31.5 pmol, 0.1) and BrettPhos (33.8 mg, 62.9 pmol, 0.2 eq). The mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. tert- Butyl (S)-2-((3-((l-(7-cyanoquinolin-5-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)methyl)azetidine-l -carboxylate (80.0 mg, 156 pmol, 49% yield) was obtained as a white solid. M + H ⁺ = 513.2 (LCMS). Step 2: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-cyanoquinolin-5-yl)cyc lopropyl)-2- methylbenzamide (412A-2)

To a solution of tert-butyl (5)-2-((3-((l-(7-cyanoquinolin-5-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)methyl)azetidine-l -carboxylate (40.0 mg, 78.0 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude (8 -5-(azetidin-2-ylmethoxy)-7V-(l- (7-cyanoquinolin-5-yl)cyclopropyl)-2-methylbenzamide (30.0 mg, TFA salt) as a white solid. M + H ⁺ = 413.2 (LCMS).

Step 3: ( S)- \-( l-(7-Cyanoqiiinolin-5-yl)cyclopropyl)-2-metliyl-5-((l-methyl azetidin-2- yl)methoxy)benzamide (Compound 738)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-7V-(l-(7-cyanoquinolin-5-yl)cyc lopropyl)-2- methylbenzamide (30.0 mg, 56.9 pmol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (5.77 mg, 56.9 pmol, 7.93 pL, 1.0 eq), followed by formaldehyde (3.42 mg, 113.9 pmol, 3.14 pL, 2.0 eq, 37% aqueous). The resulting mixture was adjusted to pH 6 with a small amount of AcOH (3.42 mg, 56.9 pmol, 3.26 pL, 1 eq). The mixture was stirred at 25 °C for 30 min, then NaBHiCN (17.9 mg, 284.90 pmol, 5.0 eq) was added. The reaction mixture was stirred at 25 °C for another 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 30% B over 8 min; mobile phase A: 0.1% aqueous HC1, mobile phase B: acetonitrile). (S)-N- (l-(7-Cyanoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methyla zetidin-2- yl)methoxy)benzamide (18.5 mg, 39.9 pmol, 70% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 427.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.81 - 10.53 (m, 1H), 9.30 (s, 1H), 9.18 (d, J= 8.5 Hz, 1H), 9.09 (dd, J= 1.4, 4.1 Hz, 1H), 8.54 (s, 1H), 8.09 (d, J= 1.6 Hz, 1H), 7.81 (dd, J= 4.1, 8.6 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 6.98 - 6.88 (m, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.61 (br s, 1H), 4.42 - 4.14 (m, 2H), 4.04 - 3.79 (m, 2H), 2.85 - 2.64 (m, 3H), 2.41 - 2.24 (m, 2H), 1.93 (s, 3H), 1.43 - 1.28 (m, 4H). Example 413: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-ethylquinolin-5-yl) cyclopropyl)-2- methylbenzamide (Compound 677)

413A-1 Compound 677

Step 1: te/7-Butyl(.S)-2-((3-(( 1 -(7-ethylquinolin-5-yl)cyclopropyl)carbanioyl)-4- methylphenoxy)methyl)azetidine-l-carboxylate (413A-1)

A solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (50.0 mg, 78.7 pmol, 1.0 eq), potassium ethyltrifluoroborate (11.8 mg, 86.5 pmol, 1.1 eq), Pd(OAc)2 (1.77 mg, 7.87 prnol, 0.1 eq), RuPhos (7.34 mg, 15.7 pmol, 0.2 eq) and CS2CO3 (76.9 mg, 236 pmol, 3.0 eq) in a mixture of toluene (3.0 mL) and H2O (0.3 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 110 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was allowed to cool to room temperature, poured into H2O (5.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.5). te/7-Buty (5)-2-((3-((l-(7-ethylquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (63.0 mg, 122 prnol, 78% yield) was obtained as a white solid. M + H ⁺ = 516.3 (LCMS).

Step 2: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-ethylquinolin-5-yl)cyc lopropyl)-2-methyl benzamide (Compound 677)

To a solution of tert-butyl (S)-2-((3-((l-(7-ethylquinolin-5-yl)cyclopropyl)carbamoyl)-4 - methylphenoxy)methyl)azetidine-l -carboxylate (63.0 mg, 122.18 pmol, 1.0 eq) in DCM (3.0 mL) was added TFA (3.08 g, 27.0 mmol, 2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 (75 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-5-(Azeti din-2 -ylmethoxy)-7V-(l-(7-ethylquinolin-5-yl) cyclopropyl)-2-methylbenzamide (30.0 mg, 56.7 pmol, 47% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 416.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.45 (br d, J= 8.6 Hz, 1H), 9.19 (s, 1H), 9.08 (dd, J= 1.3, 4.8 Hz, 1H), 7.95 (s, 1H), 7.90 - 7.82 (m, 2H), 7.09 (d, J= 8.6 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 4.69 - 4.58 (m, 1H), 4.28 - 4.17 (m, 1H), 4.16 - 4.08 (m, 1H), 3.98 - 3.77 (m, 2H), 2.89 (q, J= 7.5 Hz, 2H),

2.48 - 2.42 (m, 1H), 2.40 - 2.28 (m, 1H), 1.95 (s, 3H), 1.40 (br s, 2H), 1.34 - 1.23 (m, 5H).

Example 414: (3)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-ethyl-l,2,3,4-tetrahyd roquinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 692)

414A-2 Compound 692

Step 1 : tert-Butyl(5)-2-((4-methyl-3-((l-(7-vinylquinolin-5-yl)cyclo propyl)carbamoyl) phenoxy)methyl)azetidine- 1-carboxylate (414 A- 1) A mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (150 mg, 236 pmol, 1.0 eq), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (72.7 mg, 472 pmol, 80.1 pL, 2.0 eq), Pd(dppf)C12.CH2C12 (19.3 mg, 23.6 pmol, 0.1 eq), and lSfeCCh (57.5 mg, 543 pmol, 2.3 eq) in a mixture of dioxane (6.0 mL) and H2O (1.0 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was poured into H2O (10 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petr oleum ether from 0/1 to 1/1. tert-Butyl fS')- 2-((4-methyl-3-((l-(7-(((trifhjoromethyl)sulfonyl)oxy)quinol in-5-yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-l -carboxylate (80.0 mg, 156 pmol, 66% yield) was obtained as a yellow oil. M + H ⁺ = 514.3 (LCMS).

Step 2: tert-Butyl (5)-2-((3-((l-(7-ethyl-l,2,3,4-tetrahydroquinolin-5-yl)cyclo propyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-l-carboxylate (414A-2)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (80.0 mg, 156 pmol, 1.0 eq) in EtOAc (8.0 mL) was added 10% palladium on carbon (50.0 mg). The mixture was degassed and purged with EE three times and stirred at 20 °C for 2 h under a EE (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc (10 mL x 3). The combined organic layers were concentrated under vacuum to give the crude product tert-butyl (5)-2-((3-((l-(7-ethyl-l,2,3,4-tetrahydro quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl) azetidine-l-carboxylate (30.0 mg, 57.7 pmol, 37% yield) as a white solid. M + H ⁺ = 520.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.74 (s, 1H), 7.08 (d, J= 8.5 Hz, 2H), 6.90 (dd, J= 2.6, 8.3 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 6.68 - 6.39 (m, 1H), 4.46 - 4.38 (m, 1H), 4.18 (dd, J= 4.8, 10.4 Hz, 1H), 4.03 (dd, J= 2.8, 10.4 Hz, 1H), 3.81 - 3.67 (m, 3H), 3.30 - 3.23 (m, 3H), 3.03 -2.86 (m, 3H), 2.32 -2.23 (m, 1H), 2.10 (s, 3H), 1.94 - 1.86 (m, 2H), 1.34 (s, 9H), 1.17 -1.11 (m, 5H), 1.03 (br s, 2H).

Step 3: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-ethyl-l,2,3,4-tetrahyd roquinolin-5-yl) cyclopropyl)-2-methylbenzamide (Compound 692) To a solution of tert-butyl (5)-2-((3-((l-(7-ethyl-l,2,3,4-tetrahydroquinolin-5-yl)cyclo propyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (20.0 mg, 38.5 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: l%-30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (8)-5-(Azetidin-2-ylmethoxy)-7V-(l-(7-ethyl-l,2,3,4-tetrahyd roquinolin -5-yl)cyclopropyl)-2-methylbenzamide (4.80 mg, 11.4 pmol, 30% yield) was obtained as a white solid. M + H ⁺ = 420.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.94 - 8.76 (m, 2H), 8.69 (s, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.93 (dd, J= 2.6, 8.4 Hz, 1H), 6.87 - 6.71 (m, 2H), 4.73 - 4.64 (m, 1H), 4.32 - 4.25 (m, 1H), 4.22 - 4.15 (m, 1H), 3.96 - 3.85 (m, 2H), 3.20 (br s, 2H), 2.92 (br t, J= 5.9 Hz, 2H), 2.46 - 2.31 (m, 4H), 2.13 (s, 3H), 1.91 - 1.81 (m, 2H), 1.16 - 1.08 (m, 5H), 1.03 - 0.99 (m, 2H).

Example 415: ( )-/V-(l-(6-Methoxyquinolin-8-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 761)

Step 3

415A-3 Compound 761

Step 1: 6-Methoxyquinoline-8-carbonitrile (415A-2)

To a solution of 8-bromo-6-methoxyquinoline (13.0 g, 54.6 mmol, 1.0 eq) in DMF (250 mL) were added Zn(CN)2 (12.8 mg, 109 mmol, 6.93 mL, 2.0 eq) and Pd(PPh3)4 (6.31 g, 5.46 mmol, 0.1 eq) under a N2 atmosphere. The mixture was stirred at 100 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (400 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/9. 6- Methoxyquinoline-8-carbonitrile (9.00 g, 48.9 mmol, 89% yield) was obtained as a white solid. M + H ⁺ = 185.0 (LCMS).

Step 2: l-(6-Methoxyquinolin-8-yl)cyclopropan-l-amine (415A-3)

A mixture of 6-methoxyquinoline-8-carbonitrile (1.00 g, 5.43 mmol, 1.0 eq) in anhydrous Et2O (100 mL) was degassed and purged with N2 three times. The mixture was cooled to -78 °C. To this mixture was added Ti(z-PrO)4 (2.31 g, 8.14 mmol, 2.4 mL, 15 eq) slowly, then EtMgBr (3 M in Et2O, 4.0 mL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (1.54 g, 10.9 mmol, 1.34 mL, 2.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. TLC indicated that the starting material was completely consumed, and a main spot was detected. The reaction mixture was added into a mixture of HC1 (I M aqueous) (50 mL) and MTBE (50 mL) and extracted with MTBE (50 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (100 mL x 6). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 0/1 to 10/1. l-(6-Methoxyquinolin-8-yl)cyclopropan-l -amine (370 mg, 1.73 mmol, 32% yield) was obtained as a yellow oil. M + H ⁺ = 215.2 (LCMS).

Step 3: (5)-/V-(l-(6-Methoxyquinolin-8-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 761)

To a mixture of l-(6-methoxyquinolin-8-yl)cyclopropan-l-amine (100 mg, 467 pmol, 1.0 eq) and (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (110 mg, 467 pmol, 1.0 eq) in DMF (3.0 mL) were added HATU (444 mg, 1.17 mmol, 2.5 eq) and DIEA (181 mg, 1.40 mmol, 244 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (15 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna C18 column (100 x 40 mm, 10 pm); flow rate: 60 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-7V-(l-(6-Methoxyquinolin-8- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (42.7 mg, 75.9 pmol, 16% yield) was obtained as a white solid. M + H ⁺ = 432.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 10.54 - 9.94 (m, 1H), 9.19 (s, 1H), 9.07 - 8.96 (m, 1H), 8.77 (br d, J= 8.3 Hz, 1H), 7.73 - 7.58 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.16 - 6.95 (m, 2H), 6.88 (s, 1H), 4.91 - 4.65 (m, 1H), 4.52 - 4.28 (m, 2H), 4.21 - 4.02 (m, 5H), 2.96 - 2.86 (m, 3H), 2.47 - 2.38 (m, 2H), 2.32 (s, 3H), 1.63 - 1.54 (m, 2H), 1.49 - 1.42 (m, 2H).

Example 416: 5-(2-(/c/7-Butyl:iniino)ethoxy)- \-( l-(7-inetlioxyqiiinolin-5-yl)cyclopropyl)- 2-methylbenzamide (Compound 626)

Step 2

Compound 626

Step 1 : 5-(2-Bromoethoxy)-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl) -2- methylbenzamide (416A-1)

To a solution of 5-hydroxy-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy lbenzamide (150 mg, 431 pmol, 1.0 eq) and 1,2-dibromoethane (809 mg, 4.31 mmol, 325 pL, 10 eq) in acetone (5.0 mL) were added K2CO3 (137 mg, 990 pmol, 2.3 eq) and 18-crown-6 (5.69 mg, 21.5 pmol, 0.05 eq). The mixture was stirred at 60 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/= 0.38). 5-(2- Bromoethoxy)-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-me thylbenzamide (63.0 mg, 138 pimol, 32% yield) was obtained as a yellow solid. M + H ⁺ = 455.1 (LCMS).

Step 2: 5-(2-(terCButylamino)ethoxy)-/V-(l-(7-methoxyquinolin-5-yl)c yclopropyl)-2- methylbenzamide (Compound 626)

To a solution of 2-methylpropan-2-amine (101 mg, 1.38 mmol, 10 eq) in acetonitrile (5.0 mL) were added 5-(2-bromoethoxy)-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)- 2-methylbenzami de (63.0 mg, 138 pmol, 1.0 eq) and DIEA (53.7 mg, 415 pmol, 72.3 pL, 3.0 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Waters Xbridge BEH C18 (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 5-(2-(/ert-Butylamino)ethoxy)-A-(l-(7-methoxyquinolin-5-yl)c yclopropyl)- 2-methylbenzamide (19.2 mg, 39.2 pmol, 99% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 448.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.62 (br d, J= 8.1 Hz, 1H), 9.33 (s, 1H), 9.16 (d, J= 5.0 Hz, 1H), 8.97 (br s, 2H), 7.94 (br dd, J= 5.4, 8.3 Hz, 1H), 7.71 (d, J= 2.4 Hz, 1H), 7.61 (s, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.75 (d, J= 2.8 Hz, 1H), 4.21 (br t, J = 5.1 Hz, 2H), 4.02 (s, 3H), 3.22 (br s, 2H), 1.97 (s, 3H), 1.41 (br s, 2H), 1.31 (s, 11H).

Example 417: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy-</2)benzamide (Compound 797)

O Boc _{D D} Boc

Step 1

417A-1 417A-2

Compound 797

Step 1: tert-Butyl (5)-2-(hydroxymethyl-d2)azetidine-l-carboxylate (417A-2) To a solution of 1 -(tert-butyl) 2-methyl (S)-azetidine-l,2-dicarboxylate (400 mg, 1.86 mmol, 1.0 eq) in THF (5.0 mL) was added LiAlD4 (77.9 mg, 1.86 mmol, 106 pL, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with saturated NH4CI aqueous (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl fS')-2-(hydroxymethyl-t/2)azetidine- l -carboxylate (300 mg, 1.59 mmol, 85% yield) as a yellow oil, which was used in the next step without any further purification. M - 56 + H ⁺ = 134.1. ¹ H NMR (400 MHz, CDCh) 84.44 (t, J= 7.6 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.79 (dt, J= 4.8, 8.9 Hz, 1H), 2.18 (dtd, J= 4.8, 8.7, 11.4 Hz, 1H), 1.94 (tdd, J= 7.0, 9.3, 11.3 Hz, 1H), 1.46 (s, 9H). Step 2: tert-Butyl (5)-2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxy)methyl-</2)azetidine-l-carboxylate (417A-3)

To a solution of tert-butyl fS')-2-(hydroxymethyl-t/2)azetidine- l -carboxylate (166 mg, 878 pmol, 1.7 eq) and 5-hydroxy-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy lbenzamide (180 mg, 517 pmol, 1.0 eq) in toluene (3.0 mL) were added added TMAD (267 mg, 1.55 mmol, 3.0 eq) and PPhi (407 mg, 1.55 mmol, 3.0 eq) in one portion. The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl (S)-2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxyjmethyl-tC) azetidine- 1 -carboxylate (260 mg) as a yellow solid, which was used in the next step without any further purification. M + H ⁺ = 520.3 (LCMS).

Step 3: (5)-5-(Azetidin-2-ylmethoxy-d2)-/V-(l-(7-methoxyquinolin-5-y l)cyclopropyl)-2- methylbenzamide (417A-4)

To a solution of tert-butyl (S)-2-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxyjmethyl-tCjazetidine- l -carboxylate (260 mg, 450 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (250 pL) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 25 °C to give (5)-5-(azetidin-2-ylmethoxy-d2)-7V- (l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (180 mg, 429 pmol, 95% yield, TFA salt) as a yellow solid, which was used in the next step without any further purification.

Step 4: (.S')-\-( l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methyl azetidin-2- yl methoxy- z benzamide (Compound 797)

To a solution of (5)-5-(azetidin-2-ylmethoxy-d2)-7V-(l-(7-methoxyquinolin-5-y l)cyclopropyl)- 2-methylbenzamide (180 mg, 337 mmol, 1.0 eq, TFA) in MeOH (3.0 mL) was added TEA (50.0 pL), followed by formaldehyde (54.8 mg, 675 pmol, 50.2 pL, 37% purity in water, 2.0 eq). The mixture was adjusted to pH 5 with a small amount of AcOH, then NaBHiCN (42.4 mg, 675 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into saturated aqueous NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue, which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-N- (l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methy lazetidin-2-yl)methoxy- tLjbenzamide (77.6 mg, 179 pmol, 53% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 434.2 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.31 (br d, J= 8.5 Hz, 1H), 9.22 - 9.16 (m, 1H), 9.01 (dd, J= 1.3, 4.9 Hz, 1H), 7.72 (dd, J= 4.9, 8.4 Hz, 1H), 7.62 (d, J= 2.4 Hz, 1H), 7.41 (d, = 2.4 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.95 - 6.88 (m, 1H), 6.77 - 6.70 (m, 1H), 4.65 - 4.55 (m, 1H), 4.07 - 4.00 (m, 1H), 3.97 (s, 3H), 3.87 (q, J= 9.5 Hz, 1H), 2.83 (s, 3H), 2.40 - 2.28 (m, 2H), 1.94 (s, 3H), 1.37 (br s, 2H), 1.26 (br s, 2H).

Example 418: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- (methyl-

</5)azetidin-2-yl)methoxy)benzamide (Compound 732)

Step 3 418A-2 Compound 732

Step 1: Methyl (5)-2-methyl-5-((l-(methyl-</3)azetidin-2-yl)methoxy)benz oate (418A-1)

To a solution of CS')-m ethyl 5-(azetidin-2-ylmethoxy)-2-methylbenzoate (200 mg, 573 pmol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (100 pL), followed by formaldehyde-tL (107 mg, 687 pmol, 94.6 pL, 20% purity in D2O, 1.2 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBDsCN (36.0 mg, 573 pmol, 1.0 eq) was added. The resulting mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (20 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of DCM/MeOH from 100/1 to 10/1. Methyl CS')-2-methyl-5- ((l-(methyl-t6)azetidin-2-yl)methoxy)benzoate (80.0 mg, 317 pmol, 55% yield) was obtained as a yellow oil. M + H ⁺ = 253.1 (LCMS).

Step 2: (5)-2-Methyl-5-((l-(methyl-</3)azetidin-2-yl)methoxy)benz oic acid (418A-2)

A solution of methyl (8)-2-methyl-5-((l-(methyl-t/j)azetidin-2-yl)methoxy)benzoat e (180 mg, 713 pmol, 1.0 eq) in HC1 (2 M aqueous, 10 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, then adjusted to pH 6 with NaOH (2 M aqueous). The resulting mixture was concentrated under vacuum to remove the water completely. The resulting mixture was treated with MeOH/DCM (V/V = 10/1, 10 mL), then filtered. The filter cake was washed with MeOH/DCM (V/V = 10/1, 10 mL x 2) to ensure all product was washed from the solids. The combined organic layers were concentrated under vacuum to give (5)-2-methyl-5-((l-(methyl-t6)azeti din-2 -yl)methoxy)benzoic acid (190 mg, crude) as a hydrophilic, white solid. M + H ⁺ = 239.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 5 11.00 - 10.70 (m, 1H), 7.49 - 7.44 (m, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.16 (dd, J = 2.8, 8.4 Hz, 1H), 4.79 - 4.65 (m, 1H), 4.54 - 4.47 (m, 1H), 4.40 - 4.33 (m, 1H), 4.14 - 4.02 (m, 1H), 3.97 - 3.84 (m, 1H), 2.56 - 2.55 (m, 3H), 2.47 - 2.37 (m, 2H).

Step 3: (3)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(( l-(methyl-

</5)azetidin-2-yl)methoxy)benzamide (Compound 732)

To a solution of (V)-2-methyl-5-((l-(methyl-t6)azetidin-2-yl)methoxy)benzoic acid (190 mg, 797 pmol, 1.0 eq) and l-(7-methoxyquinolin-5-yl)cyclopropan-l -amine (188 mg, 877 pmol, 1.1 eq) in DMF (10 mL) were added DIEA (309 mg, 2.39 mmol, 417 pL, 3.0 eq) and HATU (606 mg, 1.59 mmol, 2.0 eq). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (20 mL x 6). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). (S)-7V-(l-(7- Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-(methyl-t6) azetidin-2-yl)methoxy) benzamide (52.3 mg, 120 pmol, 15% yield) was obtained as a white solid. M + H ⁺ = 435.4 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.10 (s, 1H), 9.00 - 8.90 (m, 1H), 8.86 - 8.79 (m, 1H), 7.48 - 7.39 (m, 2H), 7.31 (d, J= 2.4 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.7 Hz, 1H), 3.94 - 3.91 (m, 3H), 3.88 - 3.84 (m, 2H), 3.28 - 3.16 (m, 2H), 2.76 - 2.64 (m, 1H), 2.00 - 1.80 (m, 5H), 1.37 - 1.31 (m, 2H), 1.22 - 1.16 (m, 2H).

Example 419: tert-Butyl (65,8al?)-6-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)car bamoyl)-4-methylphenoxy)methyl)hexahydropyrrolo[l,2-a]pyrazi ne-2(lH)-carboxylate (Compound 775) and tert-butyl (75,9al?)-7-(3-((l-(7-methoxyquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)octahydro-2Z/-pyri do[ 1 ,2-a]pyrazine-2- carboxylate (Compound 776) Compound 776

Step 1: tert- Butyl (65,8al?)-6-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl) carbamoyl)-4- methylphenoxy)methyl)hexahydropyrrolo[l,2-a]pyrazine-2(lH)-c arboxylate (Compound 775) and tert-butyl (75,9al?)-7-(3-((l-(7-methoxyquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)octahydro-2Z/-pyri do[ 1 ,2-a]pyrazine-2- carboxylate (Compound 776)

To a mixture of 5-hydroxy-7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methy lbenzamide (150 mg, 431 pmol, 1.0 eq) and tert-butyl (65,8a7?)-6-(hydroxymethyl)hexahydropyrrolo[l,2- a]pyrazine-2(U7)-carboxylate (165 mg, 645 pmol, 1.5 eq) in toluene (15 mL) was added CMBP (312 mg, 1.29 mmol, 3.0 eq) in glove box. The mixture was degassed and purged with N2 three times. The mixture was stirred at 100 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL), and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). tert-Butyl (65,8a7?)- 6-((3-((l-(7 -methoxy quinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl) hexa hydropyrrolo[l,2-a]pyrazine-2(177)-carboxylate (183 mg, 311 pmol, 72% yield, eluent second) was obtained as a white solid. M + H ⁺ = 587.3 (LCMS); ^T H NMR (400 MHz, DMSO- tL) 6 9.09 (s, 1H), 8.94 (d, J= 8.4 Hz, 1H), 8.81 (d, J= 3.3 Hz, 1H), 7.51 - 7.35 (m, 2H), 7.31 (d, J= 2.4 Hz, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.84 (dd, J= 2.5, 8.4 Hz, 1H), 6.62 (d, J= 2.5 Hz, 1H), 4.06 - 3.95 (m, 1H), 3.92 (s, 3H), 3.85 - 3.79 (m, 1H), 3.13 (br d, J= 11.1 Hz, 1H), 2.83 - 2.53 (m, 3H), 2.05 - 1.91 (m, 5H), 1.90 - 1.80 (m, 1H), 1.78 - 1.66 (m, 1H), 1.61 - 1.12 (m, 17H). Zc/V-Butyl (75,9a7?)-7-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carba moyl)-4- methylphen oxy)octahydro-2J/-pyrido[l,2-a]pyrazine-2-carboxylate (9.20 mg, 15.7 pmol, 11% yield, eluent first) was obtained as a white solid. M + H ⁺ = 587.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.11 (s, 1H), 8.95 (d, J= 7.5 Hz, 1H), 8.82 (dd, J= 1.6, 4.1 Hz, 1H), 7.51 - 7.37 (m, 2H), 7.31 (d, J = 2.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.85 (dd, J= 2.6, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 4.50 - 4.40 (m, 1H), 3.92 (s, 3H), 3.84 - 3.69 (m, 2H), 2.91 (br d, J= 12.5 Hz, 1H), 2.57 (br s, 1H), 2.15 (br d, J= 11.9 Hz, 1H), 1.96 - 1.76 (m, 6H), 1.55 - 1.31 (m, 16H), 1.22 - 1.14 (m, 2H).

Example 420: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6» S,8al?)- octahydropyrrolo[l,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 789) and 7V-(l-(7- methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((75',9al?)-oc tahydro-2Z7-pyrido[l,2- a]pyrazin-7-yl)oxy)benzamide (Compound 790)

Compound 789 Compound 790

Step 1 : /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((6» S,8al?)- octahydropyrrolo[l,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 789) and \-(l-(7- methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((7»S,9al?)-o ctahydro-2Z/-pyrido[l,2- a]pyrazin-7-yl)oxy)benzamide (Compound 790)

To a mixture of Zc/'Z-butyl (65,8a7?)-6-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl) carbarn oyl)-4-methylphenoxy)methyl)hexahydropyrrolo[l,2-a]pyrazine- 2(177)-carboxylate and Zc/V-butyl (75,9a7?)-7-(3-((l-(7-methoxyquinolin-5-yl)cyclopropyl) carbamoyl)-4- methylphenoxy)octahydro-2J/-pyrido[l,2-a]pyrazine-2-carboxyl ate (70.0 mg, 119 pmol, 1.0 eq) in EtOAc (1.0 mL) was added HCI/EtOAc (4 M, 2.19 mL). The resulting mixture was stirred at 20 °C for 30 min. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5- (((65, 8a7?)-octahydropyrrolo[l,2-a]pyrazin-6-yl)m ethoxy )benzamide (26.8 mg, 51.2 pmol, 43% yield, HC1 salt, eluent second) was obtained as a yellow solid. M + H ⁺ = 487.3 (LCMS); ^X H NMR (400 MHz, DMSO4) 8 9.62 (d, J= 8.4 Hz, 1H), 9.30 (s, 1H), 9.18 - 9.08 (m, 1H), 7.94 (dd, J= 5.4, 8.5 Hz, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 2.3 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 4.40 - 4.14 (m, 2H), 4.01 (s, 3H), 3.96 - 3.82 (m, 1H), 3.77 - 3.62 (m, 2H), 3.48 - 3.16 (m, 5H), 2.28 - 2.05 (m, 2H), 1.93 (s, 3H), 1.81 - 1.59 (m, 2H), 1.41 (br s, 2H), 1.30 (br d, J = 3.4 Hz, 2H). A-(l-(7- Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((75,9a7?)-oct ahydro-2Z/-pyrido[l,2- a]pyrazin-7-yl)oxy) benzamide (11.7 mg, 22.4 pmol, 19% yield, HC1 salt, eluent first) was obtained as a yellow solid. M + H ⁺ = 487.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.54 (d, J= 8.4 Hz, 1H), 9.26 (s, 1H), 9.10 (d, J= 5.1 Hz, 1H), 7.88 (dd, J= 5.4, 8.5 Hz, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.47 (d, J= 2.3 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 7.02 - 6.92 (m, 1H), 6.80 (d, J= 2.4 Hz, 1H), 4.74 (br s, 1H), 4.00 (s, 3H), 3.53 - 3.21 (m, 7H), 3.20 - 3.03 (m, 2H), 1.97 - 1.85 (m, 4H), 1.82 - 1.57 (m, 3H), 1.39 (br s, 2H), 1.29 (br s, 2H).

Example 421: \-(l-(7-Metlioxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((65. 8a/?)-2- methyloctahydropyrrolo[l,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 784) and \-( l-(7mietlioxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((75.9a/ ?)-2-methyloctahydro- 2//-pyrido| 1.2-u | pyrazin-7-yl)oxy (benzamide (Compound 783)

Compound 789 Compound 790

Compound 784

Step 1 : A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((75', 9al?)-2-methyl oct ahydro-2//-py rido 11.2-u|py razin-7-yl)oxy (benzamide (Compound 783) and 7V-(l-(7- methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((65',8al?)-2- methyloctahydropyrrolo [l,2-a]pyrazin-6-yl)methoxy)benzamide (Compound 784)

To a mixture of A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((65,8 a7?)- octahydropyrrolo[l,2-a]pyrazin-6-yl)methoxy)benzamide and A-(l-(7-methoxyquinolin-5- yl)cyclopropyl)-2-methyl-5-(((75,9a7?)-octahydro-2J/-pyrido[ l,2-a]pyrazin-7-yl)oxy) benzamide (130 mg, 249 pmol, 1.0 eq, HC1 salt) in MeOH (5.0 mL) was added TEA (50 pL), followed by formaldehyde (40.3 mg, 497 pmol, 37.0 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH, then NaBHiCN (31.2 mg, 497 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile). A-(l-(7-methoxyquinolin- 5-yl)cyclopropyl)-2-methyl-5-(((65,8a7?)-2-methyloctahydropy rrolo[l,2-a]pyrazin-6- yl)methoxy)benzamide (16.8 mg, 32.8 pmol, 13% yield, eluent second) was obtained as a white solid. M + H ⁺ = 501.3 (LCMS); 'H NMR (400 MHz, DMSO-cL( 8 9.08 (s, 1H), 9.00 - 8.87 (m, 1H), 8.81 (dd, J= 1.6, 4.3 Hz, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.41 (dd, J= 4.3, 8.4 Hz, 1H), 7.31 (d, J= 2.5 Hz, 1H), 7.02 (d, J= 8.5 Hz, 1H), 6.83 (dd, J= 2.8, 8.4 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 3.95 - 3.87 (m, 4H), 3.78 (dd, J= 5.4, 9.7 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.81 (br d, J= 10.3 Hz, 1H), 2.69 - 2.58 (m, 2H), 2.26 - 2.09 (m, 5H), 2.02 - 1.79 (m, 5H), 1.74 - 1.59 (m, 2H), 1.54 - 1.38 (m, 1H), 1.38 - 1.30 (m, 2H), 1.28 - 1.14 (m, 3H). #-(l-(7- Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(((75,9a7?)-2-m ethyloctahydro-2Z/-pyrido [l,2-a]pyrazin-7-yl)oxy)benzamide (10.2 mg, 19.3 pmol, 8% yield, eluent first) was obtained as a white solid. M + H ⁺ = 501.3 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 89.09 (s, 1H), 8.94 (d, J= 7.6 Hz, 1H), 8.82 (dd, J = 1.5, 4.1 Hz, 1H), 7.49 - 7.37 (m, 2H), 7.31 (d, J= 2.5 Hz, 1H), 7.02 (d, J= 8.5 Hz, 1H), 6.83 (dd, J= 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 4.43 (br s, 1H), 3.92 (s, 3H), 2.88 (br d, J = 12.5 Hz, 1H), 2.58 (br dd, J = 10.1, 19.3 Hz, 3H), 2.18 - 1.88 (m, 10H), 1.82 (br d, J= 13.0 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.53 - 1.38 (m, 2H), 1.37 -

1.31 (m, 2H), 1.30 - 1.23 (m, 1H), 1.22 - 1.14 (m, 2H).

Example 422: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((2-me thyl-l, 2,3,4- tetrahydroisoquinolin-3-yl)methoxy)benzamide (Compound 799)

422A-5

Compound 799

Step 1: tert- Butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(lET)-carboxylate (422A- 2)

To a solution of (l,2,3,4-tetrahydroisoquinolin-3-yl)methanol (200 mg, 1.23 mmol, 1.0 eq) in DCM (10 mL) were added TEA (450 mg, 4.44 mmol, 620 pL, 3.6 eq) and BOC2O (321 mg, 1.47 mmol, 1.2 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (4.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. tert-Butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(177)-carboxylate (320 mg, 1.22 mmol, 99% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 208.2 (LCMS).

Step 2: tert-Butyl 3-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)-3,4-dihydroi so quinoline-2(TH)-carboxylate (422A-3)

To a solution of tert-butyl 3-(hydroxymethyl)-3,4-dihydroisoquinoline-2(lrt)-carboxylate (300 mg, 1.14 mmol, 1.0 eq) and methyl 5-hydroxy-2-methylbenzoate (189 mg, 1.14 mmol, 1.0 eq) in tolene (15 mL) were added TMAD (589 mg, 3.42 mmol, 3.0 eq) and PPI13 (896 mg, 3.42 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. Zc/V-Butyl 3-((3-(methoxycarbonyl)-4- methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(177)-carboxy late (366 mg, 890 pmol, 78% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 356.2 (LCMS).

Step 3: 5-((2-(te/7- But oxy carbonyl)- 1,2,3, 4-tetrahydr oisoquinolin-3-yl)methoxy)-2- methylbenzoic acid (422A-4)

To a solution of tert-butyl 3-((3-(methoxycarbonyl)-4-methylphenoxy)methyl)-3,4-dihydroi so quinoline-2(177)-carboxylate (366 mg, 890 pmol, 1.0 eq) in MeOH (20 mL) and THF (10 mL) was added NaOH (2 M aqueous, 1.8 mL, 4.0 eq). The mixture was stirred at 70 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL), and washed with MTBE (15 mL x 2). The aqueous layer was acidified to pH 6 with HC1 (1 M aqueous). The product was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product 5-((2-(ter/-butoxycarbonyl)- l,2,3,4-tetrahydroisoquinolin-3-yl)methoxy)-2-methylbenzoic acid (375 mg) as a yellow oil. M - 56 + H ⁺ = 342.2 (LCMS).

Step 4: te/7- Butyl 3-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4-m ethylph enoxy)methyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate (422A-5)

To a solution of l-(7-methoxyquinolin-5-yl)cyclopropan-l-amine (80.9 mg, 177 pmol, 1.0 eq) and 5-((2-(ter/-butoxycarbonyl)-l,2,3,4-tetrahydroisoquinolin-3- yl)methoxy)-2-methyl benzoicacid (150 mg, 377 pmol, 1.0 eq) in DMF (8.0 mL) were added DIEA (146 mg, 1.13 mmol, 197 pL, 3.0 eq) and HATU (359 mg, 943 pmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. tert-Butyl 3-((3-((l-(7-methoxyquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)-3,4-dihydr oisoquinoline-2(U7)- carboxylate (193 mg, 325 pmol, 86% yield) was obtained as a yellow oil. M - 56 + H ⁺ = 538.4 (LCMS). Step 5: \-( l-(7-Met hoxyquinolin-5-yl jcyclopropyl )-2-met hyl-5-(( 1.2.3.4-tetrahydroiso quinolin-3-yl)methoxy)benzamide (422A-6)

To a solution of tert-butyl 3-((3-((l-(7-methoxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)-3,4-dihydroisoquinoline-2(U7)-carboxyl ate (193 mg, 325 pmol, 1.0 eq) in EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 7.4 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give the product 7V-(l-(7-methoxyquinolin-5- yl)cyclopropyl)-2-methyl-5-((l,2,3,4-tetrahydroisoquinolin-3 -yl)methoxy)benzamide (160 mg, 302 pmol, 93% yield, HC1 salt) as a white solid. M + H ⁺ =494.3 (LCMS).

Step 6: \-( 1 -(7-Methoxyquinolin-5-yl)cyclopropyl)-2-niethyl-5-((2-methyl -l.2.3.4- tetrahydroisoquinolin-3-yl)methoxy)benzamide (Compound 799)

To a solution of 7V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l,2, 3,4-tetrahy droisoquinolin-3-yl)methoxy)benzamide (150 mg, 283 pmol, 1.0 eq, HC1 salt) in MeOH (10 mL) was added TEA (1.0 mL), followed by formaldehyde (45.9 mg, 566 pmol, 42.1 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH, then NaBHiCN (35.6 mg, 566 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (80 * 30 mm x 3 pm); flow rate: 25 mL/min; gradient: 10% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 7V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2- methyl-5-((2-methyl-l,2,3,4-tetrahydroisoquinolin-3-yl)metho xy)benzamide (65.1 mg, 120 pmol, 42% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 508.4 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.82 (d, J= 8.4 Hz, 1H), 9.34 (s, 1H), 9.07 (d, J= 5.6 Hz, 1H), 8.03

- 7.87 (m, 2H), 7.47 (d, J= 2.0 Hz, 1H), 7.38 - 7.24 (m, 4H), 7.13 (d, J= 8.4 Hz, 1H), 7.05 - 6.95 (m, 1H), 6.87 (d, J= 2.6 Hz, 1H), 4.65 - 4.41 (m, 3H), 4.38 - 4.15 (m, 2H), 4.11 (s, 3H), 3.97 (br dd, J= 4.6, 8.9 Hz, 1H), 3.46 - 3.35 (m, 1H), 3.09 - 2.87 (m, 3H), 2.03 (s, 3H), 1.62

- 1.54 (m, 2H), 1.49 - 1.39 (m, 2H). Example 423: (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl-2,2,3,3-^)-2-me thyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 794)

Step 3

Compound 794

Step 1: (Ethyl- 5)magnesium bromide (423 A-2)

A 50 mL Schlenk flask was charged with Mg (853 mg, 35.1 mmol, 2.0 eq), degassed, and purged with N2 three times. Dry THF (18 mL) was added via syringe, and the reaction was cooled to 0 °C. I2 (5 mg, 19.7 pmol) was added, followed by 1 -bromoethane- 1,1, 2, 2, 2-t/j (2.00 g, 17.5 mmol, 3.42 mL, 1.0 eq) in portions. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture turned grey and most of the Mg was consumed. The reaction mixture was used into the next step without any further purification.

Step 2: l-(7-Methoxyquinolin-5-yl)cyclopropan-2,2,3,3-^-l-amine (423A-3)

A mixture of 7-methoxyquinoline-5-carbonitrile (50.0 mg, 271 pmol, 1.0 eq) in anhydrous THF (5.0 mL) was degassed and purged with N2 three times. Then the white suspension was cooled to -78 °C. To this mixture was added Ti(z -PrO)4 (116 mg, 407 pmol, 120 pL, 1.5 eq) slowly during a period of 5 min and stirred at -78 °C for 10 min. (Ethyl-t/flmagnesium bromide (1 M in THF, 2.0 mL, 7.4 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 10 min under a N2 atmosphere. The color of the mixture turned brown after the addition was complete. The resulting mixture was stirred at the same temperature for 10 min and then warmed to room temperature (between 15-20 °C) slowly over 1.5 h. The mixture turned black. To the mixture was added BF3.Et2O (77.1 mg, 543 pmol, 67.1 pL, 2.0 eq) in portions at the same temperature and no obvious temperature changed was observed. The resulting mixture was stirred at room temperature for another 1 h. LCMS indicated that most of the starting material was consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HC1 (I M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 10/1, R/ = 0.4). l-(7-Methoxyquinolin-5-yl)cyclopropan-2,2,3,3-t -l-amine (20.0 mg, crude) was obtained as a brown gum. M + H ⁺ = 219.1 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.85 (dd, J = 1.6, 4.3 Hz, 1H), 8.68 (dd, J= 0.9, 8.4 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.24 (d, J= 2.5 Hz, 1H), 3.95 (s, 3H).

Step 3: (S)-\-( l-(7-Methoxyquinolin-5-yl)cyclopropyl-2.2.3.3-i//)-2-methyl- 5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 794)

To a solution of (8)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (37.7 mg, 160 pmol, 1.0 eq) and l-(7-methoxyquinolin-5-yl)cyclopropan-2,2,3,3-t -l-amine (35.0 mg, 160 pmol, 1.0 eq) in DMF (1.0 mL) were added DIEA (62.2 mg, 481 pmol, 83.8 pL, 3.0 eq) and HATU (152 mg, 401 pmol, 2.5 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered to give a filtrate which was purified by preparative HPLC (Phenomenex Luna column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (S)-7V-(l-(7- Methoxyquinolin-5-yl)cyclopropyl-2,2,3,3-t )-2-methyl-5-((l-methylazetidin-2-yl)methoxy) benzamide (6.60 mg, 11.5 pmol, 7% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 436.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 10.10 - 9.90 (m, 1H), 9.21 - 9.12 (m, 2H), 8.95 (d, J = 3.5 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.39 (d, J= 2.4 Hz, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.77 - 6.70 (m, 1H), 4.61 (br d, J= 4.4 Hz, 1H), 4.23 (d, J = 5.3 Hz, 2H), 4.02 (br dd, J= 4.9, 9.7 Hz, 1H), 3.96 (s, 3H), 3.87 (br dd, J= 6.0, 9.5 Hz, 1H), 2.84 (d, J= 4.6 Hz, 3H), 2.41 - 2.27 (m, 2H), 1.95 (s, 3H). Example 424: ( )-4-Hydroxy-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 750)

424A-5 Compound 750

Step 1: tert- Butyl (5)-2-((2-methoxy-5-(methoxycarbonyl)-4-methylphenoxy)methyl ) azetidine-l-carboxylate (424A-2)

To a mixture of methyl 5-hydroxy-4-methoxy-2-methylbenzoate (500 mg, 2.54 mmol, 1.0 eq) and tert-butyl (5)-2-(hydroxymethyl)azetidine-l -carboxylate (578 mg, 2.54 mmol, 1.0 eq) in toluene (12 mL) were added TMAD (1.31 g, 7.64 mmol, 3.0 eq) and PPhi (2.00 g, 7.64 mmol, 3.0 eq). The mixture was stirred at 100 °C for 16 h under aN2 atmosphere. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/5. tert-Butyl (5)-2-((2 -m ethoxy-5 - (methoxy carbonyl)-4-methylphenoxy) methyl) azetidine-l-carboxylate (900 mg, 2.46 mmol, 97% yield) was obtained as a yellow oil. M - 100 + H ⁺ = 266.1 (LCMS).

Step 2: Methyl (5)-5-(azetidin-2-ylmethoxy)-4-hydroxy-2-methylbenzoate (424A-3)

To a solution of tert-butyl (5)-2-((2-methoxy-5-(methoxycarbonyl)-4-methylphenoxy) methyl)azetidine-l -carboxylate (450 mg, 1.23 mmol, 1.0 eq) in DCM (10 mL) was added a solution of BBr ₃ (1.54 g, 6.16 mmol, 593 pL, 5.0 eq) in DCM (2.0 mL) dropwise at -78 °C. The resulting mixture was stirred at the same temperature for 1 h, then warmed to 20 °C and stirred another 3 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the crude methyl (5)-5-(azetidin-2-ylmethoxy)-4- hydroxy-2-methylbenzoate (800 mg, 2.41 mmol, HBr salt) as a red oil, which was used in the next step without any further purification. M + H ⁺ = 252.2 (LCMS).

Step 3: Methyl (5)-4-hydroxy-2-methyl-5-((l-methylazetidin-2-yl)methoxy)ben zoate (424A-4)

To a solution of methyl (5)-5-(azetidin-2-ylmethoxy)-4-hydroxy-2-methylbenzoate (400 mg, 1.20 mmol, 1.0 eq, HBr salt) in MeOH (10 mL) was added TEA (100 pL), followed by formaldehyde (195 mg, 2.41 mmol, 179 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBH ₃ CN (151 mg, 2.41 mmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (30 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give methyl fS')-4-hydroxy-2-methyl-5- ((1-methylazeti din-2 -yl)methoxy)benzoate (400 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 266.3 (LCMS).

Step 4: (5)-4-Hydroxy-2-methyl-5-((l-methylazetidin-2-yl)methoxy)ben zoic acid (424A- 5)

A solution of methyl CS')-4-hydroxy-2-methyl-5-(( l -methylazetidin-2-yl)methoxy)benzoate (300 mg, 1.13 mmol, 1.0 eq) in HC1 (2 M aqueous, 15 mL) was stirred at 100 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, treated with H2O (10 mL) and washed with MTBE (20 mL x 2). The aqueous was acidified to pH 6 with NaOH (2 M aqueous). The product was extracted with DCM (20 mL x 5) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuum to give 2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzoic acid (150 mg) as a white solid, which was used in the next step without any further purification. M + H ⁺ = 252.2 (LCMS). Step 5: (5)-4-Hydroxy-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-me thyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 750)

To a solution of 2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (60.0 mg, 239 pmol, 1.0 eq) and l-(7-methoxyquinolin-5-yl)cyclopropan-l -amine (56.3 mg, 263 pmol, 1.1 eq) in DMF (5.0 mL) were added DIEA (30.9 mg, 239 pmol, 41.6 pL, 1.0 eq) and HATU (27.0 mg, 71.6 pmol, 0.3 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 * 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-4-Hydroxy-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (34.0 mg, 70.3 pmol, 29% yield, HC1 salt) was obtained as a brown solid. M + H+ = 448.2 (LCMS); NMR (400 MHz, DMSO- d ₆ ) 6 9.55 - 9.45 (m, 1H), 9.11 - 8.98 (m, 2H), 7.87 - 7.77 (m, 1H), 7.70 - 7.62 (m, 1H), 7.50 - 7.42 (m, 1H), 6.87 - 6.80 (m, 1H), 6.64 - 6.59 (m, 1H), 4.74 - 4.51 (m, 1H), 4.31 - 4.18 (m, 2H), 4.07 - 3.80 (m, 5H), 2.93 - 2.81 (m, 3H), 2.41 - 2.32 (m, 2H), 2.01 - 1.95 (m, 3H), 1.41 - 1.36 (m, 2H), 1.30 - 1.24 (m, 2H).

Example 425: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4- (methylamino)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 737)

Compound 737 Step 1 : (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-(me thylamino)-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 737)

To a solution of (5)-4-amino-A-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (46.0 mg, 103 pmol, 1.0 eq) in MeOH (5.0 mL) was added TEA (1.0 mL), followed by formaldehyde (8.36 mg, 103 pmol, 7.68 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. Then NaBHiCN (9.72 mg, 155 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (column: Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 20% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-4-(me thylamino)- 5-((l-methylazetidin-2-yl)methoxy)benzamide (14.5 mg, 29.2 pmol, 28% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 461.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.59 (br s, 1H), 9.71 (br dd, J= 2.0, 7.8 Hz, 1H), 9.14 (br d, J= 5.6 Hz, 1H), 8.95 (s, 1H), 7.91 (br dd, J= 4.1, 7.6 Hz, 1H), 7.71 (d, J= 2.4 Hz, 1H), 7.53 (d, J= 1.8 Hz, 1H), 6.80 (s, 1H), 6.31 (br s, 1H), 4.73 - 4.51 (m, 1H), 4.32 (dd, J= 5.9, 12.1 Hz, 1H), 4.18 (dd, J= 2.6, 11.9 Hz, 1H), 4.04 (br dd, J= 2.3, 5.9 Hz, 1H), 4.01 (s, 3H), 3.87 - 3.84 (m, 1H), 2.83 (s, 3H), 2.73 - 2.69 (m, 3H), 2.42 - 2.34 (m, 2H), 2.08 (s, 3H), 1.40 (br d, J= 0.9 Hz, 2H), 1.31 - 1.24 (m, 2H).

Example 426: ( )-/V-(l-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 625)

426A-4

Compound 625

Step 1: 5-Bromo-7-methoxy-2-methylquinoline (426A-2)

A mixture of 3-bromo-5-methoxyaniline (2.50 g, 12.4 mmol, 1.0 eq) and HC1 (6 M aqueous, 10 mL) was heated to 105 °C, then (£)-but-2-enal (1.73 g, 24.8 mmol, 2.1 mL, 2.0 eq) was added slowly. The resulting mixture was stirred at 105 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into ice-cold water (20 mL), treated with NH3H2O to adjust pH 8, and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/10. 5-Bromo-7-methoxy-2-methylquinoline (750 mg, 2.98 mmol, 24% yield) was obtained as a yellow solid. M + H ⁺ = 252.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.25 (d, J= 8.5 Hz, 1H), 7.57 (d, J= 2.5 Hz, 1H), 7.45 - 7.35 (m, 2H), 3.91 (s, 3H), 2.65 (s, 3H).

Step 2: 7-Methoxy-2-methylquinoline-5-carbonitrile (426A-3)

To a solution of 5-bromo-7-methoxy-2-methyl-quinoline (1.75 g, 6.94 mmol, 1.0 eq) in DMF (25 mL) were added Zn(CN)2 (1.63 g, 13.9 mmol, 881 pL, 2.0 eq) and Pd(PPh3)4 (802 mg, 694 pmol, 0.1 eq). The mixture was degassed and purged with N2 three times. The resulting mixture was stirred at 100 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into ice-cold water (30 mL), and extracted with EtOAc (25 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 3/5. 7-Methoxy-2- methylquinoline-5-carbonitrile (980 mg, 4.95 mmol, 73% yield) was obtained as a yellow solid. M + H ⁺ = 199.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.27 (d, J= 8.5 Hz, 1H), 7.91 (d, J= 2.5 Hz, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.51 (d, J= 8.5 Hz, 1H), 3.96 (s, 3H), 2.68 (s, 3H).

Step 3: l-(7-Methoxy-2-methylquinolin-5-yl)cyclopropanamine (426A-4)

A solution of 7-methoxy-2-methylquinoline-5-carbonitrile (1.30 g, 6.56 mmol, 1.0 eq) in Et2O (160 mL) was degassed and purged with N2 three times and cooled to -78 °C. Ti(z-PrO)4 (2.80 g, 9.84 mmol, 2.90 mL, 1.5 eq) was added slowly and the mixture was stirred for 5 min. EtMgBr (3.0 M in Et2O, 4.81 mL, 2.2 eq) was added dropwise at -78 °C to maintain the temperature at -78 °C under a N2 atmosphere. The mixture was stirred at same temperature for 10 min then warmed to 20 °C over 1 h. The mixture turned to black. To the mixture was added BF3.Et2O (1.86 g, 13.1 mmol, 1.62 mL, 2.0 eq) in portions at the same temperature with no obvious temperature change. The resulting mixture was stirred at room temperature for another 1 h. LCMS showed some the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into a mixture of HC1 (I M aqueous, 100 mL) and MTBE (100 mL) and extracted with MTBE (80 mL x 2). The aqueous layer was basified to pH 8 using NaOH (2 M aqueous) and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (50 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. l-(7- Methoxy-2-methylquinolin-5-yl)cyclopropanamine (700 mg, 3.07 mmol, 47% yield) was obtained as a yellow oil. M + H ⁺ = 229.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.56 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 2.5 Hz, 1H), 7.24 (d, J= 8.5 Hz, 1H), 7.17 (d, J= 2.5 Hz, 1H), 3.94 (s, 3H), 2.73 (s, 3H), 1.21 - 1.13 (m, 2H), 0.99 (d, J= 2.1 Hz, 2H).

Step 4: (S)-/cz7-Butyl 2-((3-((l-(7-methoxy-2-methylquinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (426A-5)

To a solution of (5)-5-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-meth ylbenzoic acid (211 mg, 657 pmol, 1.0 eq) in DMF (5.0 mL) was added l-(7-methoxy-2-methylquinolin-5- yl)cyclopropanamine (150 mg, 657 pmol, 1.0 eq), followed by DIEA (255 mg, 1.97 mmol, 343 pL, 3.0 eq) and HATU (375 mg, 986 pmol, 1.5 eq). The resulting mixture was stirred at 25 °C for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with ice-water (15 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. (A')-/c/7-Butyl 2-((3-((l-(7-methoxy-2- methylquinolin-5-yl)cyclopropyl)carbamoyl)-4-methylphenoxy)m ethyl)azetidine-l- carboxylate (220 mg, 414 pmol, 63% yield) was obtained as a yellow oil. M + H ⁺ = 532.3 (LCMS).

Step 5: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-methoxy-2-methylquinolin -5- yl)cyclopropyl)-2-methylbenzamide (426A-6)

To a solution of CS')-/c77-butyl 2-((3-((l-(7-methoxy-2-methylquinolin-5-yl)cyclopropyl) carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (370 mg, 696 pmol, 1.0 eq) in DCM (12 mL) was added TFA (4.0 mL). The mixture was stirred at 25 °C for 30 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give the crude (5)-5- (azetidin-2-ylmethoxy)-7V-(l-(7-methoxy-2-methylquinolin-5-y l)cyclopropyl)-2- methylbenzamide (370 mg, crude, TFA salt) as a yellow oil. M + H ⁺ = 432.2 (LCMS).

Step 6: (5)-/V-(l-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-me thyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 625)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-A-(l-(7-methoxy-2-methylquinoli n-5- yl)cyclopropyl)-2 -methylbenzamide (220 mg, 403 pmol, 1.0 eq, TFA) in MeOH (3.0 mL) was added TEA (50 pL), followed by HCHO (49.1 mg, 605 pmol, 45 pL, 37% purity, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (30.4 mg, 484 pmol, 1.2 eq) was added. The resulting mixture was stirred at 25 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with NaHCCL aqueous (1.0 mL) and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 x 30 mm, 10 pm); flow rate: 60 mL/min; gradient: 25% - 65% B over 8 min; mobile phase A: l0 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give a white solid. The solid was diluted with a mixture of acetonitrile (1.0 mL), H2O (4.0 mL), then 146 pL HC1 (1 M aqueous) was added alowly. The resulting mixture was lyophilized to give (5)-A-(l-(7-methoxy-2-methylquinolin-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoy)be nzamide (70.1 mg, 145 pmol, 31% yield, HC1 salt) as a white solid. M + H ⁺ = 446.4 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 10.82 - 10.52 (m, 1H), 9.42 - 9.02 (m, 2H), 7.57 - 7.39 (m, 2H), 7.16 - 7.03 (m, 1H), 6.97 - 6.89 (m, 1H), 6.80 - 6.62 (m, 1H), 4.69 - 4.52 (m, 1H), 4.45 - 4.28 (m, 1H), 4.22 (dd, J= 3.2, 11.2 Hz, 1H), 4.06 - 3.90 (m, 4H), 3.85 (br dd, J= 6.2, 9.5 Hz, 1H), 2.83 - 2.66 (m, 6H), 2.47 - 2.19 (m, 3H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.23 (br s, 2H). Example 427: ( )-2-Fluoro-/V-(l-(7-methoxy-2-methylquinolin-5-yl)cyclopropy l)-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 791)

Step 2

427A-3

Compound 791

Step 1: (S)-tert-Butyl 2-((4-fluoro-3-(methoxycarbonyl)phenoxy)methyl)azetidine-l- carboxylate (427A-2)

To a solution of methyl 2-fluoro-5-hydroxybenzoate (500 mg, 2.94 mmol, 1.0 eq) and tertbutyl (S)-2-(hydroxyl methyl)azetidine-l -carboxylate (550 mg, 2.94 mmol, 1.0 eq) in toluene (10 mL) were added TMAD (759 mg, 4.41 mmol, 1.5 eq) and PPhi (1.54 g, 5.88 mmol, 2.0 eq). The mixture was stirred at 110 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/3, R/ = 0.47). OS')- tert- Butyl 2-((4-fluoro-3 -(m ethoxy carbonyl)phenoxy)methyl)azeti dine- 1 - carboxylate (950 mg, 2.80 mmol, 95% yield) was obtained as a yellow oil. M + H ⁺ = 340.2 (LCMS). Step 2: (5)-5-((l-(tert-Butoxycarbonyl)azetidin-2-yl)methoxy)-2-fluo robenzoic acid (427A-3)

To a solution of tert-butyl (5)-2-((4-fluoro-3 -(methoxy carbonyl)phenoxy)methyl)azeti dine- 1- carboxylate (950 mg, 2.80 mmol, 1.0 eq) in a mixture of MeOH (3.0 mL) and THF (9.0 mL) was added NaOH (2 M aqueous, 5.60 mL, 4.0 eq). The mixture was stirred at 70 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue. The residue was diluted with HC1 (2 M aqueous) (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give S)-5-((l-(ter/-butoxycarbonyl)azetidin-2- yl)methoxy)-2-fluorobenzoic acid (650 mg) as a yellow solid. M + H ⁺ = 326.1 (LCMS).

Step 3: (S)-te/7-Butyl 2-((4-fluoro-3-((l-(7-methoxy-2-methylquinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (427A-4)

To a solution of CS')-5-(( l -(/c/7-butoxycarbonyl)azetidin-2-yl)methoxy)-2-fluorobenzoic acid (50.0 mg, 154 pmol, 1.0 eq) and l-(7-methoxy-2-methylquinolin-5-yl)cyclopropanamine (35.1 mg, 154 pmol, 1.0 eq) in DMF (1.0 mL) were added HATU (87.7 mg, 230 pmol, 1.5 eq) and DIEA (59.6 mg, 461 pmol, 80.3 pL, 3.0 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was diluted with H2O (2.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were washed with brine (2.0 mL x 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. fS')-te/7-Butyl 2-((4-fluoro-3-((l-(7-methoxy-2- methylquinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)aze tidine-l -carboxylate (25.0 mg, 46.7 pmol, 30% yield) was obtained as a yellow solid. M + H ⁺ = 536.4 (LCMS).

Step 4: ( )-5-(Azetidin-2-ylmethoxy)-2-fluoro-/V-(l-(7-methoxy-2-methy lquinolin-5- yl)cyclopropyl)benzamide (427A-5)

To a solution of tert-butyl (25)-2-[[4-fluoro-3-[[l-(7-methoxy-2-methyl-5- quinolyl)cyclopropyl]carbamoyl]phenoxy]methyl]azetidine-l -carboxylate (30.0 mg, 56.0 pmol, 1.0 eq) in DCM (1.0 mL) was added TFA (63.9 mg, 560 pmol, 41.5 pL, 10 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give (S)-5-(azetidin-2- ylmethoxy)-2-fluoro-7V-(l-(7-methoxy-2-methylquinolin-5-yl)c yclopropyl)benzamide (30.0 mg, TFA salt) as a yellow oil M + H ⁺ = 436.2 (LCMS).

Step 5: 2-Fluoro-/V-[l-(7-methoxy-2-methyl-5-quinolyl)cyclopropyl]-5 -[[(2»y)-l- methylazetidin-2-yl] methoxy] benzamide (Compound 791)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-2-fluoro-7V-(l-(7-methoxy-2-met hylquinolin-5- yl)cyclopropyl)benzamide (30.0 mg, 54.6 pmol, 1.0 eq, TFA salt) and HCHO (8.86 mg, 109 pmol, 8.13 pL, 37% purity in H2O, 2.0 eq) in MeOH (1.0 mL) was added TEA (5.52 mg, 54.6 pmol, 7.60 pL, 1.0 eq) to adjust the pH to 8, then AcOH (3.28 mg, 54.6 pmol, 3.12 pL, 1.0 eq) was added to adjust the pH to 5. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (10.3 mg, 164 pmol, 3.0 eq) was added, and the resulting mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Fluoro-A-[l-(7-methoxy-2-methyl-5-quinolyl)cyclopropyl]-5- [[(25)- 1-methylazeti din-2 -yl]methoxy]benzamide (7.60 mg, 15.5 pmol, 28% yield, HC1 salt) was obtained as a pale yellow gum. M + H ⁺ = 450.4 (LCMS); ¹ H NMR (400 MHz, DMSO-tfe) 8 11.10 (br s, 1H), 9.60 - 9.41 (m, 2H), 7.84 (br d, J= 8.6 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.21 - 7.15 (m, 1H), 7.13 - 7.06 (m, 1H), 7.06 - 7.01 (m, 1H), 4.70 - 4.59 (m, 1H), 4.50 - 4.40 (m, 1H), 4.25 (br dd, J= 2.6, 11.0 Hz, 1H), 3.99 (s, 4H), 3.88 - 3.80 (m, 1H), 2.93 (s, 3H), 2.80 (br d, J= 4.8 Hz, 3H), 2.38 - 2.26 (m, 2H), 1.42 (br s, 2H), 1.30 (br s, 2H).

Example 428: ( )-/V-(l-(7-Methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopro pyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 817)

Compound 817

Step 1: 5-Bromo-7-methoxyquinoline 1-oxide (428A-1)

To a solution of 5 -bromo-7-methoxy quinoline (600 mg, 2.52 mmol, 1.0 eq) in DCM (10 mL) was added m-CPBA (665 mg, 3.28 mmol, 1.3 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with HC1 (2 M aqueous, 10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give 5-bromo-7- methoxyquinoline 1-oxide (650 mg, crude) as a yellow solid. M + H ⁺ = 254.1/256.1 (LCMS).

Step 2: 5-Bromo-7-methoxy-2-(trifluoromethyl)quinoline (428A-2)

To a solution of 5-bromo-7-methoxyquinoline 1-oxide (650 mg, 2.56 mmol, 1.0 eq) in THF (10 mL) were added CsF (388 mg, 2.56 mmol, 1.0 eq) and TMSCF3 (1.46 g, 10.2 mmol, 4.0 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 5-Bromo-7- methoxy-2-(trifluoromethyl)quinoline (360 mg, 1.18 mmol, 45% yield) was obtained as a yellow solid. M + H ⁺ = 306.1/308.1 (LCMS).

Step 3: 7-Methoxy-2-(trifluoromethyl)quinoline-5-carbonitrile (428A-3)

To a solution of 5-bromo-7-methoxy-2-(trifluoromethyl)quinoline (180 mg, 588 pmol, 1.0 eq) in DMF (3.0 mL) were added Zn(CN)2 (250 mg, 2.13 mmol, 3.6 eq) and Pd(PPh3)4 (67.9 mg, 58.8 pmol, 0.10 eq). The resulting mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/20. 7-Methoxy-2-(trifluoromethyl)quinoline-5-carbonitrile (130 mg, 515 pmol, 87% yield) was obtained as a yellow solid. M + H ⁺ = 253.1 (LCMS).

Step 4: l-(7-Methoxy-2-(trifluoromethyl)quinoline-5-yl)cyclopropan-l -amine (428A-4)

A solution of 7-methoxy-2-(trifluoromethyl)quinoline-5-carbonitrile (150 mg, 594 pmol, 1.0 eq) in anhydrous Et2O (50 mL) was degassed and purged with N2 three times, The mixture was stirred with a mechanical stirrer at -78 °C. To this mixture was added Ti(z-PrO)4 (185 mg, 654 pmol, 193 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et2O, 436 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (84.0 mg, 594 pmol, 73.4 pL, 1.0 eq) was added slowly with no obvious temperature change. The mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was added into a mixture of HC1 (1 M aqueous, 5.0 mL) and MTBE (10 mL) and extracted with MTBE (10 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3 to give l-(7-methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropan-l- amine (30.0 mg, 106 pmol, 87% yield) as a yellow oil. M + H ⁺ = 283.1 (LCMS).

Step 5: (5)-A-(l-(7-Methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopr opyl)-2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 817)

To a solution of l-(7-methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclopropan-l- amine (20.0 mg, 70.8 pmol, 1.0 eq) in DMF (2.0 mL) were added (5)-2-methyl-5-((l-methylazetidin-2- yl)methoxy)benzoic acid (16.6 mg, 70.8 pmol, 1.0 eq), HATU (40.4 mg, 106 pmol, 1.5 eq), and DIEA (27.4 mg, 212 pmol, 37.0 pL, 3.0 eq). The resulting mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 60 mL/min; gradient: 25% - 55% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile) to give (5)-7V-(l-(7-methoxy-2-(trifluoromethyl)quinolin-5-yl)cyclop ropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (4.90 mg, 9.10 pmol, 12% yield) as a white solid. M + H ⁺ = 500.4 (LCMS); 'H NMR (400 MHz, DMSO-tT) 5 10.01 - 9.81 (m, 1H), 9.27 - 9.18 (m, 2H), 7.88 (d, J= 8.7 Hz, 1H), 7.63 (d, J= 2.4 Hz, 1H), 7.49 (d, J= 2.3 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 2.8, 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.66 - 4.54 (m, 1H), 4.22 (d, J= 5.3 Hz, 2H), 3.97 (s, 3H), 3.91 - 3.78 (m, 2H), 2.83 (d, J= 5.0 Hz, 2H), 2.43 - 2.27 (m, 3H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.28 - 1.23 (m, 2H).

Example 429: ( )-/V-(l-(7-Hydroxy-2-methylquinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 809)

Compound 809

Step 1: 5-(l-Aminocyclopropyl)-2-methylquinolin-7-ol (429 A-l)

To a solution of l-(7-methoxy-2-methylquinolin-5-yl)cyclopropan-l-amine (1.40 g, 6.13 mmol, 1.0 eq) in DCM (60 mL) was added a solution of BBr, (23.0 g, 92.0 mmol, 8.86 mL, 15 eq) in DCM (10 mL) dropwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred at the same temperature for 2 h, then warmed to 20 °C and stirred another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with MeOH (20 mL) at 0 °C and treated with NH3H2O to adjust the pH 8. The mixture was concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1, followed by DCM/MeOH from 100/1 to 10/1. 5-(l-Aminocyclopropyl)-2-methylquinolin-7-ol (1.40 g, 6.53 mmol, crude) was obtained as a yellow solid. M + H ⁺ = 215.1 (LCMS).

Step 2: (5)-/V-(l-(7-Hydroxy-2-methylquinolin-5-yl)cyclopropyl)-2-me thyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 809)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (150 mg, 638 pmol, 1.0 eq) and 5-(l-aminocyclopropyl)-2-methylquinolin-7-ol (137 mg, 638 pmol, 1.0 eq) in DMF (10 mL) were added HATU (170 mg, 446 pmol, 0.7 eq) and DIEA (82.4 mg, 638 pmol, 111 pL, 1.0 eq). The mixture was stirred at 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (100 * 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (A')-M( l -(7 -Hydroxy -2-methylquinolin-5-yl)cy cl opropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (80.0 mg, 147 pmol, 23% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 432.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 6 9.40 (br d, J= 8.5 Hz, 1H), 9.23 - 9.17 (m, 1H), 7.72 (d, J= 8.6 Hz, 1H), 7.62 (d, J= 2.1 Hz, 1H), 7.31 (d, J= 1.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.99 - 6.90 (m, 1H), 6.80 - 6.73 (m, 1H), 4.68 - 4.56 (m, 1H), 4.23 (d, J= 5.3 Hz, 2H), 4.08 - 3.99 (m, 1H), 3.92 - 3.81 (m, 1H), 2.84 (d, J= 3.1 Hz, 6H), 2.44 - 2.28 (m, 2H), 2.00 - 1.91 (m, 3H), 1.38 (br s, 2H), 1.29 - 1.12 (m, 2H).

Example 430: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(2,2, 2- trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (Compound 795)

Compound 795 Step 1: (S)-/c/7-Butyl 2-((3-((l-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy)methyl)azetidine-l-carboxylate (430A-1)

To a mixture of 5-(l-aminocyclopropyl)quinolin-7-ol (300 mg, 1.50 mmol, 1.0 eq) and (5)-5- ((l-(/ert-butoxycarbonyl)azetidin-2-yl)methoxy)-2-methylbenz oic acid (337 mg, 1.05 mmol, 0.7 eq) in DMF (5.0 mL) were added DIEA (194 mg, 1.50 mmol, 261 pL, 1.0 eq) and HATU (399 mg, 1.05 mmol, 0.7 eq). The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 8). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of petroleum ether/EtOAc from 1/0 to 0/1. S)-/erLButyl 2-((3-((l-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl)-4- methylphenoxy )methyl)azeti dine- 1 -carboxylate (450 mg, 894 pmol, 60% yield) was obtained as a yellow solid. M + H ⁺ = 504.2 (LCMS).

Step 2: tert-Butyl (5)-2-((4-Methyl-3-((l-(7-(2,2,2-trifluoroethoxy)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (430A-2)

To a mixture of tert-butyl (S)-2-((3-((l-(7-hydroxyquinolin-5-yl)cyclopropyl)carbamoyl) -4- methylphenoxy)methyl)azetidine-l -carboxylate (200 mg, 397 pmol, 1.0 eq) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (92.2 mg, 397 pmol, 1.0 eq) in DMF (10 mL) was added K2CO3 (110 mg, 794 pmol, 2.0 eq). The mixture was degassed and purged with N2 three times, and the resulting mixture was stirred at 20 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of petroleum ether/EtOAc from 1/0 to 2/1. tert- Butyl (5)-2-((4-methyl-3-((l-(7-(2,2,2-trifluoroethoxy)quinolin-5y l)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-l -carboxylate (100 mg, 171 pmol, 43% yield) was obtained as a white solid. M + H ⁺ = 586.4 (LCMS).

Step 3: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(2,2,2-trifluor oethoxy)quinolin-5- yl)cyclopropyl)benzamide (430A-3)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(2,2,2-trifluoroethoxy)quinolin- 5yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (100 mg, 171 pmol, 43% yield) in DCM (5.0 mL) was added TFA (195 mg, 1.71 mmol, 126 pL, 10 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give (5)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(2,2,2-triflu oroethoxy)quinolin- 5-yl)cyclopropyl)benzamide (80 mg, crude, TFA salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 486.4 (LCMS)

Step 4: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(2,2,2-trifluor oethoxy)quinolin-5- yl)cyclopropyl)benzamide (Compound 795)

To a solution of (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(2,2,2-triflu oroethoxy) quinolin-5-yl)cyclopropyl)benzamide (80.0 mg, crude, TFA salt) in MeOH (5.0 mL) was added TEA (50.0 pL), followed by formaldehyde (27.0 mg, 330 pmol, 24.5 pL, 37% purity in water, 2.0 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (20.7 mg, 330 pmol, 2.0 eq) was added. The resulting reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was treated with H2O (5.0 mL) and extracted with DCM (1.0 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-A-(l-(7- (2,2,2-trifluoroethoxy)quinolin-5-yl)cyclopropyl)benzamide (23.7 mg, 23% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 500.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.94 - 9.82 (m, 1H), 9.20 - 9.12 (m, 1H), 9.03 (d, J = 8.6 Hz, 1H), 8.90 (dd, J= 1.3, 4.2 Hz, 1H), 7.59 - 7.50 (m, 3H), 7.10 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 4.98 (q, J= 8.8 Hz, 2H), 4.64 - 4.57 (m, 1H), 4.25 - 4.20 (m, 2H), 4.07 - 4.00 (m, 1H), 3.87 (br dd, J= 6.3, 9.8 Hz, 1H), 2.84 (d, J= 5.0 Hz, 3H), 2.41 - 2.30 (m, 2H), 1.95 (s, 3H), 1.35 (br s, 2H), 1.25 (br s, 2H).

Example 431: ( )-2-Methyl-/V-(l-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin -5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 815)

431A-4

Step 6

Compound 815

Step 1: (3,3,3-Trifluoropropyl)zinc(II) iodide (431 A-2) To a solution of Zinc powder (876 mg, 13.4 mmol, 3.0 eq) in THF (3.0 mL) was added 1,2- dibromoethane (178 mg, 939 pmol, 71.7 pL, 0.21 eq). The mixture was stirred at 70 °C for 10 min under a N2 atmosphere, then cooled to 25 °C, and TMSC1 (28.3 mg, 260 pmol, 33.0 pL, 0.06 eq) was added. The mixture was stirred at 25 °C for 10 min. A solution of 1,1,1-trifluoro- 3-iodopropane (1.00 g, 4.47 mmol, 524 pL, 1.0 eq) in THF (2.0 mL) was added dropwise. The mixture was stirred at 25 °C until the reaction mixture turned gray. The mixture was used in the next step without any further purification.

Step 2: 5-(l-Aminocyclopropyl)-2-methylquinolin-7-yl trifluoromethanesulfonate (431A- 3)

To a solution of 5-(l-aminocyclopropyl)-2-methylquinolin-7-ol (1.40 g, 6.53 mmol, 1.0 eq) in THF (60 mL) was added LBuOK (1.47 g, 13.1 mmol, 2.0 eq) at 0 °C under a N2 atmosphere.

The mixture was stirred at 0 °C for 15 min. 1,1,1-Trifhioro-A-phenyl-TV- (trifluorom ethyl sulfonyl) methanesulfonamide (4.67 g, 13.1 mmol, 2.0 eq) was added in portions. The resulting reaction mixture was stirred at 20 °C for 15 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. 5-(l-Aminocyclopropyl)-2-methylquinolin-7-yl trifluoromethanesulfonate (850 mg, 2.45 mmol, 53% yield) was obtained as a yellow oil. M + H ⁺ = 333.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.88 (d, J= 8.8 Hz, 1H), 7.83 (d, J= 2.4 Hz, 1H), 7.63 - 7.57 (m, 2H), 2.76 (s, 3H), 1.25 (d, J= 7.3 Hz, 2H), 1.07 - 1.03 (m, 2H).

Step 3: tert-Butyl (5)-2-((4-methyl-3-((l-(2-methyl-7-(((trifluoromethyl)sulfon yl)oxy) quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine -l-carboxylate (431A-4)

To a solution of 5-(l-aminocyclopropyl)-2-methylquinolin-7-yl trifluoromethanesulfonate (850 mg, 2.45 mmol 1.0 eq) and (S)-5-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-2- methylbenzoic acid (789 mg, 2.45 mmol, 1.0 eq) in DMF (20 mL) were added DIEA (952 mg, 7.36 mmol, 1.28 mL, 3.0 eq) and HATU (2.33 g, 6.14 mmol, 2.5 eq). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (50 mL) and extracted with EtOAc (30 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/0. /c/V-Butyl (8)- 2-((4-methyl-3-((l-(2-methyl-7-(((trifluoromethyl)sulfonyl)o xy)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl) azetidine- 1 -carboxylate (1.30 g, 2.00 mmol, 82% yield) was obtained as a yellow gum. M + H ⁺ = 650.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.20 (s, 1H), 9.01 (d, J= 8.7 Hz, 1H), 7.95 (d, J= 2.4 Hz, 1H), 7.80 (d, J= 2.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.05 (d, J= 8.4 Hz, 1H), 6.89 (dd, J= 2.7, 8.3 Hz, 1H), 6.68 (d, J= 2.6 Hz, 1H), 4.44 - 4.32 (m, 1H), 4.15 (dd, J = 4.8, 10.3 Hz, 1H), 4.01 - 3.96 (m, 1H), 3.74 (br d, J= 5.7 Hz, 2H), 2.70 (s, 3H), 2.30 - 2.24 (m, 1H), 2.10 - 2.03 (m, 1H), 1.94 (s, 3H), 1.42 - 1.26 (m, 13H).

Step 4: tert-Butyl (5)-2-((4-methyl-3-((l-(2-methyl-7-(3,3,3-trifluoropropyl)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (431A-5)

To a solution of Zc/V-butyl (5)-2-((4-methyl-3-((l-(2-methyl-7-(((trifluoromethyl) sulfonyl)oxy)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)met hyl)azetidine-l-carboxylate (150 mg, 231 pmol, 1.0 eq) and (3,3,3-trifhioropropyl)zinc(II) iodide (1 M, 693 pL, 3.0 eq) in DMA (8.0 mL) were added Pd(C6HsCN)2C12 (4.43 mg, 11.5 pmol, 0.05 eq) and MePhos (8.42 mg, 23.1 pmol, 0.1 eq). The mixture was stirred at 60 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert- Butyl (5)-2-((4-methyl-3-((l-(2-methyl-7-(3,3,3-trifluoropropyl)qu inolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (120 mg, 200 pmol) was obtained as a brown oil. M + H ⁺ = 598.3 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.06 (s, 1H), 8.92 (d, J = 8.8 Hz, 1H), 7.72 (d, J= 4.0 Hz, 2H), 7.42 (d, J= 8.6 Hz, 1H), 7.04 (d, J= 8.5 Hz, 1H), 6.87 (dd, J= 2.5, 8.4 Hz, 1H), 6.64 (d, J= 2.5 Hz, 1H), 4.43 - 4.33 (m, 1H), 4.14 (dd, J= 4.7, 9.9 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.78 - 3.67 (m, 2H), 3.06 - 2.99 (m, 2H), 2.73 - 2.68 (m, 2H), 2.30 - 2.22 (m, 1H), 2.12 - 2.04 (m, 1H), 1.36 - 1.27 (m, 11H), 1.20 (br d, J= 4.1 Hz, 2H).

Step 5: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(2-methyl-7-(3,3 ,3-trifluoropropyl) quinolin-5-yl)cyclopropyl)benzamide (431A-6)

To a solution of tert-butyl (8)-2-((4-methyl-3-((l-(2-methyl-7-(3,3,3-trifluoropropyl)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (110 mg, 184 pmol, 1.0 eq) in DCM (5.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.0 mL, 73.4 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 20 °C to give the crude (8)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(2-methyl-7-(3,3 ,3- trifluoro propyl)quinolin -5-yl)cyclopropyl)benzamide (110 mg, 180 pmol, TFA salt) as a brown oil. M + H ⁺ = 498.2 (LCMS).

Step 6: (5)-2-Methyl-/V-(l-(2-methyl-7-(3,3,3-trifluoropropyl)quinol in-5-yl)cyclopropyl)- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 815)

To a solution of (8)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(2-methyl-7-(3,3 ,3- trifluoropropyl) quinolin-5-yl)cyclopropyl)benzamide (110 mg, 180 pmol, 1.0 eq, TFA salt) in MeOH (5.0 mL) was added TEA (0.1 mL), followed by formaldehyde (110 mg, 1.36 mmol, 101 pL, 37% purity in water, 7.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (33.9 mg, 540 prnol, 3.0 eq) was added. The reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was diluted with saturated aqueous NaHCOs (100 pL) and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (S)-2- Methyl-A-(l-(2-methyl-7-(3,3,3-trifluoropropyl)quinolin-5-yl )cyclopropyl)-5-((l- methylazetidin-2-yl)methoxy)benzamide (50.1 mg, 97.2 pmol, 54% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 512.2 (LCMS); 'H NMR (400 MHz, DMSO ) 6 11.50 - 11.21 (m, 1H), 9.74 - 9.61 (m, 1H), 9.45 - 9.33 (m, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 8.02 (br d, J = 8.8 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.98 - 6.89 (m, 1H), 6.84 - 6.73 (m, 1H), 4.70- 4.55 (m, 1H), 4.47 (dd, J= 8.5, 11.0 Hz, 1H), 4.34 - 4.19 (m, 1H), 4.02 - 3.93 (m, 1H), 3.90 - 3.81 (m, 1H), 3.19 - 3.12 (m, 2H), 2.99 (s, 3H), 2.83 - 2.67 (m, 5H), 2.41 - 2.24 (m, 2H), 1.97 (s, 3H), 1.43 (br s, 2H), 1.32 (br s, 2H).

Example 432: (5)-/V-(l-(7-Cyclopentylquinolin-5-yl)cyclopropyl)-2-methyl- 5-((l-methyl azetidin-2-yl)methoxy)benzamide (Compound 648)

Step 1: (5)-/V-(l-(7-Cyclopentylquinolin-5-yl)cyclopropyl)-2-methyl- 5-((l-methylazetidin

-2-yl)methoxy)benzamide (Compound 648)

To a solution of (5)-7V-(l-(7-(cyclopent-l-en-l-yl)quinolin-5-yl)cyclopropyl) -2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (90.0 mg, 192 pmol, 1.0 eq) in EtOH (10 mL) was added 10% palladium on carbon (90.0 mg) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The resulting mixture was stirred at 20 °C for 16 h under a H2 (15 psi) atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The suspension was filtered through a pad of Celite and the pad was washed with EtOH (5.0 mL x 3). The combined filtrates were concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(7- Cyclopentylquinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methyla zetidin-2-yl)methoxy) benzamide (3.00 mg, 5.99 pmol, 3% yield, HC1 salt) was obtained as a white solid. M + H ⁺ = 570.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 5 10.12 - 9.95 (m, 1H), 9.16 - 9.12 (m, 1H), 9.05 - 8.88 (m, 1H), 7.89 (s, 1H), 7.85 - 7.80 (m, 1H), 7.73 - 7.60 (m, 1H), 7.13 - 7.05 (m, 1H), 6.98 - 6.86 (m, 1H), 6.68 (s, 1H), 4.78 - 4.44 (m, 1H), 4.24 (br d, J= 7.7 Hz, 2H), 4.07 - 3.92 (m, 1H), 3.91 - 3.70 (m, 1H), 2.84 - 2.82 (m, 2H), 2.64 - 2.59 (m, 2H), 2.16 - 2.11 (m, 2H), 2.09 - 2.07 (m, 2H), 2.00 - 1.96 (m, 3H), 1.88 - 1.81 (m, 2H), 1.75 - 1.64 (m, 4H), 1.43

- 1.33 (m, 2H), 1.24 (br s, 2H).

Example 433: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(pyrr olidin-l- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 683)

Compound 683 Step 1: tert-Butyl (5)-2-((4-methyl-3-((l-(7-(pyrrolidin-l-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (433A-1)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (100 mg, 157 pmol, 1.0 eq) and pyrrolidine (13.4 mg, 189 pmol, 15.8 pL, 1.2 eq) in 2-methylbutan-2-ol (2.0 mL) were added CS2CO3 (103 mg, 315 pmol, 2.0 eq) and XPhos Pd G3 (66.6 mg, 78.7 pmol, 0.5 eq) at 20 °C. The mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl (5)-2-((4-methyl-3-((l-(7-(pyrrolidin-l- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l-carboxylate (150 mg, 75.5 pmol, 48% yield) was obtained as a yellow oil. M + H ⁺ = 557.4 (LCMS).

Step 2: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(pyrrolidin-l-y l)quinolin-5- yl)cyclopropyl)benzamide (433A-2)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(pyrrolidin-l-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (150 mg, 269 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (1.54 g, 13.5 mmol, 1.0 mL, 50 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give (5)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(5-(pyrrolidi n-l- ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (170 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 457.3 (LCMS).

Step 3: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(py rrolidin-l- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 683)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(5-(pyrrolidi n-l- ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (150 mg, 328 pmol, 1.0 eq) in MeOH (2.0 mL) were added HO Ac (1.85 mg, 30.0 pmol, 1.76 pL, 0.1 eq) and formaldehyde (37.4 mg, 461 pmol, 34.4 pL, 37% purity in H2O, 1.5 eq) at 20 °C for 1 h.Then NaBHsCN (48.3 mg, 768 pmol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC ((Phenomenex Gemini C18 column (150 x 40 mm, 10 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile)). (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)- 7V-(l-(7-(pyrrolidin-l-yl)quinolin-5-yl)cyclopropyl)benzamid e(3.00 mg, 6.37 pmol, 2% yield) was obtained as a white solid. M + H ⁺ = 471.3 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 8 9.07 - 9.00 (m, 1H), 8.75 - 8.83 (m, 1H), 8.64 (m, 1H), 7.38 (m, 1H), 7.15 (m, 1H), 6.98 - 7.06 (m, 1H), 6.83 (m, 1H), 6.75 (m, 1H), 6.59 (m, 1H), 3.82 - 3.90 (m, 2H), 3.40 (m, 4H), 3.17 - 3.25 (m, 3H), 2.69 - 2.76 (m, 1H), 2.17 - 2.24 (m, 3H), 1.91 - 2.05 (m, 8H), 1.80 - 1.89 (m, 1H), 1.29 - 1.38 (m, 2H), 1.12 - 1.21 (m, 2H). Example 434: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(7-(thiophen-2-yl)q uinolin-5- yl)cyclopropyl)benzamide (Compound 630)

Compound 630 Step 1: 5-(l-(5-(2-((tert-Butoxycarbonyl)(methyl)amino)ethoxy)-2-met hylbenzamido)cy clopropyl)quinolin-7-yl trifluoromethanesulfonate (434A-1)

To a solution of 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 602 pmol, 1.0 eq) and 5-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylben zoic acid (186 mg, 602 pmol, 1.0 eq) in DMF (5.0 mL) were added DIEA (233 mg, 1.81 mmol, 315 pL, 3.0 eq) and HATU (572 mg, 1.50 mmol, 2.5 eq). The mixture was stirred at 20 °C for 14 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured intio H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. 5-( l -(5-(2-((/c/7-Butoxycarbonyl) (methyl)amino)ethoxy)-2-methylbenzamido)cyclopropyl)quinolin -7-yl trifluoromethane sulfonate (260 mg, 417 pmol, 69% yield) was obtained as a brown oil. M + H ⁺ = 624.2 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.22 (s, 1H), 9.14 (br d, J= 8.6 Hz, 1H), 9.08 - 9.01 (m, 1H), 8.08 (d, J= 2.5 Hz, 1H), 7.88 (d, J= 2.5 Hz, 1H), 7.73 (dd, J= 4.1, 8.6 Hz, 1H), 7.04 (br d, J= 8.4 Hz, 1H), 6.85 (dd, J = 2.5, 8.4 Hz, 1H), 6.63 (br s, 1H), 3.98 (br t, J = 5.8 Hz, 2H), 3.46 (br t, J= 5.6 Hz, 2H), 2.86 -2.74 (m, 3H), 1.93 (s, 3H), 1.44 - 1.23 (m, 13H).

Step 2: tert-Butyl methyl(2-(4-methyl-3-((l-(7-(thiophen-2-yl)quinolin-5-yl)cyc lopropyl) carbamoyl)phenoxy)ethyl)carbamate (434A-2)

To a solution of 5-( l -(5-(2-((/c77-butoxycarbonyl)(methyl)amino)ethoxy)-2- methylbenzamido)cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 320.70 pmol, 1.0 eq) and thiophen-2-ylboronic acid (82.1 mg, 641 pmol, 2.0 eq) in DMSO (5.0 mL) were added KOAc (94.4 mg, 962 pmol, 3.0 eq), Pd(OAc)2 (14.4 mg, 64.1 pmol, 0.2 eq) and cataCxium A (46.0 mg, 128 pmol, 0.4 eq). The mixture was degassed and purged with N2 three times, and the mixture was stirred at 80 °C for 15 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 7/3. tert- Butyl methyl(2-(4-methyl-3-((l-(7-(thiophen-2-yl)quinolin-5-yl)cyc lopropyl)carbamoyl) phenoxy)ethyl)carbamate (180 mg, 323 pmol, crude) was obtained as a brown oil. M + H ⁺ = 558.3 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.15 (s, 1H), 9.04 (br d, J= 8.5 Hz, 1H), 8.92 (br d, J = 3.4 Hz, 1H), 8.15 (s, 2H), 7.78 (d, J= 3.3 Hz, 1H), 7.68 (d, J = 5.0 Hz, 1H), 7.56 (dd, J= 4.1, 8.5 Hz, 1H), 7.31 - 7.17 (m, 1H), 7.04 (br d, J= 8.3 Hz, 1H), 6.84 (dd, J = 2.3, 8.3 Hz, 1H), 6.61 (br s, 1H), 4.00 - 3.91 (m, 2H), 3.46 (br t, J= 5.5 Hz, 2H), 2.81 (br d, J = 8.0 Hz, 3H), 1.96 (s, 3H), 1.49 - 1.25 (m, 13H). Step 3: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(7-(thiophen-2-yl)q uinolin-5-yl)cyclop ropyl)benzamide (Compound 630)

To a solution of tert-butyl methyl(2-(4-methyl-3-((l-(7-(thiophen-2-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)ethyl)carbamate (180 mg, 323 pmol, 1.0 eq) in EtOH (2.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 40% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). 2-Methyl-5-(2-(methylamino)ethoxy)-7V-(l-(7-(thiophen-2-yl)q uinolin-5- yl)cyclopropyl)benzamide (70.1 mg, 141 pmol, 44% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 458.1 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.46 (br d, J= 8.4 Hz, 1H), 9.33 (s, 1H), 9.15 (d, J = 4.0 Hz, 1H), 8.97 (br d, J= 3.5 Hz, 2H), 8.33 (d, J= 5.8 Hz, 2H), 7.94 - 7.84 (m, 2H), 7.79 (d, J = 4.5 Hz, 1H), 7.29 (dd, J = 3.8, 5.0 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.4 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 4.17 (t, J= 5.0 Hz, 2H), 3.26 - 3.21 (m, 2H), 2.59 - 2.55 (m, 3H), 1.98 (s, 3H), 1.44 (br s, 2H), 1.38 (br s, 2H).

Example 435: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(thiophen-2-yl) quinolin-5- yl)cyclopropyl)benzamide (Compound 608)

435A-1 Compound 608

Step 1: tert- Butyl (5)-2-((4-methyl-3-((l-(7-(thiophen-2-yl)quinolin-5-yl)cyclo propyl)carb amoyl)phenoxy)methyl)azetidine-l-carboxylate (435A-1)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (200 mg, 315 pmol, 1.0 eq) and thiophen-2-ylboronic acid (80.5 mg, 629 pmol, 2.0 eq) in DMSO (5.0 mL) were added KOAc (92.6 mg, 944 pmol, 3.0 eq), Pd(0Ac)2 (14.1 mg, 62.9 pmol, 0.2 eq) and cataCxium A (45.1 mg, 126 pmol, 0.4 eq). The resulting mixture was stirred at 80 °C for 13 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl fS')-2-((4- methyl-3-((l-(7-(thiophen-2-yl)quinolin-5-yl)cyclopropyl)car bamoyl)phenoxy) methyl)azetidine-l -carboxylate (400 mg) as a brown oil, which was used in the next step without any further purification. M + H ⁺ = 570.3 (LCMS).

Step 2: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(thiophen-2-yl) quinolin-5-yl) cyclopropyl)benzamide (Compound 608)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(thiophen-2-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (150 mg, 263 pmol, 1.0 eq) in DCM (1.5 mL) was added TFA (540 mg, 4.74 mmol, 351 pL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give a residue which was purified by preparative HPLC (Phenom enex Luna Cl 8 column (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-A-(l-(7- (thiophen-2-yl)quinolin-5-yl) cyclopropyl)benzamide (74.3 mg, 127 pmol, 48% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ =470.1 (LCMS); ^T H NMR (400 MHz, DMSO-tL) 8 9.18 (s, 1H), 9.09 (d, J = 8.8 Hz, 1H), 8.96 (dd, J = 1.4, 4.1 Hz, 1H), 8.89 - 8.66 (m, 2H), 8.18 (d, J= 2.0 Hz, 2H), 7.86 - 7.77 (m, 1H), 7.71 (d, J = 5.1 Hz, 1H), 7.62 (dd, J= 4.3, 8.5 Hz, 1H), 7.25 (dd, J= 3.8, 4.9 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.3 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 4.70 - 4.68 (m, 1H), 4.68 - 4.62 (m, 1H), 4.23 (dd, J= 7.1, 11.1 Hz, 1H), 4.16 - 4.10 (m, 1H), 3.95 - 3.80 (m, 2H), 2.45 - 2.27 (m, 2H), 1.98 (s, 3H), 1.40 (br s, 2H), 1.33 (br s, 2H). Example 436: (S)-\-( l-(7-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-5-yl)cycloprop yl)-

2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 753)

Compound 753

Step 1: (5)-/V-(l-(7-(5-Formylthiophen-2-yl)quinolin-5-yl)cyclopropy l)-2-methyl-5-((l- meth ylazetidin-2-yl)methoxy)benzamide (436A-1)

A mixture of (5)-5-(l-(2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do)cyclopropyl) quinolin-7-yltrifluoromethanesulfonate (250 mg, 455 pmol, 1.0 eq), 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)thiophene-2-carbaldehyde (142 mg, 910 pmol, 2.0 eq), KOAc (134 mg, 1.36 mmol, 3.0 eq), cataCxium A (32.6 mg, 91.0 pmol, 0.2 eq) and Pd(OAc)2 (10.2 mg, 45.5 pmol, 0.1 eq) in DMSO (5.0 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL), and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/5. (5)-7V-(l-(7-(5-Formylthiophen-2- yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methylazetidin- 2-yl)methoxy)benzamide (230 mg, 450 pmol, 99% yield) was obtained as a yellow solid. M + H ⁺ = 512.3 (LCMS). Step 2: (5)-A-(l-(7-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-5-yl)cy clopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 753)

To a stirred solution of (5)-A-(l-(7-(5-formylthiophen-2-yl)quinolin-5-yl)cyclopropyl )-2- methyl-5-((l-methylazeti din-2 -yl)methoxy)benzamide (40.0 mg, 78.2 pmol, 1.0 eq) in MeOH (2.0 mL) was added NaBHj (5.92 mg, 156 pmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (2.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (S)-7V-(1- (7-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl )-2-methyl-5-((l- methylazetidin-2-yl) methoxy )benzamide (19.0 mg, 33.1 pmol, 42% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 514.3 (LCMS); 'H NMR (400 MHz, DMSO ) 8 10.50 - 10.21 (m, 1H), 9.45 - 9.20 (m, 2H), 9.13 - 8.96 (m, 1H), 8.32 - 8.17 (m, 2H), 7.85 - 7.63 (m, 2H), 7.15 - 7.03 (m, 2H), 7.00 - 6.91 (m, 1H), 6.92 - 6.89 (m, 1H), 6.75 - 6.71 (m, 1H), 4.74 - 4.68 (m, 2H), 4.64 - 4.61 (m, 1H), 4.65 - 4.58 (m, 1H), 4.32 - 4.17 (m, 2H), 4.06 - 3.98 (m, 1H), 3.88 - 3.82 (m, 1H), 2.83 - 2.75 (m, 3H), 2.36 - 2.28 (m, 2H), 2.01 - 1.94 (m, 4H), 1.47 - 1.34 (m, 4H), 1.29 - 1.21 (m, 2H).

Example 437: 2-Methyl-5-((( )-l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5-(l- (pyrrolidin-l-yl)ethyl)thiophen-2-yl)quinolin-5-yl)cycloprop yl)benzamide (Compound 780)

Compound 780

Step 1: tert- Butyl (5)-2-((3-((l-(7-(5-acetylthiophen-2-yl)quinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (437A-1)

A mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (100 mg, 157 pmol, 1.0 eq), (5-acetyl-2-thienyl)boronic acid (53.5 mg, 314 pmol, 2.0 eq), Pd(OAc)2 (10.6 mg, 47.2 pmol, 0.3 eq), KO Ac (46.3 mg, 471 pmol, 3.0 eq) and bis(l-adamantyl)- butyl-phosphane (11.3 mg, 31.5 pmol, 0.2 eq) in DMSO (2.0 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was consumed, and the desired mass was detected. The mixture was treated with water (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl 2-((3 -(methoxy carbonyl)-4-methylphenyl)ethynyl)azeti dine- 1- carboxylate (130 mg) was obtained as a colorless oil. M + H ⁺ = 612.3 (LCMS). Step 2: tert-Butyl (25)-2-((4-methyl-3-((l-(7-(5-(l-(pyrrolidin-l-yl)ethyl)thio phen-2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l-carboxylate (437A- 2)

To a solution of tert-butyl 2-((3-(m ethoxy carbonyl)-4-methylphenyl)ethynyl)azeti dine- 1- carboxylate (130 mg, 212 pmol, 1.0 eq) in EtOH (1.0 mL) were added tetraisopropoxytitanium (603 mg, 2.13 mmol, 627 pL, 10 eq) and pyrrolidine (75.6 mg, 1.06 mmol, 88.7 pL, 5.0 eq). The mixture was stirred at 40 °C for 12 h. The reaction mixture was allowed to cool to room temperature, then NaBEU (120 mg, 3.19 mmol, 15 eq) was added to the mixture. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 30% - 60% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). tert-Butyl (25)-2-((4- methyl-3-((l-(7-(5-(l-(pyrrolidin-l-yl)ethyl)thiophen-2-yl)q uinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (20.0 mg, 22.2 pmol, 10% yield, TFA salt) was obtained as a white solid. M + H ⁺ = 667.5 (LCMS).

Step 3: 5-(((5)-Azetidin-2-yl)methoxy)-2-methyl-/V-(l-(7-(5-(l-(pyrr olidin-l- yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (437A-3)

To a solution of tert-butyl (25)-2-((4-methyl-3-((l-(7-(5-(l-(pyrrolidin-l-yl)ethyl)thio phen-2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l -carboxylate (20.0 mg,

29.9 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (86.6 mg, 759 pmol, 56.3 pL, 25 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product 5-(((5)-azetidin-2-yl)methoxy)- 2-methyl-7V-(l-(7-(5-(l-(pyrrolidin-l-yl)ethyl)thiophen-2-yl )quinolin-5- yl)cyclopropyl)benzamide (20.0 mg, TFA salt) as a colorless oil. M - 100 + H ⁺ = 567.3 (LCMS).

Step 4: 2-Methyl-5-(((5)-l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5- (l-(pyrrolidin-l- yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 780)

To a solution of 5-(((5)-azetidin-2-yl)methoxy)-2-methyl-7V-(l-(7-(5-(l-(pyrr olidin-l- yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (20.0 mg, 35.3 pmol, 1.0 eq) in MeOH (2.0 mL) were added HOAc (211 pg, 3.53 pmol, 0.1 eq) and formaldehyde (4.30 mg,

52.9 pmol, 3.94 pL, 37% purity in FEO, 1.5 eq) at 20 °C for 1 h. Then NaBEECN (5.54 mg, 88.2 pmol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 °C for 1 h. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Luna C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% HC1, mobile phase B: acetonitrile). 2-Methyl-5-(((5)-l-methylazetidin-2-yl)methoxy)-A-(l-(7-(5-( l-(pyrrolidin-l- yl)ethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (8.20 mg, 12.5 pmol, 35% yield, 2 HC1 salt) was obtained as a white solid. M + H ⁺ = 581.3 (LCMS); NMR (400 MHz, DMSO-t/e) 8 11.55 - 11.40 (m, 1H), 10.89 - 10.73 (m, 1H), 9.51 - 9.28 (m, 2H), 9.13 (m, 1H), 8.43 - 8.24 (m, 2H), 7.93 - 7.82 (m, 2H), 7.56 (m, 1H), 7.14 - 7.06 (m, 1H), 6.96 - 6.87 (m, 1H), 6.74 (m, 1H), 4.96 - 4.84 (m, 1H), 4.71 - 4.57 (m, 1H), 4.38 (m, 1H), 4.21 (m, 1H), 4.03

- 3.94 (m, 2H), 3.90 - 3.84 (m, 2H), 3.00 - 3.07 (m, 4H), 2.80 (m, 3H), 2.67 (m, 1H), 2.37 - 2.25 (m, 2H), 1.96 (m, 4H), 1.78 (m, 3H), 1.50 - 1.30 (m, 4H).

Example 438: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5-(p yrrolidin-l- ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 669)

Compound 669

Step 1: tert- Butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (438A-1)

A mixture of 5-(l-aminocyclopropyl)quinolin-7-yl trifluoromethanesulfonate (200 mg, 314 pmol, 1.0 eq), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-c arbaldehyde (58.9 mg, 377 pmol, 1.2 eq), di(l-adamantyl)-N-butylphosphine hydroiodide (22.6 mg, 63.0 pmol, 0.2 eq), Pd(OAc)2 (7.10 mg, 31.0 pmol, 0.1 eq) and KOAc (93.0 mg, 94.0 pmol, 3.0 eq) in DMSO (3.0 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The reaction was allowed to cool to room temperature. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over TsfeSOy filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert- Butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (150 mg, 231 pmol, 74% yield) was obtained as a white solid. M + H ⁺ = 598.4 (LCMS).

Step 2: tert-Butyl (5)-2-((4-methyl-3-((l-(7-(5-(pyrrolidin-l-ylmethyl)thiophen -2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l-carboxylate (438A- 2)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carbox ylate (150 mg, 251 pmol, 1.0 eq) in MeOH (2.0 mL) was added HO Ac (1.51 mg, 25.0 pmol, 1.44 pL, 0.1 eq), pyrrolidine (26.8 mg, 376 pmol, 31.0 pL, 1.5 eq) at 20 °C for 1 h. Then NaBH ₃ CN (39.4 mg, 627 pmol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was treated with water (10 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 0/1. tert- Butyl (5)-2-((4-methyl-3-((l-(7-(5-(pyrrolidin-l-ylmethyl)thiophen -2-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (160 mg, 237 pmol, 95% yield) was obtained as a yellow oil. M + H ⁺ = 653.4 (LCMS).

Step 3: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-(pyrrolidi n-l- ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide(4 38A-3)

To a solution of /c/7-butyl (5)-2-((4-methyl-3-((l-(7-(5-(pyrrolidin-l-ylmethyl)thiophen -2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l-carboxylate (160 mg, 245 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (708 mg, 6.21 mmol, 459 pL, 25 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product (5)-5-(azeti din-2 -ylmethoxy)-2-methyl-A-(l-(7-(5- (pyrrolidin-l-ylmethyl)thiophen-2-yl)quinolin-5-yl)cycloprop yl)benzamide (170 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 553.4 (LCMS).

Step 4: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5- (pyrrolidin-l- ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 669)

To a solution of (5)-5-(azeti din-2 -ylmethoxy)-2-methyl-A-(l-(7-(5-(pyrrolidin-l- ylmethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (170 mg, 307 pmol, 1.0 eq) in MeOH (2.0 mL) were added HO Ac (1.85 mg, 30.0 pmol, 1.76 pL, 0.1 eq) and formaldehyde (37.4 mg, 461 pmol, 34.4 pL, 37% purity in H2O, 1.5 eq) at 20 °C for 1 h .Then NaBH ₃ CN (48.3 mg, 768 pmol, 2.5 eq) was added to the mixture. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(l-(7-(5- (pyrrolidin-l-ylmethyl)thiophen-2-yl)quinolin-5-yl)cycloprop yl)benzamide (64.5 mg, 94.8 pmol, 31% yield, 2 HC1 salt) was obtained as a yellow solid. M + H ⁺ = 567.4 (LCMS); 'H NMR (400 MHz, DMSO ) 6 11.26 - 11.11 (m, 1H), 11.07 - 10.87 (m, 1H), 9.60 - 9.41 (m, 1H), 9.36 (m, 1H), 9.16 (m, 1H), 8.40 (m, 1H), 8.32 (m, 1H), 7.94 - 7.88 (m, 1H), 7.87 (m, 1H), 7.54 (m, 1H), 7.09 (m, 1H), 6.92 (m, 1H), 6.75 (m, 1H), 4.66 (m, 3H), 4.40 (m, 1H), 4.25 - 4.18 (m, 1H), 4.05 - 3.93 (m, 1H), 3.89 - 3.77 (m, 1H), 3.50 - 3.38 (m, 2H), 3.18 - 3.06 (m,

2H), 2.80 (m, 3H), 2.37 - 2.24 (m, 2H), 2.03 (m, 2H), 1.97 (m, 3H), 1.94 - 1.87 (m, 2H), 1.48 - 1.43 (m, 2H), 1.40 - 1.35 (m, 2H).

Example 439: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5-(p yrrolidine- l-carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 767)

Compound 767

Step 1: tert-Butyl (5)-2-((3-((l-(7-(5-(methoxycarbonyl)thiophen-2-yl)quinolin- 5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (439A-1)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy) methyl)azetidine-l -carboxylate (120 mg, 188 pmol, 1.0 eq) and (5-(methoxycarbonyl)thiophen-2-yl)boronic acid (70.2 mg, 377 pmol, 2.0 eq) in DMSO (2.0 mL) were added Pd(OAc)2 (12.7 mg, 56.6 pmol, 0.30 eq), KOAc (55.6 mg, 566 prnol, 3.0 eq) and bis(l-adamantyl)-butyl-phosphane (13.5 mg, 37.7 pmol, 0.2 eq) at 20 °C and then the mixture was stirred at 80 °C for 12 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL), and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl (S)-2-((3-((l-(7-(5- (methoxycarbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl) carbamoyl)-4-methylphenoxy) methyl)azetidine-l -carboxylate (140 mg) was obtained as a yellow liquid. M + H ⁺ = 628.3 (LCMS).

Step 2: (5)-5-(5-(l-(5-((l-(tert-Butoxycarbonyl)azetidin-2-yl)methox y)-2- methylbenzamido)cyclopropyl)quinolin-7-yl)thiophene-2-carbox ylic acid (439A-2)

To a solution of tert-butyl (5)-2-((3-((l-(7-(5-(methoxycarbonyl)thiophen-2-yl)quinolin- 5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (120 mg, 191 pmol, 1.0 eq) in a mixture of H2O (1.0 mL), THF (1.0 mL) and MeOH (1.0 mL) was added LiOH.JLO (80.2 mg, 1.91 mmol, 10 eq). The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum to give a residue, which was diluted with H2O (5.0 mL). The aqueous layer was adjusted to pH 6 with HC1 (1 M aqueous), then extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (5)-5-(5-(l-(5-((l-(tert-butoxycarbonyl)azetidin-2- yl)methoxy)-2-methylbenzamido)cyclopropyl)quinolin-7-yl)thio phene-2-carboxylic acid (92.0 mg) as a white solid. M + H ⁺ = 614.3 (LCMS).

Step 3: tert-Butyl (5)-2-((4-methyl-3-((l-(7-(5-(pyrrolidine-l-carbonyl)thiophe n-2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l-carboxylate (439A- 3)

To a solution of (5)-5-(5-(l-(5-((l-(tert-butoxycarbonyl)azetidin-2-yl)methox y)-2- methylbenzamido)cyclopropyl)quinolin-7-yl)thiophene-2-carbox ylic acid (92.0 mg, 149 pmol, 1.0 eq) in DMF (5.0 mL) were added HATU (114 mg, 299 pmol, 2.0 eq) and DIEA (58.1 mg, 449 pmol, 78.33 pL, 3.0 eq). The reaction mixture was stirred at 20 °C for 20 min. Then pyrrolidine (10.6 mg, 149 pmol, 12.5 pL, 1.0 eq) was added and the mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into H2O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give tert-butyl (5)-2-((4-methyl-3-((l-(7-(5-(pyrrolidine-l-carbonyl)thiophe n-2-yl)quinolin-5- yl)cyclopropyl)carbamoyl) phenoxy)methyl)azetidine-l -carboxylate (99.6 mg 149 pmol, 99% yield) as a brown gum. M + H ⁺ = 667.4 (LCMS).

Step 4: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-(pyrrolidi ne-l- carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (439A-4)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(5-(pyrrolidine-l-carbonyl)thiophe n-2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine- 1 -carboxylate (99.6 mg, 149 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product (5)-5-(azetidin-2- ylmethoxy)-2-methyl-A-(l -(7-(5-(pyrrolidine-l -carbonyl)thi ophen-2 -yl)quinolin-5- yl)cyclopropyl)benzamide (70.0 mg) as a yellow gum. M + H ⁺ = 567.3 (LCMS). Step 5: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5- (pyrrolidine-l- carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 767)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-2-methyl-A-(l-(7-(5-(pyrrolidin e-l- carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (70.0 mg, 123 pmol, 1.0 eq) in MeOH (2.0 mL) were added HO Ac (1.85 mg, 30.0 pmol, 1.76 pL, 0.1 eq) and formaldehyde (20.0 mg, 247 pmol, 18.3 pL, 37% purity in H2O, 2.0 eq) at 20 °C. The mixture was stirred at 20 °C for 1 h, then NaBHiCN (48.3 mg, 768 pmol, 2.5 eq) was added. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: gradient: 10% - 40% B over 8 min; mobile phase A: 0.04% HC1, mobile phase B: acetonitrile). (5 -2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-7V-(l-(7-(5-(py rrolidine-l- carbonyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)benzamide (42.5 mg, 63.7 pmol, 51% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 581.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.22 (s, 1H), 9.15 (br d, J= 8.9 Hz, 1H), 9.00 (br d, J= 3.0 Hz, 1H), 8.27 (s, 1H), 8.22 (d, J= 1.6 Hz, 1H), 7.82 (d, J= 3.9 Hz, 1H), 7.75 - 7.63 (m, 2H), 7.10 (d, J= 8.6 Hz, 1H), 6.98 - 6.87 (m, 1H), 6.72 (d, J= 2.9 Hz, 1H), 4.66 - 4.51 (m, 1H), 4.31 - 4.18 (m, 2H), 4.06 - 3.95 (m, 1H), 3.90 - 3.77 (m, 4H), 2.82 (d, J= 5.0 Hz, 3H), 2.72 - 2.63 (m, 1H), 2.42 - 2.23 (m, 2H), 1.95 (s, 5H), 1.91 - 1.83 (m, 2H), 1.46 - 1.26 (m, 4H).

Example 440: ( )-/V-(l-(7-(4-Chloro-2-methylthiazol-5-yl)quinolin-5-yl)cycl opropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 812)

Compound 812

Step 1: tert-Butyl (5)-2-((4-methyl-3-((l-(7-(2-methylthiazol-5-yl)quinolin-5-y l) cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxylate (440A-1)

To a stirred solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl) sulfonyl)oxy)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy) methyl) azetidine- 1 -carboxylate (200 mg, 315 pmol, 1.0 eq) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)thiazole (106 mg, 472 pmol, 1.5 eq) in a mixture of dioxane (8.0 mL) and H2O (0.8 mL) were added ISfeCCh (76.7 mg, 724 pmol, 2.3 eq) and Pd(dppf)C12.CH2C12 (30.8 mg, 37.8 pmol, 0.12 eq) in one portion. The mixture was degassed and purged with N2 three times and then stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/1. tert-Butyl (8)-2-((4-methyl-3-((l-(7-(2-methylthiazol- 5-yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azet idine-l-carboxylate (260 mg, 444 pmol, 71% yield) was obtained as a yellow solid. M + H ⁺ = 585.4 (LCMS); ^T H NMR (400 MHz, CDCL) 6 9.25 - 9.15 (m, 1H), 8.99 - 8.91 (m, 1H), 8.21 (br d, J= 14.6 Hz, 2H), 8.07 (s, 1H), 7.58 - 7.49 (m, 1H), 7.02 (s, 1H), 6.85 (s, 1H), 6.77 (br s, 1H), 4.47 - 4.36 (m, 1H), 4.24

- 4.17 (m, 1H), 4.05 - 3.99 (m, 1H), 3.90 - 3.81 (m, 2H), 2.78 (s, 3H), 2.35 - 2.22 (m, 2H), 2.17 (s, 3H), 1.32 (br s, 13H).

Step 2: tert-Butyl (5)-2-((3-((l-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-y l) cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l-ca rboxylate (440A-2)

To a mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(2-methylthiazol-5-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (210 mg, 360 pmol, 1.0 eq) in acetonitrile (9.0 mL) was added NCS (57.0 mg, 432 pmol, 1.2 eq). The mixture was stirred at 60 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/EtOAc = 2/1, R/= 0.4). tert- Butyl (5)-2-((3-((l-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-y l) cyclopropyl)carbamoyl)-

4-methylphenoxy)methyl)azetidine-l -carboxylate (40.0 mg, 64.6 pmol, 18% yield) was obtained as a white solid. M + H ⁺ = 619.4 (LCMS); 'H NMR (400 MHz,CDCh) 5 9.19 - 9.11 (m, 1H), 8.97 (br d, J= 2.9 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J= 1.5 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.05 - 7.01 (m, 1H), 6.86 - 6.82 (m, 1H), 6.80 - 6.75 (m, 1H), 4.49 - 4.38 (m, 1H), 4.25

- 4.17 (m, 1H), 4.06 - 3.98 (m, 1H), 3.92 - 3.82 (m, 2H), 2.75 (s, 3H), 2.35 - 2.20 (m, 2H), 2.16 (s, 3H), 1.33 (br s, 13H).

Step 3: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(4-chloro-2-methylthiazo l-5-yl)quinolin-5- yl)cyclopropyl)-2-methylbenzamide (440A-3)

To a solution of tert-butyl (5)-2-((3-((l-(7-(4-chloro-2-methylthiazol-5-yl)quinolin-5-y l) cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l-ca rboxylate (80.0 mg, 130 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (221 mg, 1.04 mmol, 142 pL, 15 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give (5)-5-(azetidin-2-ylmethoxy)-7V-(l-(7-(4-chloro-2-methylthia zol-5-yl)quinolin-

5-yl)cyclopropyl)-2-methylbenzamide (80.0 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 519.3 (LCMS).

Step 4: (S)-\-( l-(7-(4-Chloro-2-iiiethylthiazol-5-yl)qiiiiiolin-5-yl)cyclop ropyl)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 812) To a solution of (5)-5-(azetidin-2-ylmethoxy)-A-(l-(7-(4-chloro-2-methylthiaz ol-5- yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (80.0 mg, 126 pmol, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (100 pL), followed by formaldehyde (7.69 mg, 94.8 pmol, 7.06 pL, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (7.94 mg, 126 pmol, 2.0 eq) was added. The resulting mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-A-(l-(7-(4-Chloro-2- methylthiazol-5-yl)quinolin-5-yl)cy cl opropyl)-2-methyl-5-((l-methylazeti din-2- yl)methoxy)benzamide (30.0 mg, 51.4 pmol, 41% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 533.2 (LCMS); ^X H NMR (400 MHz, DMSO ) 8 9.33 (br d, J= 8.1 Hz, 1H), 9.26 (s, 1H), 9.10 (d, J= 3.4 Hz, 1H), 8.34 (d, J= 0.9 Hz, 1H), 8.21 (d, J= 1.5 Hz, 1H), 7.84 (dd, J= 4.6, 8.6 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.7, 8.4 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.61 (br dd, J = 3.0, 7.3 Hz, 1H), 4.34 - 4.18 (m, 2H), 4.01 (dt, J = 4.5, 9.5 Hz, 1H), 3.86 (q, J= 9.7 Hz, 1H), 2.82 (s, 3H), 2.75 - 2.69 (m, 3H), 2.43 - 2.25 (m, 2H), 1.97 (s, 3H), 1.43 (br s, 2H), 1.30 (br s, 2H).

Example 441: ( )-/V-(l-(8-Chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cycl opropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 814) 2

441 A-1

Compound 814

Step 1: tert-Butyl (5)-2-((3-((l-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (441A-1)

To a mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(2-methylthiazol-5-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (210 mg, 360 pmol, 1.0 eq) in acetonitrile (9.0 mL) was added NCS (57.0 mg, 432 pmol, 1.2 eq). The mixture was stirred at 60 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL), and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCMZEtOAc = 2/1, R/= 0.4). tert- Butyl (5)-2-((3-((l-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5-y l)cyclopropyl)carbamoyl)- 4-methylphenoxy)methyl)azetidine-l -carboxylate (100 mg, 161 pmol, 45% yield) was obtained as a yellow solid. M + H ⁺ = 619.3 (LCMS); ^X HNMR (400 MHz, CDCh) 59.21 - 9.15 (m, 1H), 9.13 - 9.07 (m, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.63 - 7.53 (m, 1H), 7.06 - 6.98 (m, 1H), 6.86 - 6.82 (m, 1H), 6.77 - 6.74 (m, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.16 (m, 1H), 4.05 - 3.99 (m, 1H), 3.91 - 3.82 (m, 2H), 2.80 (s, 3H), 2.16 (s, 3H), 1.45 (br s, 13H).

Step 2: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(8-chloro-7-(2-methylthiazo l-5-yl)quinolin-5- yl)cyclopropyl)-2-methylbenzamide (441A-2)

To a solution of tert-butyl (5)-2-((3-((l-(8-chloro-7-(2-methylthiazol-5-yl)quinolin-5- yl)cyclopropyl)carbamoyl)-4-methylphenoxy)methyl)azetidine-l -carboxylate (140 mg, 226 pmol, 1.0 eq) in DCM (4.0 mL) was added TFA (251 pL). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 20 °C to give (S)-5- (azetidin-2-ylmethoxy)-A-(l-(8-chloro-7-(2-methylthiazol-5-y l)quinolin-5-yl)cyclopropyl)-2- m ethylbenzamide (140 mg, TFA salt) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 519.2 (LCMS).

Step 3: (5)-/V-(l-(8-Chloro-7-(2-methylthiazol-5-yl)quinolin-5-yl)cy clopropyl)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 814)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-A-(l-(8-chloro-7-(2-methylthiaz ol-5- yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (140 mg, 221 pmol, 1.0 eq, TFA salt) in MeOH (4.0 mL) was added TEA (200 pL), followed by formaldehyde (27.0 mg, 332 pmol, 24.9 pL, 37% purity in water, 1.5 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBHiCN (28.0 mg, 442 pmol, 2.0 eq) was added. The reaction mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (20 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (80 X 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 15% - 45% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-A-(l-(8-Chloro-7-(2-methylthiazol-5- yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methylazetidin- 2-yl)methoxy)benzamide (46.4 mg, 81.5 pmol, 37% yield, HC1 salt) was obtained as a green solid. M + H ⁺ = 533.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.27 - 9.18 (m, 1H), 9.12 - 9.02 (m, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.78 (dd, J= 4.2, 8.5 Hz, 1H), 7.08 (d, J= 8.6 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.72 (d, = 2.7 Hz, 1H), 4.63 (dq, J = 2.9, 8.5 Hz, 1H), 4.36 (br dd, J= 8.0, 11.3 Hz, 1H), 4.20 (br dd, J= 3.1, 11.2 Hz, 1H), 3.99 (td, J= 4.8, 9.5 Hz, 1H), 3.89 - 3.85 (m, 1H), 2.82 - 2.66 (m, 6H), 2.39 - 2.25 (m, 2H), 1.96 (s, 3H), 1.40 (br s, 2H), 1.34 (br s, 2H).

Example 442: ( )-2-Methyl-5-((l-(methyl-</3)azetidin-2-yl)methoxy)-/V-(l -(7-(2- methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 782)

Step 1

391A-3

Compound 782

Step 1: tert- Butyl (5)-2-((4-methyl-3-((l-(7-(2-methyloxazol-5-yl)quinolin-5-yl ) cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxylate (442A-1)

To a stirred solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy) quinolin-5-yl)cyclopropyl) carbamoyl) phenoxy )m ethyl) azetidine- 1 -carboxylate (150 mg, 236 pmol, 1.0 eq) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxaz ole (98.7 mg, 472 pmol, 2.0 eq) in a mixture of dioxane (5.0 mL) and H2O (0.5 mL) were added ISfeCCh (57.5 mg, 543 pmol, 2.3 eq) and Pd(dppf)C12.CH2C12 (28.9 mg, 35.4 pmol, 0.2 eq). The mixture was degassed and purged with N2 three times and then stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (20 mL) and extracted with EtOAc (20 mL x 4). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/0, R/= 0.3). tert-Butyl fS')-2-((4- methyl-3-((l-(7-(2-methyloxazol-5-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl) azetidine- 1 -carboxylate (110 mg, 193 pmol, 82% yield) was obtained as a yellow solid. M + H ⁺ = 569.4 (LCMS); (400 MHz, CDCL) 8 9.29 - 9.11 (m, 1H), 9.01 - 8.89 (m, 1H), 8.41 - 8.31 (m, 1H), 8.27 - 8.20 (m, 1H), 7.57 - 7.48 (m, 2H), 7.07 - 7.01 (m, 1H), 6.88 - 6.72 (m, 3H), 4.46 - 4.37 (m, 1H), 4.26 - 4.17 (m, 1H), 4.06 - 4.00 (m, 1H), 3.91 - 3.82 (m, 2H), 2.62 - 2.58 (m, 3H), 2.33 - 2.21 (m, 2H), 2.19 - 2.14 (m, 3H), 1.32 (br s, 13H).

Step 2: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(2-methyloxazol -5-yl)quinolin-5- yl)cyclopropyl)benzamide (442A-2)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(2-methyloxazol-5-yl)quinolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (110 mg, 193 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (441 mg, 3.87 mmol, 286 pL, 20 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give the crude (8)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(2-methyloxaz ol-5-yl)quinolin- 5-yl)cyclopropyl)benzamide (110 mg) as a yellow oil, which was used in the next step without any further purification. M + H ⁺ = 469.3 (LCMS).

Step 3: (5)-2-Methyl-5-((l-(methyl-</3)azetidin-2-yl)methoxy)-/V- (l-(7-(2-methyloxazol-5- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 782)

To a solution of (8)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(2-methyloxaz ol-5- yl)quinolin-5-yl)cyclopropyl)benzamide (110 mg, 189 pmol, 11.7 pL, 1.0 eq, TFA salt) in MeOH (2.0 mL) was added TEA (100 pL), followed by formaldehyde-tC (35.2 mg, 227 pmol, 4.73 pL, 20% purity in D2O, 1.2 eq). The resulting mixture was adjusted to pH 6 with a small amount of AcOH. The mixture was stirred at 20 °C for 30 min, then NaBDsCN (11.9 mg, 189 pmol, 1.0 eq) was added. The reaction mixture was stirred at 20 °C for another 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (5)-2-Methyl-5-((l-(methyl- t )azetidin-2-yl)methoxy)-7V-(l-(7-(2-methyloxazol-5-yl)quinol in-5-yl)cyclopropyl) benzamide (52.1 mg, 96.6 pmol, 51% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 486.2 (LCMS); 'H NMR (400 MHz, DMSO ) 8 9.56 - 9.49 (m, 1H), 9.36 - 9.31 (m, 1H), 9.22 - 9.15 (m, 1H), 8.34 - 8.29 (m, 2H), 8.00 - 7.93 (m, 2H), 7.13 - 7.06 (m, 1H), 6.98 (s, 1H), 6.80 - 6.71 (m, 1H), 4.68 - 4.59 (m, 1H), 4.35 - 4.28 (m, 1H), 4.26 - 4.19 (m, 1H), 4.06 - 3.96 (m, 1H), 3.91 - 3.81 (m, 1H), 2.60 - 2.57 (m, 3H), 2.41 (br s, 2H), 1.99 - 1.94 (m, 3H), 1.44 (br s, 2H), 1.41 -1.35 (m, 2H). Example 443: (3)-/V-(l-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl) -2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 806)

Compound 806

Step 1: 2-(2-Methyl-l,3-dioxolan-2-yl)oxazole (443 A-2)

To a solution of l-(oxazol-2-yl)ethan-l-one (300 mg, 2.70 mmol, 1.0 eq) in toluene (3.0 mL) was added PTSA (23.3 mg, 135 pmol, 0.05 eq) at 20 °C for 1 h. Then ethylene glycol (3.35 g, 54.0 mmol, 3.0 mL, 20 eq) was added and the mixture was stirred at 130 °C for 12 h under a

N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenom enex Gemini Cl 8 column (100 * 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 5% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). 2-(2-Methyl-l,3-dioxolan-2-yl)oxazole (200 mg, 1.25 mmol, 46% yield) was obtained as a yellow oil. M + H ⁺ = 156 (LCMS).

Step 2: 5-Bromo-2-(2-methyl-l,3-dioxolan-2-yl)oxazole (443A-3)

To a solution of 2-(2 -methyl- 1,3 -di oxolan-2-yl)oxazole (100 mg, 644 pmol, 1.0 eq) in THF (3.0 mL) was added w-BuLi (2.5 M, 644 pL, 2.5 eq) at -78 °C, the mixture was stirred at -78 °C for 1 h. Then carbon tetrabromide (384 mg, 1.16 mmol, 1.8 eq) was added to the mixture at - 78 °C, and then the mixture was allowed to warm up to 20 °C and stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed. The mixture was poured into water (10 mL) and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/3. 5-Bromo-2-(2-methyl-l,3-dioxolan-2-yl)oxazole (110 mg, 455 pmol, 70% yield) was obtained as a yellow oil. M + H ⁺ = 234.2/236.2 (LCMS).

Step 3: terf-Butyl (5)-2-((4-methyl-3-((l-(7-(2-(2-methyl-l,3-dioxolan-2-yl)oxa zol-5- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l-carboxylate (443A- 4)

A mixture of tert-butyl (25)-2-[[4-methyl-3-[[l-[7-(4,4,5,5-tetramethyl-l,3,2-dioxab orolan-2- yl)-5-quinolyl]cyclopropyl]carbamoyl]phenoxy]methyl]azetidin e-l -carboxylate (196 mg, 320 pmol, 1.0 eq), 5-bromo-2-(2-methyl-l,3-dioxolan-2-yl)oxazole (90.0 mg, 384 pmol, 1.2 eq), Pd(dppf)C12 (23.5 mg, 32.0 pmol, 0.10 eq), and NazCOs (101 mg, 961 pmol, 3.0 eq) in a mixture of dioxane (1.0 mL) and H2O (200 pL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C under a N2 atmosphere for 16 h. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL), and extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. tert-Butyl (5)-2-((4-methyl-3-((l-(7-(2-(2-methyl-l,3- dioxolan-2-yl)oxazol-5-yl)quinolin-5-yl)cyclopropyl)carbamoy l)phenoxy)methyl)azetidine- 1-carboxylate (90.0 mg, 122 pmol, 38% yield) was obtained as a white amorphous solid. M + H ⁺ = 641.6 (LCMS). Step 4: (5)-/V-(l-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl) -5-(azetidin-2- ylmethoxy)-2-methylbenzamide (443 A-5)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(2-(2-methyl-l,3-dioxolan-2-yl)oxa zol-5- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l -carboxylate (90.0 mg, 140 pmol, 1.0 eq) in a mixture of DCM (2.0 mL) and H2O (1.0 mL) was added TFA (16.0 mg, 140 pmol, 10.4 pL, 1.0 eq). The mixture was stirred at 20 °C for 60 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum at 30 °C to give the crude product (S)-7V-(l-(7-(2- acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-5-(azetidin-2-y lmethoxy)-2-methylbenzamide (80.0 mg, 128 pmol, TFA salt) as a yellow solid. M + H ⁺ = 497.3 (LCMS).

Step 5: (.S')-\-( l-(7-(2-Acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl)-2-methy l-5-(( 1- methylazetidin-2-yl)methoxy)benzamide (Compound 806)

To a solution of (5)-7V-(l-(7-(2-acetyloxazol-5-yl)quinolin-5-yl)cyclopropyl) -5-(azetidin-2- ylmethoxy)-2-methylbenzamide (70 mg, 114 pmol, 1.0 eq, TFA salt) in MeOH (2.0 mL) were added HOAc (688 pg, 11.4 pmol, 0.1 eq) and formaldehyde (13.9 mg, 171 pmol, 12.8 pL, 37% purity in H2O, 1.5 eq) at 20 °C for 1 h. Then NaBFLCN (7.20 mg, 114 pmol, 1.0 eq) was added to the mixture. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed. The mixture was concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge Prep OBD Cl 8 column (80 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 5% - 35% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (S)-7V-(l-(7-(2-Acetyloxazol-5-yl)quinolin- 5-yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy )benzamide (4.00 mg, 7.31 pmol, 6% yield) was obtained as a white solid. M + H ⁺ = 511.4 (LCMS); (400 MHz, CDCL) 8 10.92 - 10.77 (m, 1H), 9.46 - 9.32 (m, 2H), 9.21 - 9.09 (m, 1H), 8.50 (m, 1H), 8.42 - 8.30 (m, 2H), 7.95 - 7.80 (m, 1H), 7.15 - 7.03 (m, 1H), 6.95 - 6.88 (m, 1H), 6.75 (m, 1H), 4.71 - 4.56 (m, 1H), 4.39 (m, 1H), 4.26 - 4.18 (m, 1H), 4.04 - 3.93 (m, 1H), 3.92 - 3.81 (m, 2H), 2.80 (m, 3H), 2.72 - 2.61 (m, 3H), 2.39 - 2.23 (m, 2H), 1.96 (m, 3H), 1.53 - 1.31 (m, 3H). Example 444: (.S’)-\-( l-(7-( l//-I’yr:izol-l-yl)qiiinolin-5-yl)cyclopropyl)-2-methyl-5- (( 1- methylazetidin-2-yl)methoxy)benzamide (Compound 619)

Compound 619

Step 1: 5-Broino-7-( l//-pyrazol-l -y I (quinoline (444A-1)

A solution of 5,7-dibromoquinoline (2.50 g, 8.71 mmol, 1.0 eq) in DMA (175 mL) was degassed and purged with N2 three times. To the mixture were added UT-pyrazole (711 mg, 10.4 mmol, 1.2 eq), CuiBuCx2 (347 mg, 871 pmol, 0.1 eq) and CS2CO3 (5.68 g, 17.4 mmol, 2.0 eq) at 20 °C. The resulting mixture was stirred at 120 °C for 14 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (200 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (EtOAc/petroleum ether = 1/1, R/ = 0.3). 5-Bromo-7-(U/-pyrazol-l- yl)quinoline (400 mg, 1.46 mmol, 8% yield) was obtained as a colorless oil. M + H ⁺ = 273.9 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.99 - 8.93 (m, 1H), 8.57 - 8.50 (m, 2H), 8.23 (d, J= 1.6 Hz, 1H), 8.13 (d, J= 2.5 Hz, 1H), 7.82 (s, 1H), 7.51 (dd, J= 4.3, 8.5 Hz, 1H), 6.57 (t, J= 2.1 Hz, 1H). Step 2: 7-( 1 //-Py razol- 1 -yl )qiiinoline-5-carbonil rile (444A-2)

A solution of 5-bromo-7-(U/-pyrazol-l-yl)quinoline (900 mg, 3.28 mmol, 1.0 eq) in DMF (90 mL) was degassed and purged with N2 three times. To the mixture were added Zn(CN)2 (771 mg, 6.57 mmol, 2.0 eq), Brettphos Pd G3 (595 mg, 657 pmol, 0.2 eq) and Brettphos (353 mg, 657 pmol, 0.2 eq) at 20 °C. The resulting mixture was stirred at 80 °C for 1 h under a N2 atmosphere. TLC indicated that the starting material was completely consumed. The reaction mixture was allowed to cool to room temperature, poured into H2O (100 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 1/1. 7-( IT/-Pyrazol- l-yl)quinoline-5-carbonitrile (200 mg, 908 mmol, 28% yield) was obtained as a white solid. ^X H NMR (400 MHz, CDCh) 8 9.08 (dd, J= 1.5, 4.3 Hz, 1H), 8.66 (d, J= 2.3 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8.15 (d, J = 2.5 Hz, 1H), 7.84 (d, J= 1.5 Hz, 1H), 7.62 (dd, J= 4.3, 8.5 Hz, 1H), 6.66 - 6.58 (m, 1H).

Step 3: 1 -(7-( 1 //-Pyrazol- 1 -yl)qiiinolin-5-yl)cyclopropan-l -amine (444A-3)

A mixture of 7-(U/-pyrazol-l-yl)quinoline-5 -carbonitrile (50.0 mg, 227 pmol, 1.0 eq) in anhydrous Et2O (5.0 mL) was degassed and purged with N2 three times, then cooled to -78 °C. To this mixture was added Ti(z-PrO)4 (71.0 mg, 250 pmol, 73.7 pL, 1.1 eq) slowly, and then EtMgBr (3 M in Et2O, 166 pL, 2.2 eq) was added dropwise to maintain the temperature between -78 °C and -75 °C over 1 h under a N2 atmosphere. After the addition was complete, the resulting mixture was stirred at the same temperature for 10 min and warmed to 20 °C over 1 h. BF3.Et2O (64.5 mg, 454 pmol, 48.3 mL, 2.0 eq) was added slowly with no obvious temperature change. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was added into a mixture of HC1 (1 M aqueous) (5.0 mL) and MTBE (5.0 mL) and extracted with MTBE (5.0 mL x 2). The aqueous layer was basified to pH 8 by using NaOH (2 M aqueous), and a precipitate was formed. The mixture was filtered through a pad of Celite and the slurry was washed with DCM several times. The combined filtrate was extracted with DCM (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative TLC (DCM/MeOH = 1/1, R/ = 0.6). 1 -(7-( UT-Py razol- 1- yl)quinolin-5-yl) cyclopropan-1 -amine (50.0 mg, 200 pmol, 22% yield) was obtained as a yellow oil. M + H ⁺ = 251.1 (LCMS). Step 4: (S)-\-( l-(7-(l//-I’yr:izol-l-yl)qiiinolin-5-yl)cyclopropyl)-2-nie tliyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 619)

To a solution of l-(7-(U/-pyrazol-l-yl)quinolin-5-yl)cyclopropan-l-amine (40.0 mg, 160 pmol, 3.0 eq) and (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (12.5 mg, 53.3 pmol, 1.0 eq) in DMF (4 mL) were added HATU (50.6 mg, 133 pmol, 2.5 eq) and DIEA (20.6 mg, 160 pmol, 27.8 pL, 3 eq). The mixture was stirred at 20 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (5.0 mL) and extracted with DCM (3.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Waters Xbridge BEH Cl 8 column (100 x 30 mm, 10 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (8 -A-(l-(7-(lJ/-Pyrazol-l-yl)quinolin- 5-yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy )benzamide (4.5 mg, 9.42 pmol, 18% yield) was obtained as a yellow solid. M + H ⁺ = 468.1 (LCMS); ^T H NMR (400 MHz, CD ₃ OD) 8 9.86 - 9.77 (m, 1H), 9.19 (d, J = 4.9 Hz, 1H), 8.78 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.11 - 8.00 (m, 1H), 7.92 (d, J= 1.5 Hz, 1H), 7.18 - 7.10 (m, 1H), 6.98 (dd, J= 2.6, 8.3 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.75 - 6.68 (m, 1H), 4.72 - 4.66 (m, 1H), 4.35 - 4.14 (m, 3H), 4.02 - 3.90 (m, 1H), 2.95 (s, 3H), 2.60 - 2.51 (m, 2H), 2.04 (s, 3H), 1.63 (br s, 2H), 1.58 - 1.52 (m, 2H).

Example 445: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(pyri din-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 653)

445A-1

Compound 653

Step 1: tert- Butyl (5)-2-((4-methyl-3-((l-(7-(pyridin-3-yl)quinolin-5- yl)cyclopropyl)carbam oyl)phenoxy)methyl)azetidine-l-carboxylate (445A-1)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin- 5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (200 mg, 315 pmol, 1.0 eq) and 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (64.5 mg, 315 pmol, 1.0 eq) in a mixture of dioxane (20 mL) and H2O (6.0 mL) were added Pd(dppf)C12.CH2C12 (25.7 mg, 31.5 pmol, 0.1 eq) and ISfeCCh (76.7 mg, 724 pmol, 2.3 eq). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (15 mL), and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 1/100 to 4/5. tert-Butyl (5)-2-((4-methyl-3-((l-(7-(pyridin-3- yl)quinolin-5-yl)cyclopropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (140 mg, 248 pmol, 79% yield) was obtained as a white solid. M + H ⁺ = 565.5 (LCMS).

Step 2: (5)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(pyridin-3-yl )quinolin-5- yl)cyclopropyl)benzamide (445A-2)

To a solution of tert-butyl (5)-2-((4-methyl-3-((l-(7-(pyridin-3-yl)quinolin-5-yl)cyclop ropyl) carbamoyl)phenoxy)methyl)azetidine-l -carboxylate (140 mg, 248 pmol, 1.0 eq) in DCM (7.0 mL) was added TFA (2.32 g, 20.4 mmol, 1.5 mL, 82 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give the crude (5)-5- (azetidin-2-ylmethoxy)-2-methyl-A-(l-(7-(pyridin-3-yl)quinol in-5-yl)cyclopropyl)benzamide (130 mg, TFA salt) as a yellow oil. M+ H+ = 465.2 (LCMS).

Step 3: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(py ridin-3-yl)quinolin- 5-yl)cyclopropyl)benzamide (Compound 653)

To a solution of (5)-5-(azetidin-2-ylmethoxy)-2-methyl-7V-(l-(7-(pyridin-3-yl )quinolin-5- yl)cyclopropyl)benzamide (120 mg, 207 pmol, 1.0 eq, TFA salt) in MeOH (10 mL) was added TEA (1.0 mL), followed by formaldehyde (415 mg, 415 pmol, 38.1 pL, 37% purity in water, 2.0 eq). The resulting mixture was treated with a small amount of AcOH to adjust the pH 6, then NaBHsCN (26.1 mg, 415 pmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex C18 (75 x 30 mm, 3 pm); flow rate: 25 mL/min; gradient: 1% - 25% B over 8 min; mobile phase A: 0.04% aqueous HC1, mobile phase B: acetonitrile). (A)-2-Methyl-5-((l- methylazetidin-2-yl)methoxy)-A-(l-(7-(pyridin-3-yl)quinolin- 5-yl)cyclopropyl)benzamide (36.6 mg, 61.5 pmol, 30% yield, HC1 salt) was obtained as a yellow solid. M + H ⁺ = 479.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.27 - 9.13 (m, 3H), 9.03 (dd, J= 1.5, 4.1 Hz, 1H), 8.75 (dd, J= 1.4, 5.0 Hz, 1H), 8.50 (br d, J= 8.0 Hz, 1H), 8.36 (d, J= 1.4 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.82 - 7.62 (m, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.72 (d, J= 2.6 Hz, 1H), 4.68 - 4.54 (m, 1H), 4.51 - 4.16 (m, 4H), 2.83 (d, J= 4.6 Hz, 3H), 2.38 - 2.30 (m, 2H), 1.97 (s, 3H), 1.41 (s, 4H).

Example 446: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-morpholinopy ridin-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 689)

391A-3 Step 1

Compound 689

Step 1: tert-Butyl (5)-2-((4-methyl-3-((l-(7-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)q uinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine- l-carboxylate (446A-1)

A mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(((trifluoromethyl)sulfonyl)oxy)qu inolin-5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (800 mg, 1.26 mmol, 1.0 eq), BPD (639 mg, 2.52 mmol, 2.0 eq), KO Ac (308 mg, 3.15 mmol, 2.5 eq), Pd(dppf)C12.CH2C12 (102 mg, 126 pmol, 0.10 eq) in dioxane (20 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 16 h under a N2 atmosphere.

LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL), and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 2/1. tert-Butyl (5)-2-((4-methyl-3-((l-(7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-5-yl)c yclopropyl)carbamoyl) phenoxy) methyl)azeti dine- 1 -carboxylate (420 mg, 376 pmol, 30% yield) was obtained as a white solid. M - 82 + H ⁺ = 532.4 (LCMS). Step 2: te/7- Butyl (5)-2-((4-methyl-3-((l-(7-(5-morpholinopyridin-3-yl)quinolin -5-yl)cycl opropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxylate (446A-2)

A mixture of tert-butyl (5)-2-((4-methyl-3-((l-(7-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2- yl)quinolin-5-yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetid ine-l -carboxylate (150 mg, 246 pmol, 1.0 eq), 4-(5-bromo-3-pyridyl)morpholine (65.8 mg, 270 pmol, 1.1 eq), Pd(OAc)2 (16.6 mg, 73.8 pmol, 0.3 eq), bis(l-adamantyl)-butyl-phosphane (17.6 mg, 49.2 pmol, 0.2 eq) and KOAc (72.5 mg, 738 pmol, 3.0 eq) in DMSO (2.0 mL) was degassed and purged with N2 three times. The resulting mixture was stirred at 80 °C for 16 h under a N2 atmosphere. LCMS indicated that the starting material was completely consumed. The mixture was allowed to cool to room temperature, treated with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 2/1. tert-Butyl (5)-2-((4-methyl-3-((l-(7-(5- morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)carbamoyl)p henoxy)methyl)azetidine-l- carboxylate (170 mg, 143 pmol, 58% yield) was obtained as a white solid. M + H ⁺ = 650.5 (LCMS).

Step 3: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-morpholinopy ridin-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 689)

To a solution of tert-butyl (S)-2-((4-methyl-3-((l-(7-(5-morpholinopyridin-3-yl)quinolin -5- yl)cyclopropyl)carbamoyl)phenoxy)methyl)azetidine-l-carboxyl ate (170 mg, 261 pmol, 1.0 eq) in DCM (2.0 mL) was added TFA (755 mg, 6.63 mmol, 490 pL, 25 eq). The mixture was stirred at 20 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was concentrated under vacuum at 30 °C to give a residue which was purified by preparative HPLC (Phenomenex Gemini C18 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 28% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (8)-5-(Azetidin-2-ylmethoxy)-2-methyl- 7V-(l-(7-(5-morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl )benzamide (22.5 mg, 33.9 pmol, 13% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 550.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.21 (m, 1H), 9.17 - 9.10 (m, 1H), 9.04 - 8.99 (m, 1H), 8.92 - 8.74 (m, 2H), 8.64 (m, 1H), 8.46 (m, 1H), 8.41 (m, 1H), 8.24 - 8.17 (m, 1H), 8.04 (m, 1H), 7.73 - 7.64 (m, 1H), 7.10 (m, 1H), 6.91 (m, 1H), 6.70 (m, 1H), 4.70 - 4.60 (m, 1H), 4.23 (m, 2H), 4.13 (m, 2H), 3.81 (m, 4H), 3.46 - 3.40 (m, 4H), 2.46 - 2.40 (m, 1H), 2.38 - 2.29 (m, 1H), 1.96 (m, 3H), 1.47 - 1.35 (m, 4H). Example 447 : ( )-/V-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl) -2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 821)

Compound 821

Step 1: /V-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-s ulfinamide (447A- 1) w-BuLi (2.5 M in Et20, 139 pL, 1.0 eq) was added dropwise to a solution of 5,7- dibromoquinoline (100 mg, 349 pmol, 59.5 pL, 1.0 eq) and 2-methyl-7V-(oxetan-3- ylidene)propane-2-sulfinamide (61.1 mg, 349 pmol, 1.0 eq) in THF (2.0 mL) at -78 °C under a N2 atmosphere. The resulting mixture was stirred at -78 °C for 1 h. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The reaction mixture was allowed to warm to room temperature, poured into NH4CI aqueous (20 ml) and extracted with EtOAc (10 mL x 4). The combined organic layers were dried over TsfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. N-(3-(7- Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamid e (200 mg, 522 pmol, 21% yield) was obtained as a yellow gum. 'H NMR (400 MHz, CDCL) 6 8.94 (dd, J= 1.5, 4.1 Hz, 1H), 8.33 (d, J= 1.1 Hz, 1H), 7.89 (d, J= 8.5 Hz, 1H), 7.65 (d, J= 1.8 Hz, 1H), 7.41 (dd, J=

4.1, 8.6 Hz, 1H), 5.53 (d, = 7.3 Hz, 1H), 5.26 - 5.15 (m, 3H), 1.11 (s, 10H).

Step 2: /V-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2 -methylpropane-2- sulfinamide (447A-2)

To a mixture of (5-acetylthiophen-2-yl)boronic acid (63.2 mg, 372 mol, 1.5 eq) and /V-(3-(7- bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamid e (95.0 mg, 248 pmol, 1.0 eq) in DMSO (4.0 mL) were added KOAc (97.3 mg, 991 pmol, 4.0 eq), cataCxium A (44.4 mg, 124 pmol, 0.5 eq) and Pd(OAc)2 (11.1 mg, 49.6 pmol, 0.2 eq). The resulting mixture was stirred at 80 °C for 2 h under a N2 atmosphere. LCMS indicated that the starting material completely consumed, and the desired product was detected. The reaction mixture was allowed to cool to room temperature, poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 7V-(3-(7-(5- Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methylpropa ne-2-sulfmamide (160 mg, 373 prnol, 75% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCL-tf) 8 8.97 (dd, J = 1.4, 4.1 Hz, 1H), 8.43 (s, 1H), 7.98 - 7.72 (m, 4H), 7.56 (d, J= 4.0 Hz, 1H), 7.41 (dd, J =

4.2, 8.6 Hz, 1H), 5.35 - 5.21 (m, 4H), 2.68 - 2.63 (m, 3H), 1.12 (s, 9H).

Step 3: l-(5-(5-(3-Aminooxetan-3-yl)quinolin-7-yl)thiophen-2-yl)etha n-l-one (447A-3)

To a solution of 7V-(3-(7-(5-acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2 -methylpropane- 2-sulfinamide (150 mg, 350 pmol, 1.0 eq) in MeOH (5.0 mL) was added HCl/dioxane (4 M, 637 pL, 7.3 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. LCMS indicated that the starting material completely consumed, and the desired mass was detected. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the crude l-(5-(5-(3-aminooxetan-3-yl)quinolin-7-yl)thiophen-2-yl)etha n-l-one (120 mg, 333 pmol, 95% yield, HC1 salt) as a yellow solid, which was used in the next step without any further purification. 'H NMR (400 MHz, DMSO-tL) 8 9.78 (br s, 3H), 9.21 (br d, J= 3.6 Hz, 1H), 8.66 (br s, 1H), 8.47 - 8.31 (m, 1H), 8.26 - 8.00 (m, 3H), 7.96 - 7.78 (m, 1H), 5.44 - 5.31 (m, 4H), 2.60 (br s, 3H). Step 4: (5)-/V-(3-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-y l)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 821)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (78.2 mg, 333 pmol, 1.0 eq) and l-(5-(5-(3-aminooxetan-3-yl)quinolin-7-yl)thiophen-2-yl)etha n-l-one (120 mg, 333 pmol, 1.0 eq, HCI salt) in DMF (5.0 mL) were added HATU (316 mg, 831 pmol, 2.5 eq) and DIEA (129 mg, 998 pmol, 174 pL, 3.0 eq). The mixture was stirred at 25 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex Luna Cl 8 column (100 x 30 mm, 5 pm); flow rate: 25 mL/min; gradient: 10% - 40% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (5)-7V-(3-(7-(5- Acetylthiophen-2-yl)quinolin-5-yl)oxetan-3-yl)-2-methyl-5-(( l-methylazeti din-2- yl)methoxy) benzamide (21.6 mg, 32.9 pmol, 10% yield) was obtained as a yellow solid. M + H ⁺ = 542.4 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.96 (dd, J= 1.4, 4.4 Hz, 1H), 8.36 (s, 1H), 8.31 - 8.24 (m, 2H), 7.95 (d, J= 4.0 Hz, 1H), 7.83 (d, J= 4.1 Hz, 1H), 7.63 (dd, J= 4.4, 8.6 Hz, 1H), 7.15 (d, J= 8.4 Hz, 1H), 6.99 (dd, J= 2.8, 8.5 Hz, 1H), 6.88 (d, J= 2.6 Hz, 1H), 5.47 (d, J= 7.1 Hz, 2H), 5.35 (d, J= 7.1 Hz, 2H), 4.74 - 4.63 (m, 1H), 4.35 - 4.16 (m, 3H), 4.02 - 3.92 (m, 1H), 3.00 - 2.92 (m, 3H), 2.62 (s, 3H), 2.58 - 2.48 (m, 2H), 2.04 (s, 3H).

Example 448: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(3-(7-(2- methyloxazol-5-yl)quinolin-5-yl)oxetan-3-yl)benzamide (Compound 808)

Compound 808

Step 1: /V-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-s ulfinamide (448A- 1)

To a solution of 5,7-dibromoquinoline (500 mg, 1.74 mmol, 59.5 pL, 1.0 eq) in THF (10 mL) was added w-BuLi (2.5 M in hexane, 697 pL, 1.0 eq) dropwise at -78 °C under a N2 atmosphere. The resulting mixture was stirred at -78 °C for 1 h, then a solution of 2-methyl-7V-(oxetan-3- ylidene)propane-2-sulfinamide (305 mg, 1.74 mmol, 1.0 eq) in THF (1.0 mL) was added dropwise at -78 °C. The resulting mixture was warmed to 25 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over ISfeSCU, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. 7V-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-s ulfmamide (150 mg, 391 pmol, 22% yield) was obtained as a yellow gum. M + H ⁺ = 383.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.95 (d, J= 4.3 Hz, 1H), 8.48 - 8.36 (m, 1H), 8.06 - 7.89 (m, 1H), 7.69 (br s, 1H), 7.52 - 7.40 (m, 1H), 5.53 (d, = 7.4 Hz, 1H), 5.30 - 5.08 (m, 3H), 1.11 (s, 9H).

Step 2: 3-(7-Bromoquinolin-5-yl)oxetan-3-amine (448A-2)

To a solution of 7V-(3-(7-bromoquinolin-5-yl)oxetan-3-yl)-2-methylpropane-2-s ulfinamide (150 mg, 391 pmol, 1.0 eq) in MeOH (8 mL) was added HCl/dioxane (4 M, 712 pL, 7.3 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under vacuum to give 3-(7-bromoquinolin-5-yl)oxetan-3-amine (120 mg, 380 pmol, 97% yield, HC1 salt) as a yellow solid. M + H ⁺ = 279.1 (LCMS).

Step 3: (3)-/V-(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((l- methylazetidin-2- yl)methoxy)benzamide (448A-3)

To a solution of (5)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzoic acid (82.0 mg, 349 pmol, 1.0 eq) and 3-(7-bromo-5-quinolyl)oxetan-3-amine (110 mg, 349 pmol, 1.0 eq, HC1 salt) in DMF (5.0 mL) were added HATU (331 mg, 871 pmol, 2.5 eq) and DIEA (135 mg, 1.05 mmol, 182 pL, 3.0 eq). The mixture was stirred at 25 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was poured into water (10 mL) and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by flash silica gel chromatography using a gradient of EtOAc/petroleum ether from 0/1 to 1/0. fS')-/' -(3-(7-Bromoquinolin-5-yl)oxetan-3-yl)-2-methyl-5-(( l -methylazetidin- 2-yl)methoxy)benzamide (80.0 mg, 161 pmol, 46% yield) was obtained as a yellow gum. M + H ⁺ = 496.3 (LCMS).

Step 4: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(3-(7-(2-me thyloxazol-5- yl)quinolin-5-yl)oxetan-3-yl)benzamide (Compound 808)

To a solution of (5)-7V-(3-(7-bromoquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((l- methylazetidin- 2-yl)methoxy)benzamide (60.0 mg, 121 pmol, 1.0 eq) in a mixture of dioxane (6.0 mL) and H2O (0.6 mL) were added 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxaz ole (37.9 mg, 181 pmol, 1.5 eq), Pd(dppf)C12.CH2C12 (9.87 mg, 12.1 pmol, 0.1 eq) and ISfeCCL (29.5 mg, 278 pmol, 2.3 eq) under a N2 atmosphere. The resulting mixture was stirred at 80 °C for 4 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into water (10 mL), and extracted with EtOAc (5.0 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give a residue which was purified by preparative HPLC (Phenomenex luna C18 column (100 x 40 mm, 5 pm); flow rate: 25 mL/min; gradient: 1% - 30% B over 8 min; mobile phase A: 0.1% aqueous TFA, mobile phase B: acetonitrile). (ri)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A-(3-(7-(2- methyloxazol-5-yl)quinolin-5-yl)oxetan-3-yl)benzamide (6.40 mg, 9.89 pmol, 8% yield, TFA salt) was obtained as a yellow solid. M + H ⁺ = 499.4 (LCMS); 1H NMR (400 MHz, CD ₃ OD) 8 8.96 (d, J= 4.1 Hz, 1H), 8.30 (s, 1H), 8.26 - 8.19 (m, 2H), 7.78 (s, 1H), 7.62 (dd, J= 4.3, 8.6 Hz, 1H), 7.14 (d, J= 8.5 Hz, 1H), 6.99 (dd, J= 2.6, 8.4 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 5.46 (br d, J= 7.0 Hz, 2H), 5.34 (d, J= 7.0 Hz, 2H), 4.80 - 4.66 (m, 2H), 4.35 - 4.28 (m, 1H), 4.25 - 4.18 (m, 1H), 3.96 (q, J= 9.8 Hz, 1H), 3.05 - 2.91 (m, 3H), 2.62 (s, 3H), 2.59 - 2.51 (m, 2H), 2.01 (s, 3H).

Example 449: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(5,6,7,8-tetrahydronap hthalen-l- yl)ethyl)benzamide (Compound 181)

Compound 181

The synthesis of compound 181 was described in example 1 as intermediate 1A-8. M + H ⁺ = 464.3.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 87.23 (d, J= 7.1 Hz, 1H), 7.12 - 7.07 (m, 1H), 7.03 - 6.95 (m, 2H), 6.56 - 6.49 (m, 2H), 5.43 - 5.36 (m, 1H), 4.61 - 4.58 (m, 1H), 4.29 - 4.17 (m, 3H), 3.74 - 3.69 (m, 2H), 3.10 - 3.02 (m, 1H), 2.83 - 2.77 (m, 3H), 2.21 - 2.18 (m, 3H), 1.95 - 1.87 (m, 2H), 1.83 - 1.77 (m, 2H), 1.48 - 1.46 (m, 1H), 1.46 - 1.45 (m, 9H), 1.31 - 1.30 (m, 1H).

Example 450: (l?)-2-Methyl-/V-(l-(naphthalen-l-yl)ethyl)-5-nitrobenzamide (Compound 104)

Compound 104

The synthesis of compound 104 was described in example 14 as intermediate 14A-3. M + H ⁺ = 335.2 (LCMS); ^X H NMR (400 MHz, CDCh) 8 8.21 (d, J = 8.5 Hz, 1H), 8.16 - 8.09 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.66 - 7.45 (m, 4H), 7.36 (d, J = 8.3 Hz, 1H), 6.20 -6.12 (m, 1H), 6.12 - 6.04 (m, 1H), 2.60 - 2.44 (m, 3H), 1.84 (d, J = 6.5 Hz, 3H).

Example 451: terf-Butyl 3-((3-((l-([l,l'-biphenyl]-3-yl)cyclopropyl)carbamoyl)-4- methylphenyl)amino)azetidine-l-carboxylate (Compound 188)

Compound 188

The synthesis of compound 188 was described in example 201 as intermediate 201 A-2. M + H ⁺ = 398.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 7.61 - 7.52 (m, 4H), 7.44 (t, J= 7.7 Hz, 4H), 7.41 - 7.32 (m, 3H), 7.08 - 6.99 (m, 1H), 4.28 - 4.22 (m, 2H), 4.21 - 4.14 (m, 1H), 3.78 - 3.71 (m, 2H), 2.32 (s, 3H), 1.46 (br s, 2H), 1.45 (s, 9H), 1.43 (br s, 2H). Example 452: 2-(l-(Naphthalen-l-yl)ethyl)-7-nitro-l,2,3,4-tetrahydroisoqu inoline

(Compound 127)

Compound 127

The synthesis of compound 127 was described in example 256 as intermediate 256A-1. M + H ⁺ = 332.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.42 (br s, 1H), 8.02 - 7.94 (m, 1H), 7.93 - 7.86 (m, 2H), 7.80 (br d, J = 8.1 Hz, 1H), 7.66 (br d, J= 6.4 Hz, 1H), 7.53 - 7.42 (m, 3H),

7.23 (d, J= 8.4 Hz, 1H), 4.36 (br s, 1H), 4.01 (br d, J= 14.6 Hz, 1H), 3.73 (br d, J= 14.9 Hz, 1H), 3.05 - 2.64 (m, 4H), 1.62 (br d, J= 6.5 Hz, 3H). Example 453: (5)-5-(l-(2-Methyl-5-((l-methylazetidin-2-yl)methoxy)benzami do) cyclopropyl)quinolin-7-yl trifluoromethanesulfonate (Compound 739)

Compound 739

The synthesis of compound 739 was described in example 352 as intermediate 352A-1. M + H ⁺ = 550.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.79 - 10.63 (m, 1H), 9.31 (s, 1H), 9.18 (d, J= 8.6 Hz, 1H), 9.06 (dd, J = 1.4, 4.1 Hz, 1H), 8.10 (d, J= 2.5 Hz, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 4.3, 8.6 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.98 - 6.86 (m, 1H), 6.82 - 6.70 (m, 1H), 4.70 - 4.54 (m, 1H), 4.36 (dd, J= 7.9, 11.2 Hz, 1H), 4.21 (dd, J = 3.2, 11.3 Hz, 1H), 4.08 - 3.93 (m, 1H), 3.84 (br dd, J = 6.6, 9.6 Hz, 1H), 2.80 (d, J = 5.0 Hz, 3H), 2.41 - 2.24 (m, 2H), 1.93 (s, 3H), 1.47 - 1.37 (m, 2H), 1.33 - 1.25 (m, 2H).

Example 454: 2-Methyl-/V-(naphthalen-l-yl(oxetan-3-yl)methyl)-5-nitrobenz amide

(Compound 110)

Compound 110

Compound 110 was synthesized according to an analogous procedure to the one described for compound 105. M + H ⁺ = 377.1 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.32 (d, J= 8.5 Hz, 1H), 8.16 - 8.07 (m, 2H), 7.94 - 7.84 (m, 2H), 7.69 - 7.55 (m, 2H), 7.48 - 7.34 (m, 2H), 7.20 (d, J= 7.1 Hz, 1H), 6.53 (t, J= 8.8 Hz, 1H), 6.10 (br d, J= 8.8 Hz, 1H), 5.13 - 5.00 (m, 2H), 4.89 (t, J= 13 Hz, 1H), 4.51 (t, J = 6.5 Hz, 1H), 4.00 - 3.79 (m, 1H), 3.50 (s, 2H), 2.54 (s, 3H). Example 455: 2-Methyl-/V-(naphthalen-l-yl(tetrahydrofuran-3-yl)methyl)-5- nitrobenzamide (Compound 123)

Compound 123

Compound 123 was synthesized according to an analogous procedure to the one described for compound 105. M + H ⁺ = 391.0 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.40 - 8.28 (m, 1H),

8.23 - 8.11 (m, 2H), 7.94 (dd, J= 4.6, 7.3 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.68 - 7.48 (m, 4H), 7.44 - 7.35 (m, 1H), 6.22 - 6.03 (m, 1H), 4.17 - 4.01 (m, 1H), 3.99 - 3.76 (m, 2H), 3.56 - 3.43 (m, 1H), 3.29 - 3.03 (m, 1H), 2.51 (d, J = 9.8 Hz, 3H), 2.29 (q, J = 13 Hz, 1H), 2.25 - 1.76 (m, 1H). Example 456: /V-(3-Methoxy-l-(naphthalen-l-yl)propyl)-2-methyl-5-nitroben zamide

(Compound 113)

Compound 113 was synthesized according to an analogous procedure to the one described for compound 108. M + H+ = 379.2 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.35 (d, J= 2.4 Hz, 1H), 8.22 - 8.15 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.62 - 7.46 (m,

4H), 7.45 - 7.37 (m, 2H), 6.21 (dt, J= 4.6, 7.1 Hz, 1H), 3.58 - 3.42 (m, 2H), 3.40 (s, 3H), 2.55 (s, 3H), 2.51 - 2.20 (m, 2H). Example 457: 5-Amino-2-methyl-N-(naphthalen-l-yl(oxetan-3-yl)methyl) benzamide (Compound 114)

Compound 114

Compound 114 was synthesized according to an analogous procedure to the one described for compound 109. M + H ⁺ = 347.0 (LCMS); 'H NMR (400 MHz, CDCh) 6 8.33 (d, J= 8.4 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.64 - 7.53 (m, 2H), 7.44 - 7.35 (m, 1H), 7.13 (d, J= 7.1 Hz, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.66 - 6.53 (m, 2H), 6.45 (t, J= 8.7 Hz, 1H), 6.10 (br d, J= 9.3 Hz, 1H), 5.11 - 4.91 (m, 2H), 4.83 (dd, J= 6.6, 8.0 Hz, 1H), 4.52 (t, J= 6.6 Hz, 1H), 3.94 - 3.71 (m, 1H), 2.34 - 2.24 (m, 3H).

Example 458: 5-Amino-/V-(3-methoxy-l-(naphthalen-l-yl)propyl)-2-methylben zamide (Compound 117)

Compound 117

Compound 117 was synthesized according to an analogous procedure to the one described for compound 118. M+ H ⁺ = 349.2 (LCMS); 'H NMR (400 MHz, CDCh) 8 8.20 (d, J= 8.3 Hz, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.77 (br d, J= 8.0 Hz, 1H), 7.59 - 7.37 (m, 4H), 7.18 - 7.04 (m, 1H), 6.92 (br d, J= 7.6 Hz, 1H), 6.89 - 6.68 (m, 2H), 6.14 (br d, J= 4.6 Hz, 1H), 3.49 - 3.37 (m, 2H), 3.33 - 3.28 (m, 3H), 2.33 (br d, J= 6.6 Hz, 1H), 2.27 (s, 3H), 2.21 (br d, J= 10.4 Hz, 1H). Example 459: 5-(Azetidin-3-ylamino)-2-methyl-/V-(l-(l,2,3,4-tetrahydro naphthalen-1- yl)ethyl)benzamide (Compound 182)

Compound 182

Compound 182 was synthesized according to an analogous procedure to the one described for compound 172. M + H ⁺ = 364.1 (LCMS); ^X H NMR (400 MHz, CDCh) 6 9.99 - 9.63 (m, 2H), 7.35 - 7.28 (m, 1H), 7.18 - 7.06 (m, 3H), 7.03 - 6.89 (m, 1H), 6.50 - 6.24 (m, 2H), 6.05 - 5.68 (m, 1H), 4.83 - 4.63 (m, 1H), 4.40 - 4.04 (m, 3H), 3.85 - 3.59 (m, 2H), 3.28 - 2.99 (m, 1H), 2.84 (br d, J= 2.1 Hz, 1H), 2.26 - 1.87 (m, 5H), 1.83 - 1.47 (m, 2H), 1.36 - 1.10 (m, 3H).

Example 460: 2-(Aminomethyl)-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl)-5 - methylbenzofuran-6-carboxamide (Compound 607)

Compound 607

Compound 607 was synthesized according to an analogous procedure to the one described for compound 197. M + H ⁺ = 402.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 8 9.12 (s, 1H), 8.96 (d, J= 8.4 Hz, 1H), 8.83 (dd, J= 1.4, 4.1 Hz, 1H), 7.48 (d, = 2.6 Hz, 1H), 7.44 (dd, J= 4.2, 8.4 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.20 (s, 1H), 6.60 (s, 1H), 3.93 (s, 3H), 3.79 (s, 2H), 2.11 (s,

3H), 1.40 - 1.32 (m, 2H), 1.23 - 1.18 (m, 2H).

Example 461: 2-((Dimethylamino)methyl)-/V-(l-(7-methoxyquinolin-5-yl)cycl opropyl)-5- methylbenzofuran-6-carboxamide (Compound 606)

Compound 606 Compound 606 was synthesized according to an analogous procedure to the one described for compound 198. M + H ⁺ = 364.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 11.26 (br d, J= 2.5 Hz, 1H), 9.62 (br d, J= 8.6 Hz, 1H), 9.42 (s, 1H), 9.16 (d, J= 5.0 Hz, 1H), 7.93 (dd, J = 5.3, 8.4 Hz, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.66 (d, J= 1.9 Hz, 1H), 7.48 (s, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 4.51 (s, 2H), 4.02 (s, 3H), 2.73 (s, 6H), 2.13 (s, 3H), 1.44 (br s, 2H), 1.32 (br s, 2H).

Example 462: 5-(2-Aminoethoxy)-/V-(l-(7-methoxyquinolin-5-yl)cyclopropyl) -2- methylbenzamide (Compound 513)

Compound 513

Compound 513 was synthesized according to an analogous procedure to the one described for compound 215. M + H ⁺ = 392.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.12 - 9.07 (m, 1H), 8.94 (dd, J= 1.0, 8.4 Hz, 1H), 8.82 (dd, J= 1.6, 4.2 Hz, 1H), 7.47 (d, J= 2.6 Hz, 1H), 7.42 (dd, J= 4.3, 8.5 Hz, 1H), 7.31 (d, = 2.4 Hz, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.83 (dd, J= 2.7, 8.3 Hz, 1H), 6.61 (d, J= 2.8 Hz, 1H), 3.92 (s, 3H), 3.82 (t, J= 5.8 Hz, 2H), 2.80 (t, J= 5.8 Hz, 2H), 1.94 (s, 3H), 1.38 - 1.29 (m, 2H), 1.23 - 1.14 (m, 2H).

Example 463: 5-(Azetidin-3-ylmethoxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 430)

Compound 430

Compound 430 was synthesized according to an analogous procedure to the one described for compound 263. M + H ⁺ = 387.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.12 - 9.07 (m, 1H), 8.79 - 8.62 (m, 3H), 7.98 - 7.91 (m, 1H), 7.86 - 7.79 (m, 2H), 7.61 - 7.42 (m, 3H), 7.11 - 7.03 (m, 1H), 6.91 - 6.83 (m, 1H), 6.71 - 6.65 (m, 1H), 4.07 - 3.99 (m, 4H), 3.82 - 3.71 (m, 2H), 3.18 - 3.05 (m, 1H), 2.03 - 1.90 (m, 3H), 1.40 - 1.31 (m, 2H), 1.23 - 1.13 (m, 2H). Example 464: 5-(((H?,2 )-2-Aminocyclohexyl)oxy)-2-methyl-/V-(l-(naphthalen-l- yl)cyclopropyl)benzamide (Compound 428)

Compound 428

Compound 428 was synthesized according to an analogous procedure to the one described for compound 263. M + H ⁺ = 415.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.14 - 9.08 (m, 1H), 8.70 - 8.62 (m, 1H), 8.02 - 7.88 (m, 4H), 7.87 - 7.78 (m, 2H), 7.61 - 7.41 (m, 3H), 7.11 - 7.03 (m, 1H), 6.96 - 6.89 (m, 1H), 6.76 - 6.70 (m, 1H), 4.53 - 4.44 (m, 1H), 3.36 (br s, 1H), 2.01 - 1.93 (m, 3H), 1.92 - 1.84 (m, 1H), 1.77 - 1.65 (m, 3H), 1.50 - 1.32 (m, 6H), 1.22 - 1.12 (m, 2H).

Example 465: 5-(((ll?,21?)-2-Aminocyclohexyl)oxy)-2-methyl-/V-(l-(naphtha len-l- yl)cyclopropyl)benzamide (Compound 429)

Compound 429

Compound 429 was synthesized according to an analogous procedure to the one described for compound 263. M + H ⁺ = 415.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 9.15 - 9.09 (m, 1H), 8.69 - 8.62 (m, 1H), 8.02 - 7.78 (m, 6H), 7.63 - 7.41 (m, 3H), 7.11 - 7.03 (m, 1H), 6.95 - 6.88 (m, 1H), 6.71 - 6.64 (m, 1H), 4.14 - 3.97 (m, 1H), 3.20 - 3.07 (m, 1H), 2.12 - 2.03 (m, 1H), 1.98 (s, 4H), 1.74 - 1.61 (m, 2H), 1.38 - 1.15 (m, 8H).

Example 466: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(2-methoxyphenyl)cycloprop yl)-2- methylbenzamide (Compound 277)

Compound 277 Compound 277 was synthesized according to an analogous procedure to the one described for compound 271. M + H ⁺ = 369.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.04 - 8.75 (m, 1H), 7.26 - 7.14 (m, 3H), 7.00 - 6.91 (m, 2H), 6.86 (d, J= 8.9 Hz, 2H), 4.40 - 4.25 (m, 2H), 3.73 (s, 3H), 3.55 - 3.44 (m, 2H), 2.84 (s, 6H), 2.22 (s, 3H), 1.17 (br d, J= 6.5 Hz, 4H). Example 467: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-methoxyphenyl)cycloprop yl)-2- methylbenzamide (Compound 278)

Compound 278

Compound 278 was synthesized according to an analogous procedure to the one described for compound 271. M + H ⁺ = 369.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 7.33 (d, J= 8.8 Hz, 2H), 7.23 - 7.14 (m, 1H), 7.04 - 6.93 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.43 - 4.26 (m, 2H), 3.78 (s, 3H), 3.66 - 3.51 (m, 2H), 2.98 (s, 6H), 2.27 (s, 3H), 1.17 - 1.34 (m, 4H).

Example 468: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(phenant hren-9- yl)cyclopropyl)benzamide (Compound 569)

Compound 569 Compound 569 was synthesized according to an analogous procedure to the one described for compound 272. M + H ⁺ = 451.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.10 (s, 1H), 8.80 (br d, J= 7.6 Hz, 3H), 8.12 (s, 1H), 8.03 - 7.96 (m, 1H), 7.72 - 7.62 (m, 4H), 7.04 (d, J= 8.5 Hz, 1H), 6.85 (br d, J= 2.5 Hz, 1H), 6.63 (d, J= 2.5 Hz, 1H), 3.96 (br d, J= 3.4 Hz, 2H), 2.89 (s, 2H), 2.73 (s, 2H), 2.40 (br s, 3H), 2.02 - 1.90 (m, 4H), 1.46 - 1.37 (m, 2H), 1.28 (br s, 2H). Example 469: 2-Methyl-5-((l-methylazetidin-3-yl)methoxy)-/V-(l-(naphthale n-l- yl)cyclopropyl)benzamide (Compound 427)

Compound 427

Compound 427 was synthesized according to an analogous procedure to the one described for compound 283. M + H ⁺ = 401.1 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 6 10.39 - 9.96 (m, 1H), 9.14 - 9.06 (m, 1H), 8.70 - 8.61 (m, 1H), 7.99 - 7.90 (m, 1H), 7.89 - 7.73 (m, 2H), 7.64 - 7.40 (m, 3H), 7.15 - 7.01 (m, 1H), 6.93 - 6.82 (m, 1H), 6.74 - 6.61 (m, 1H), 4.28 - 4.17 (m, 1H), 4.11 - 4.06 (m, 1H), 4.05 - 3.95 (m, 3H), 3.81 - 3.75 (m, 1H), 3.13 - 3.04 (m, 1H), 2.81 - 2.76 (m, 3H), 2.02 - 1.88 (m, 3H), 1.41 - 1.29 (m, 2H), 1.23 (br s, 1H). Example 470: 5-(2-(Dimethylamino)ethoxy)-/V-(l-(3-hydroxyphenyl)cycloprop yl)-2- methylbenzamide (Compound 306)

Compound 306

Compound 306 was synthesized according to an analogous procedure to the one described for compound 294. M + H ⁺ = 355.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.38 - 10.09 (m, 1H), 9.30 (br s, 1H), 8.91 (s, 1H), 7.18 (br d, J= 8.0 Hz, 1H), 7.07 (br t, J= 7.9 Hz, 1H), 7.07

(br t, J= 7.9 Hz, 1H), 7.03 - 6.93 (m, 2H), 6.69 (s, 1H), 6.59 (br dd, J= 7.9, 13.5 Hz, 2H), 4.35 (br t, J= 4.6 Hz, 2H), 3.50 (br d, J= 4.5 Hz, 2H), 2.84 (br d, J= 4.4 Hz, 6H), 2.17 - 2.31 (m, 3H), 1.21 (br s, 4H). Example 471: 5-(2-Amino-3-methylbutoxy)-/V-(l-(7-methoxyquinolin-5-yl)cyc lopropyl)- 2-methylbenzamide (Compound 572)

Compound 572

Compound 572 was synthesized according to an analogous procedure to the one described for compound 324. M + H ⁺ = 434.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 8 9.48 (br d, J= 4.0

Hz, 1H), 9.28 (s, 1H), 9.10 (br d, J= 5.0 Hz, 1H), 8.12 (br d, J= 2.1 Hz, 3H), 7.88-7.80 (m, 1H), 7.67 (d, J= 2.1 Hz, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.93 (dd, J= 2.8, 8.4 Hz, 1H), 6.75 (d, = 2.8 Hz, 1H), 4.15 - 4.10 (m, 1H), 4.00 (s, 3H), 3.98 (br s, 1H), 3.23 (br d, J= 4.1 Hz, 1H), 2.05 - 1.98 (m, 1H), 1.95 (s, 3H), 1.39 (br s, 2H), 1.29 (br s, 2H), 0.99 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.8 Hz, 3H).

Example 472: ( )-5-((l-(2-Fluoroethyl)azetidin-2-yl)methoxy)-/V-(l-(7-metho xyquinolin- 5-yl)cyclopropyl)-2-methylbenzamide (Compound 567)

Compound 567

Compound 567 was synthesized according to an analogous procedure to the one described for compound 348. M + H ⁺ = 464.2. 'H NMR (400 MHz, DMSO-t/e) 8 9.09 (s, 1H), 8.94 (br d, J = 8.3 Hz, 1H), 8.81 (br d, J= 3.4 Hz, 1H), 8.40 - 8.11 (m, 1H), 7.50 - 7.38 (m, 2H), 7.31 (d, J = 1.8 Hz, 1H), 7.03 (br d, J= 8.6 Hz, 1H), 6.93 - 6.78 (m, 1H), 6.60 (d, J= 2.1 Hz, 1H), 4.42 (br t, J= 4.6 Hz, 1H), 4.30 (br t, J= 4.8 Hz, 1H), 4.02 - 3.76 (m, 6H), 2.97 - 2.73 (m, 3H), 2.59 (br d, J= 3.0 Hz, 1H), 2.10 - 1.81 (m, 5H), 1.44 - 1.28 (m, 2H), 1.23 - 1.09 (m, 2H). Example 473: 5-(2-((2-Fluoroethyl)(methyl)amino)ethoxy)-/V-(l-(7-methoxyq uinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 571)

Compound 571

Compound 571 was synthesized according to an analogous procedure to the one described for compound 348. M + H ⁺ = 452.1 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 5 10.82 - 10.62 (m, 1H), 9.63 - 9.49 (m, 1H), 9.31 (s, 1H), 9.13 (br d, J= 4.5 Hz, 1H), 7.97 - 7.82 (m, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.57 (d, J= 1.5 Hz, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.75 (d, J= 2.6 Hz, 1H), 4.97 - 4.79 (m, 2H), 4.31 (s, 2H), 4.01 (s, 3H), 3.72 - 3.60 (m, 4H), 2.86 (br d, J= 2.3 Hz, 3H), 1.96 (s, 3H), 1.44 - 1.36 (m, 2H), 1.30 (br s, 2H). Example 474: /V-(l-(7-Fluoronaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 444)

Compound 444

Compound 444 was synthesized according to an analogous procedure to the one described for compound 365. M + H ⁺ = 419.1 (LCMS); ^X H NMR (400 MHz, CD ₃ OD) 8 8.57 - 8.46 (m, 1H), 8.34 - 8.23 (m, 1H), 8.01 - 7.90 (m, 2H), 7.87 - 7.80 (m, 1H), 7.47 - 7.39 (m, 1H), 7.36 - 7.27

(m, 1H), 7.12 - 7.04 (m, 1H), 6.93 - 6.87 (m, 1H), 6.73 - 6.67 (m, 1H), 4.30 - 4.03 (m, 3H), 3.92 - 3.79 (m, 1H), 3.66 - 3.51 (m, 1H), 2.76 - 2.67 (m, 3H), 2.43 - 2.28 (m, 2H), 2.05 - 1.95 (m, 3H), 1.48 - 1.42 (m, 2H), 1.34 - 1.26 (m, 2H). Example 475: 5-((Hexahydro-lH-pyrrolizin-7a-yl)methoxy)-/V-(l-(7-methoxyq uinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 559)

Compound 559

Compound 559 was synthesized according to an analogous procedure to the one described for compound 376. M + H ⁺ = 472.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.08 (s, 1H), 8.99

- 8.94 (m, 1H), 8.81 (dd, J= 1.6, 4.2 Hz, 1H), 7.47 (d, J= 2.6 Hz, 1H), 7.41 (dd, J= 4.3, 8.5 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.82 (dd, J= 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.8 Hz, 1H), 3.92 (s, 3H), 3.52 (s, 2H), 2.93 - 2.82 (m, 2H), 2.58 - 2.51 (m, 2H), 1.93 (s, 3H), 1.85 - 1.63 (m, 6H), 1.56 - 1.47 (m, 2H), 1.38 - 1.30 (m, 2H), 1.21 - 1.16 (m, 2H). Example 476: 5-(((2/?.7u.S)-2-I luorohex:ihydro-l//-pyrrolizin-7:i-yl)methoxy)- \-( l-(7- methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 596)

Compound 596

Compound 596 was synthesized according to an analogous procedure to the one described for compound 376. M + H ⁺ = 490.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.83 (br d, J= 8.1 Hz, 1H), 9.08 (d, J = 5.5 Hz, 1H), 8.03 - 7.88 (m, 2H), 7.46 (br s, 1H), 7.12 (d, J= 8.3 Hz, 1H), 6.97 (br d, J= 8.7 Hz, 1H), 6.86 (d, J= 2.4 Hz, 1H), 5.67 - 5.46 (m, 1H), 4.27 - 3.99 (m, 5H), 3.95 - 3.70 (m, 3H), 3.52 - 3.41 (m, 1H), 2.76 - 2.44 (m, 2H), 2.41 - 2.16 (m, 3H), 2.01 (d, J= 2.1 Hz, 3H), 1.63 - 1.53 (m, 2H), 1.48 - 1.36 (m, 3H). Example 477: \-( 1 -(lsoquinolin-l-yl)cyclopropyl)-2-methyl-5-(( l-methylazetidin-2- yl)methoxy)benzamide (Compound 454)

Compound 454

Compound 454 was synthesized according to an analogous procedure to the one described for compound 384. M + H ⁺ = 402.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.25 (s, 1H), 8.82 (d, J= 8.3 Hz, 1H), 8.38 (d, J= 5.6 Hz, 1H), 7.97 (d, J= 8.1 Hz, 1H), 7.83 - 7.54 (m, 3H), 7.10 - 6.96 (m, 1H), 6.90 - 6.81 (m, 1H), 6.68 (d, J = 2.7 Hz, 1H), 3.89 (d, J = 5.4 Hz, 2H), 3.31 - 3.24 (m, 2H), 2.78 - 2.70 (m, 1H), 2.24 (s, 3H), 2.02 - 1.82 (m, 5H), 1.62 - 1.46 (m, 2H), 1.43 - 1.27 (m, 2H). Example 478: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(quinolin- 4- yl)cyclopropyl)benzamide (Compound 473)

Compound 473

Compound 473 was synthesized according to an analogous procedure to the one described for compound 384. M + H ⁺ = 402.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.20 (s, 1H), 8.87 (d, J= 4.4 Hz, 1H), 8.66 (d, J= 7.6 Hz, 1H), 8.05 (d, J= 7.8 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J

= 4.4 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.63 (d, = 2.8 Hz, 1H), 3.86 (d, = 5.4 Hz, 2H), 3.28 - 3.11 (m, 2H), 2.71 (br dd, J= 1.3, 7.9 Hz, 1H), 2.21 (s, 3H), 2.03 - 1.94 (m, 1H), 1.93 (s, 3H), 1.91 - 1.78 (m, 1H), 1.38 (d, J= 1.9 Hz, 2H), 1.25 (d, J= 1.9 Hz, 2H). Example 479: /V-(l-(3-Methoxyisoquinolin-5-yl)cyclopropyl)-2-methyl-5-((l - methylazetidin-2-yl)methoxy)benzamide (Compound 456)

Compound 456

Compound 456 was synthesized according to an analogous procedure to the one described for compound 384. M + H ⁺ = 432.1 (LCMS); ¹ H NMR (400 MHz, CD ₃ OD) 8 8.97 (s, 1H), 8.07 - 7.97 (m, 1H), 7.92 (d, J= 8.25 Hz, 1H), 7.80 (s, 1H), 7.43 - 7.37 (m, 1H), 7.04 (d, J= 8.38 Hz, 1H), 6.84 (dd, J= 8.38, 2.75 Hz, 1H), 6.66 (d, J= 2.63 Hz, 1H), 4.05 (s, 3H), 3.97 - 3.91 (m, 2H), 3.64 - 3.55 (m, 1H), 3.46 (td, J = 7.66, 3.19 Hz, 1H), 3.04 (q, J = 8.34 Hz, 1H), 2.49 - 2.40 (m, 3H), 2.14 - 2.06 (m, 2H), 2.01 (s, 3H), 1.49 - 1.43 (m, 2H), 1.30 - 1.26 (m, 2H). Example 480: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(2-methyln aphthalen- l-yl)cyclopropyl)benzamide (Compound 458)

Compound 458

Compound 458 was synthesized according to an analogous procedure to the one described for compound 384. M + H ⁺ = 415.1 (LCMS); ^X H NMR (400 MHz, CD ₃ OD) 8 8.99 - 8.82 (m, 2H), 7.80 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.47 - 7.39 (m, 1H), 7.32 (d, J =

8.4 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.96 (dd, J= 2.8, 8.4 Hz, 1H), 6.79 (d, J= 2.8 Hz, 1H), 4.74 - 4.59 (m, 1H), 4.33 - 4.25 (m, 1H), 4.24 - 4.12 (m, 2H), 3.96 (q, J = 9.6 Hz, 1H), 2.93 (d, J= 13.6 Hz, 6H), 2.62 - 2.50 (m, 2H), 2.10 (s, 3H), 1.82 - 1.72 (m, 1H), 1.66 - 1.56 (m, 1H), 1.44 - 1.34 (m, 1H), 1.24 - 1.14 (m, 1H). Example 481: /V-(l-(Anthracen-9-yl)cyclopropyl)-2-methyl-5-((l-methylazet idin-2- yl)methoxy)benzamide (Compound 507)

Compound 507

Compound 507 was synthesized according to an analogous procedure to the one described for compound 384. M + H ⁺ = 451.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 89.74 (s, 1H), 8.62 (s, 1H), 8.18 - 8.09 (m, 4H), 7.57 - 7.50 (m, 4H), 7.09 - 7.01 (m, 1H), 6.92 - 6.74 (m, 3H), 3.93 - 3.83 (m, 2H), 3.26 (br d, J= 4.6 Hz, 1H), 2.30 - 2.15 (m, 7H), 2.05 - 1.79 (m, 3H), 1.25 (d, J = 7.0 Hz, 4H).

Example 482: /V-(l-(7-Hydroxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 488)

Compound 488

Compound 488 was synthesized according to an analogous procedure to the one described for compound 433. M + H ⁺ = 418.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.12 (s, 1H), 9.08 (s, 1H), 8.89 (d, J= 7.9 Hz, 1H), 8.73 (dd, J= 1.5, 4.3 Hz, 1H), 7.45 (d, J= 2.4 Hz, 1H), 7.32 (dd, J= 4.2, 8.4 Hz, 1H), 7.15 (d, J= 2.4 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.84 (dd, J=

2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.8 Hz, 1H), 3.88 (d, J= 5.4 Hz, 2H), 3.27 (br t, J= 6.6 Hz, 2H), 2.84 - 2.72 (m, 1H), 2.23 (s, 3H), 2.01 - 1.78 (m, 5H), 1.37 - 1.30 (m, 2H), 1.20 - 1.11 (m, 2H). Example 483: ( )-/V-(l-(2-Chloro-7-methoxyquinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 617)

Compound 617

Compound 617 was synthesized according to an analogous procedure to the one described for compound 436. M + H ⁺ = 466.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 59.11 (s, 1H), 8.99 (d, J= 8.8 Hz, 1H), 7.49 (dd, J= 3.1, 5.6 Hz, 2H), 7.29 (d, J = 2.5 Hz, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.61 (d, J= 2.8 Hz, 1H), 3.92 (s, 3H), 3.87 (d, J= 5.4 Hz, 2H), 3.28 - 3.19 (m, 2H), 2.78 - 2.68 (m, 1H), 2.21 (s, 3H), 1.99 - 1.80 (m, 5H), 1.33 (s, 2H), 1.25 - 1.17 (m, 2H). Example 484: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(quinolin-5-yl)cyclopropyl ) benzamide (Compound 498)

Compound 498

Compound 498 was synthesized according to an analogous procedure to the one described for compound 445. M + H ⁺ = 376.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.22 - 9.13 (m, 2H), 8.98 (dd, J = 4.25, 1.38 Hz, 1H), 8.01 - 7.86 (m, 5H), 7.78 (dd, J = 8.38, 7.25 Hz, 1H),

7.68 (dd, J= 8.63, 4.25 Hz, 1H), 7.08 (d, J = 8.50 Hz, 1H), 6.89 (dd, J = 8.38, 2.75 Hz, 1H), 6.67 (d, J= 2.75 Hz, 1H), 4.02 (dd, J= 10.26, 3.88 Hz, 1H), 3.85 (dd, J= 10.38, 7.13 Hz, 1H), 3.60 - 3.48 (m, 1H), 1.95 (s, 3H), 1.41 - 1.34 (m, 2H), 1.26 - 1.18 (m, 5H). Example 485: 5-(2-Aminopropoxy)-/V-(l-(isoquinolin-5-yl)cyclopropyl)-2- methylbenzamide (Compound 446)

Compound 446

Compound 446 was synthesized according to an analogous procedure to the one described for compound 445. M + H ⁺ = 376.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.63 (s, 1H), 9.25

(s, 1H), 8.68 - 8.82 (m, 2H), 8.25 (dd, J= 7.69, 4.06 Hz, 2H), 7.97 - 8.11 (m, 3H), 7.83 (t, J= 7.75 Hz, 1H), 7.08 (d, J= 8.51 Hz, 1H), 6.90 (dd, J= 8.38, 2.63 Hz, 1H), 6.70 (d, J= 2.75 Hz, 1H), 4.03 (dd, J= 10.26, 3.88 Hz, 1H), 3.87 (dd, J= 10.19, 7.07 Hz, 1H), 3.48 - 3.62 (m, 1H), 1.94 (s, 3H), 1.39 (br s, 2H), 1.19 - 1.28 (m, 5H). Example 486: ( )-/V-(3-(7-Methoxyquinolin-5-yl)oxetan-3-yl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 566)

Compound 566

Compound 566 was synthesized according to an analogous procedure to the one described for compound 450. M + H ⁺ = 448.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.78 (dd, J= 1.5, 4.4 Hz, 1H), 8.09 (d, J= 8.1 Hz, 1H), 7.56 (d, J= 2.5 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.06 (d, J

= 8.5 Hz, 1H), 6.87 (dd, J = 2.6, 8.4 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 5.36 - 5.28 (m, 4H), 4.00 (s, 3H), 3.93 (d, J= 5.5 Hz, 2H), 3.56 - 3.46 (m, 1H), 3.41 (dt, J= 2.8, 7.8 Hz, 1H), 3.03 - 2.89 (m, 1H), 2.39 (s, 3H), 2.15 - 2.01 (m, 2H), 1.98 (s, 3H). Example 487: 5-(3-Aminoazetidin-l-yl)-2-methyl-/V-(l-(naphthalen-l-yl)cyc lopropyl) benzamide (Compound 464)

Compound 464

Compound 464 was synthesized according to an analogous procedure to the one described for compound 463. M + H ⁺ = 372.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.02 (s, 1H), 8.65 (d, J= 8.4 Hz, 1H), 8.26 (br s, 3H), 7.98 - 7.89 (m, 1H), 7.86 - 7.77 (m, 2H), 7.60 - 7.42 (m, 3H), 6.95 (d, J= 8.1 Hz, 1H), 6.41 (dd, J = 2.4, 8.2 Hz, 1H), 6.18 (d, J= 2.5 Hz, 1H), 4.09 - 4.02 (m, 1H), 3.97 (t, J= 7.7 Hz, 2H), 3.68 - 3.65 (m, 2H), 1.91 (s, 3H), 1.40 - 1.31 (m, 2H), 1.23 - 1.13 (m, 2H). Example 488: 5-(3-Aminopyrrolidin-l-yl)-2-methyl-/V-(l-(naphthalen-l-yl)c yclopropyl) benzamide (Compound 485)

Compound 485

Compound 485 was synthesized according to an analogous procedure to the one described for compound 463. M + H ⁺ = 386.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.01 (s, 1H), 8.6 7 (d, J= 8.3 Hz, 1H), 8.16 (br s, 3H), 7.93 (d, J= 7.9 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.61 - 7.4

3 (m, 3H), 6.94 (d, J= 8.4 Hz, 1H), 6.48 (dd, J= 2.6, 8.3 Hz, 1H), 6.25 (d, J= 2.5 Hz, 1H), 3. 46 - 3.29 (m, 2H), 3.22 - 3.12 (m, 2H), 2.58 - 2.52 (m, 1H), 2.34 - 2.21 (m, 1H), 2.07 - 1.96 (m, 1H), 1.91 (s, 3H), 1.35 (s, 2H), 1.22 - 1.13 (m, 2H). Example 489: 5-((3»S,51?)-3,5-Dimethylpiperazin-l-yl)-2-methyl-/V-(l-(na phthalen-l- yl)cyclopropyl)benzamide (Compound 506)

Compound 506

Compound 506 was synthesized according to an analogous procedure to the one described for compound 463. M + H ⁺ = 414.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.54 - 9.30 (m, 1H), 9.05 (s, 1H), 8.91 - 8.63 (m, 2H), 7.93 (d, J= 7.5 Hz, 1H), 7.82 (dd, J = 7.6, 10.5 Hz, 2H), 7.60 - 7.41 (m, 3H), 7.03 - 6.97 (m, 1H), 6.91 (s, 1H), 6.64 (d, J= 2.5 Hz, 1H), 3.67 (br d, J = 11.4 Hz, 2H), 3.27 (br s, 2H), 2.56 (br t, J = 11.9 Hz, 2H), 1.92 (s, 3H), 1.36 (s, 2H), 1.26 (d, J= 6.4 Hz, 6H), 1.18 (br s, 2H). Example 490: 5-(2-Aminopropoxy)-2-methyl-/V-(l-(3-(5-methylthiophen-2- yl)naphthalen-l-yl)cyclopropyl)benzamide (Compound 479)

Compound 479

Compound 479 was synthesized according to an analogous procedure to the one described for compound 470. M + H ⁺ = 471.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.24 (s, 1H), 8.56 - 8.49 (m, 1H), 8.18 (d, J= 1.88 Hz, 1H), 7.94 (d, J= 1.50 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.55 -

7.46 (m, 2H), 7.37 (d, J= 3.50 Hz, 1H), 7.08 (d, J= 8.50 Hz, 1H), 6.90 (dd, J= 8.50, 2.75 Hz, 1H), 6.81 (dd, J= 3.56, 1.06 Hz, 1H), 6.71 (d, J= 2.63 Hz, 1H), 4.07 (dd, J= 10.32, 3.56 Hz, 1H), 3.86 (dd, J= 10.38, 7.25 Hz, 1H), 3.62 (td, J = 6.88, 3.50 Hz, 1H), 2.53 (s, 3H), 2.04 (s, 3H), 1.47 (s, 2H), 1.39 - 1.30 (m, 5H). Example 491: 5-(2-Aminopropoxy)-/V-(l-(3-(5-chlorothiophen-2-yl)naphthale n-l- yl)cyclopropyl)-2-methylbenzamide (Compound 502)

Compound 502

Compound 502 was synthesized according to an analogous procedure to the one described for compound 470. M + H ⁺ = 491.2 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 89.12 (s, 1H), 8.67 - 8.59 (m, 1H), 8.06 (d, J= 1.50 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.61 - 7.51 (m, 3H), 7.23 (d, J = 3.88 Hz, 1H), 7.02 (d, J= 8.50 Hz, 1H), 6.83 (dd, J = 8.32, 2.69 Hz, 1H), 6.60 (d, J = 2.63 Hz, 1H), 3.67 - 3.56 (m, 2H), 3.11 - 3.00 (m, 1H), 1.96 (s, 3H), 1.38 (br s, 2H), 1.30 - 1.23 (m, 2H), 1.00 (d, J= 6.50 Hz, 3H). Example 492: 5-(2-Aminopropoxy)-/V-(l-(3-(4-fluorophenyl)naphthalen-l- yl)cyclopropyl)-2-methylbenzamide (Compound 480)

Compound 480

Compound 480 was synthesized according to an analogous procedure to the one described for compound 470. M + H ⁺ = 469.3 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 8.60 (d, J = 8.13 Hz, 1H), 8.23 (d, J= 1.88 Hz, 1H), 8.06 (d, J= 1.38 Hz, 1H), 8.03 - 7.97 (m, 1H), 7.85 (dd, J = 8.75, 5.38 Hz, 2H), 7.65 - 7.53 (m, 2H), 7.25 (t, J= 8.82 Hz, 2H), 7.11 (d, J= 8.50 Hz, 1H), 6.94 (br d, J= 2.75 Hz, 1H), 6.73 (d, J= 2.63 Hz, 1H), 4.10 (dd, J= 10.26, 3.50 Hz, 1H), 3.88 (s, 1H), 3.70 - 3.59 (m, 1H), 2.05 (s, 3H), 1.50 (br s, 2H), 1.44 - 1.38 (m, 2H), 1.36 (d, J = 6.75 Hz, 3H). Example 493: /V-(l-(3-Ethoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 478)

Compound 478

Compound 478 was synthesized according to an analogous procedure to the one described for compound 474. M + H ⁺ = 445.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.11 - 9.04 (m, 1H), 8.57 - 8.50 (m, 1H), 8.22 - 8.15 (m, 1H), 7.86 - 7.77 (m, 1H), 7.48 - 7.33 (m, 3H), 7.25 - 7.17 (m, 1H), 7.07 - 6.98 (m, 1H), 6.88 - 6.78 (m, 1H), 6.67 - 6.52 (m, 1H), 4.18 - 4.09 (m, 2H), 3.90 - 3.84 (m, 2H), 3.30 - 3.24 (m, 2H), 2.76 (br d, J= 7.8 Hz, 1H), 2.23 (s, 3H), 2.03 - 1.78 (m, 5H), 1.44 - 1.38 (m, 3H), 1.35 - 1.29 (m, 2H), 1.19 - 1.12 (m, 2H). Example 494: /V-(l-(3-Isopropoxynaphthalen-l-yl)cyclopropyl)-2-methyl-5-( (l-methyl azetidin-2-yl)methoxy)benzamide (Compound 476)

Compound 476

Compound 476 was synthesized according to an analogous procedure to the one described for compound 474. M + H ⁺ = 459.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.09 - 9.03 (m, 1H), 8.56 - 8.49 (m, 1H), 8.22 - 8.17 (m, 1H), 7.83 - 7.76 (m, 1H), 7.47 - 7.33 (m, 3H), 7.24

- 7.19 (m, 1H), 7.05 - 6.99 (m, 1H), 6.85 - 6.80 (m, 1H), 6.62 - 6.57 (m, 1H), 4.82 - 4.68 (m, 1H), 3.91 - 3.82 (m, 2H), 3.27 - 3.20 (m, 2H), 2.77 - 2.70 (m, 1H), 2.23 - 2.19 (m, 3H), 2.03 - 1.78 (m, 5H), 1.37 - 1.33 (m, 6H), 1.33 - 1.30 (m, 2H), 1.18 - 1.12 (m, 2H). Example 495: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7- (neopentyloxy)quinolin-5-yl)cyclopropyl)benzamide (Compound 787)

Compound 787

Compound 787 was synthesized according to an analogous procedure to the one described for compound 474. M + H ⁺ = 488.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.67 - 9.59 (m, 1H), 9.34 - 9.28 (m, 1H), 9.12 - 9.05 (m, 1H), 7.97 - 7.88 (m, 1H), 7.77 - 7.71 (m, 1H), 7.53 - 7.46 (m, 1H), 7.13 - 7.06 (m, 1H), 6.95 - 6.89 (m, 1H), 6.76 - 6.71 (m, 1H), 4.66 - 4.56 (m, 1H), 4.31 - 4.16 (m, 2H), 4.05 - 3.98 (m, 1H), 3.92 - 3.85 (m, 3H), 2.86 - 2.67 (m, 3H), 2.43 - 2.26 (m, 2H), 1.96 - 1.90 (m, 3H), 1.46 - 1.39 (m, 2H), 1.35 - 1.27 (m, 2H), 1.09 - 1.02 (m, 9H).

Example 496: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-(5-meth ylthiophen-

2-yl)naphthalen-l-yl)cyclopropyl)benzamide (Compound 493)

Compound 493

Compound 493 was synthesized according to an analogous procedure to the one described for compound 475. M + H ⁺ = 497.1 (LCMS); 1H NMR (400 MHz, DMSO-tL) 8 9.91 (br s, 1H), 9.13 (s, 1H), 8.64 - 8.52 (m, 1H), 8.04 - 7.98 (m, 2H), 7.97 - 7.93 (m, 1H), 7.57 - 7.49 (m, 2H), 7.44 (d, J= 3.5 Hz, 1H), 7.08 (d, J= 8.3 Hz, 1H), 6.94 - 6.85 (m, 2H), 6.69 (d, J = 2.6 Hz, 1H), 4.63 - 4.51 (m, 1H), 4.27 - 4.17 (m, 2H), 4.05 - 3.96 (m, 1H), 3.84 (br dd, J = 6.5, 9.4 Hz, 1H), 2.82 (d, J= 4.8 Hz, 3H), 2.50 (br s, 3H), 2.43 - 2.28 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.25 (br s, 2H). Example 497 : /V-(l-(3-(5-Chlorothiophen-2-yl)naphthalen-l-yl)cyclopropyl) -2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 514)

Compound 514

Compound 514 was synthesized according to an analogous procedure to the one described for compound 475. M + H ⁺ = 517.0 (LCMS); ^X H NMR (400 MHz, DMSO-t/e) 6 10.38 - 10.11 (m, 1H), 9.15 (s, 1H), 8.66 - 8.61 (m, 1H), 8.07 (d, J= 1.5 Hz, 1H), 8.03 - 7.98 (m, 2H), 7.59 - 7.54 (m, 3H), 7.24 (d, J= 4.0 Hz, 1H), 7.08 (s, 1H), 6.93 - 6.87 (m, 1H), 6.70 (d, J= 2.8 Hz, 1H), 4.68 - 4.56 (m, 1H), 4.32 - 4.18 (m, 2H), 4.06 - 3.95 (m, 1H), 3.90 - 3.76 (m, 1H), 2.82 (d, J= 5.1 Hz, 3H), 2.38 - 2.28 (m, 2H), 1.98 (s, 3H), 1.38 (br s, 2H), 1.28 (br s, 2H). Example 498: /V-(l-(3-(4-Fluorophenyl)naphthalen-l-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 518)

Compound 518

Compound 518 was synthesized according to an analogous procedure to the one described for compound 475. M + H ⁺ = 495.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 59.13 (s, 1H), 8.66 (d, = 7.9 Hz, 1H), 8.24 - 8.16 (m, 1H), 8.14 - 8.08 (m, 2H), 8.01 (br d, J= 7.5 Hz, 1H), 7.87

(dd, J= 5.9, 7.9 Hz, 2H), 7.65 - 7.50 (m, 2H), 7.37 (s, 2H), 7.08 - 6.97 (m, 1H), 6.89 - 6.76 (m, 1H), 6.60 (d, J= 2.4 Hz, 1H), 3.86 (d, J= 5.0 Hz, 2H), 3.26 (br d, J= 1.1 Hz, 2H), 2.78 - 2.68 (m, 1H), 2.22 (s, 3H), 1.98 (s, 3H), 1.94 (br s, 2H), 1.38 (br s, 2H), 1.29 (br d, J= 2.6 Hz, 2H). Example 499: /V-(l-(3-Acetamidonaphthalen-l-yl)cyclopropyl)-2-methyl-5-(( l- methylazetidin-2-yl)methoxy)benzamide (Compound 500)

Compound 500

Compound 500 was synthesized according to an analogous procedure to the one described for compound 482. M + H ⁺ = 458.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.20 (s, 1H), 9.93 - 9.80 (m, 1H), 9.12 (s, 1H), 8.58 - 8.50 (m, 1H), 8.35 (d, J = 1.50 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.50 - 7.39 (m, 2H), 7.10 (d, J= 8.38 Hz, 1H), 6.91 (dd, J= 8.38, 2.75 Hz, 1H), 6.76 - 6.68 (m, 1H), 4.60 (br d, J= 3.63 Hz, 1H), 4.28 - 4.14 (m, 2H), 4.07 - 3.96 (m, 1H), 3.92 - 3.80 (m, 1H), 2.83 (d, J= 4.13 Hz, 3H), 2.43 - 2.27 (m, 2H), 2.10 (s, 3H), 1.99 (s, 3H), 1.35 (br s, 2H), 1.16 (br s, 2H).

Example 500: 5-(((21?,45)-4-Fluoropyrrolidin-2-yl)methoxy)-A ^z -(l-(3- methoxynaphthalen-l-yl)cyclopropyl)-2-methylbenzamide (Compound 510)

Compound 510

Compound 510 was synthesized according to an analogous procedure to the one described for compound 490. M + H ⁺ = 449.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.04 (br d, J = 8.0 Hz, 1H), 9.73 - 9.48 (m, 1H), 9.13 (s, 1H), 8.55 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.53 - 7.34 (m, 3H), 7.24 (d, J= 2.5 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 6.90 (dd, J= 2.8, 8.4 Hz, 1H), 6.68 (d, J= 2.6 Hz, 1H), 5.62 - 5.30 (m, 1H), 4.27 - 4.20 (m, 1H), 4.19 - 4.10 (m, 1H), 4.09 - 3.98 (m, 1H), 3.87 (s, 3H), 3.50 (br s, 2H), 2.44 - 2.28 (m, 1H), 2.12 - 1.91 (m, 4H), 1.34 (br s, 2H), 1.16 (br s, 2H). Example 501: 5-(((2»S,41?)-4-Fluoropyrrolidin-2-yl)methoxy)-/V-(l-(7-met hoxyquinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 512)

Compound 512

Compound 512 was synthesized according to an analogous procedure to the one described for compound 490. M + H ⁺ = 450.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.26 - 10.11 (m, 1H), 9.88 - 9.68 (m, 2H), 9.44 - 9.36 (m, 1H), 9.22 - 9.14 (m, 1H), 8.02 - 7.94 (m, 1H), 7.76 - 7.69 (m, 2H), 7.09 (d, J = 8.5 Hz, 1H), 6.92 (dd, J = 2.6, 8.4 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 5.60 - 5.32 (m, 1H), 4.29 - 4.16 (m, 3H), 4.02 (s, 3H), 3.63 - 3.40 (m, 2H), 2.45 - 2.29 (m, 1H), 2.00 (br s, 1H), 1.99 - 1.95 (m, 3H), 1.45 - 1.40 (m, 2H), 1.35 - 1.28 (m, 2H). Example 502: 5-(((27?,45)-4-Fluoropyrrolidin-2-yl)methoxy)-N-(l-(7-methox yquinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 556)

Compound 556

Compound 556 was synthesized according to an analogous procedure to the one described for compound 490. M + H ⁺ = 450.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.09 (s, 1H), 9.01 - 8.88 (m, 1H), 8.81 (dd, J = 1.6, 4.2 Hz, 1H), 7.51 - 7.37 (m, 2H), 7.31 (d, J= 2.5 Hz, 1H),

7.03 (d, J= 8.4 Hz, 1H), 6.83 (dd, J = 2.6, 8.4 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 5.34 - 5.10 (m, 1H), 3.92 (s, 3H), 3.82 - 3.68 (m, 2H), 3.60 - 3.48 (m, 1H), 3.02 (d, J= 2.1 Hz, 1H), 2.97 - 2.90 (m, 1H), 2.15 - 1.98 (m, 1H), 1.94 (s, 3H), 1.77 - 1.52 (m, 1H), 1.42 - 1.29 (m, 2H), 1.21 - 1.12 (m, 2H). Example 503: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-vinylna phthalen-l- yl)cyclopropyl)benzamide (Compound 517)

Compound 517

Compound 517 was synthesized according to an analogous procedure to the one described for compound 508. M + H ⁺ = 427.1 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 10.26 - 10.15 (m, 1H), 9.11 (s, 1H), 8.61 (d, J = 1.5 Hz, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.94 - 7.90 (m, 1H), 7.84 (s, 1H), 7.53 (dquin, J= 1.4, 6.9 Hz, 2H), 7.11 - 7.07 (m, 1H), 6.96 - 6.87 (m, 2H), 6.69 (d, J = 2.8 Hz, 1H), 5.98 (d, J= 17.5 Hz, 1H), 5.39 (d, J= 11.4 Hz, 1H), 4.69 - 4.51 (m, 1H), 4.32 - 4.16 (m, 2H), 4.08 - 3.94 (m, 1H), 3.90 - 3.77 (m, 1H), 2.82 (d, J= 4.9 Hz, 3H), 2.75 - 2.59 (m, 1H), 2.38 - 2.26 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.23 (br s, 2H).

Example 504: /V-(l-(3-Allylnaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l-me thylazetidin- 2-yl)methoxy)benzamide (Compound 503)

Compound 503

Compound 503 was synthesized according to an analogous procedure to the one described for compound 508. M + H ⁺ = 441.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.31 - 10.10 (m, 1H), 9.09 (s, 1H), 8.61 (br d, J= 7.5 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.68 (d, J= 1.5 Hz, 1H), 7.61 (s, 1H), 7.54 - 7.46 (m, 2H), 7.09 (d, J= 8.4 Hz, 1H), 6.90 (dd, J= 2.6, 8.3 Hz, 1H), 6.69 (d, ./= 2,6 Hz, 1H), 6.06 (tdd, = 6.8, 10.1, 17.0 Hz, 1H), 5.23 - 5.07 (m, 2H), 4.65 - 4.54 (m, 1H), 4.32 - 4.16 (m, 2H), 4.05 - 3.94 (m, 1H), 3.90 - 3.79 (m, 1H), 3.54 (d, J= 6.6 Hz, 2H), 2.81 (br s, 3H), 2.39 - 2.28 (m, 2H), 1.98 (s, 3H), 1.35 (br s, 2H), 1.21 - 1.12 (m, 2H). Example 505: ( S)-2-Methyl-\-(l-(7-( 1 -methyl- l//-pyr:izol-5-yl)quinolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 578)

Compound 578

Compound 578 was synthesized according to an analogous procedure to the one described for compound 508. M + H ⁺ = 482.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 5 11.11 (hr s, 1H), 9.76 (d, J= 8.6 Hz, 1H), 9.55 - 9.41 (m, 1H), 9.32 (d, J= 4.0 Hz, 1H), 8.50 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 8.12 (dd, J = 5.1, 8.6 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.98 - 6.89 (m, 1H), 6.83 - 6.73 (m, 2H), 4.68 - 4.59 (m, 1H), 4.44 (dd, J= 8.3, 11.2 Hz, 1H), 4.26 - 4.19 (m, 1H), 4.08 - 4.00 (m, 5H), 2.85 - 2.65 (m, 3H), 2.38 - 2.25 (m, 2H), 2.01 - 1.95 (m, 3H), 1.47 (br s, 2H), 1.39 (br s, 2H).

Example 506: (l?)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-methoxyquinolin-5-yl) cyclopropyl)- 2-methylbenzamide (Compound 554)

Compound 554

Compound 554 was synthesized according to an analogous procedure to the one described for compound 511. M + H ⁺ = 418.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.72 (d, J= 8.4 Hz, 1H), 9.35 (s, 1H), 9.17 (dd, J= 1.2, 5.4 Hz, 1H), 7.99 (dd, J= 5.4, 8.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.61 (d, J= 2.3 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.75 (d, J= 2.8 Hz, 1H), 4.65 (dq, J = 3.3, 7.9 Hz, 1H), 4.29 (dd, J= 7.4, 11.2 Hz, 1H), 4.15 (dd, J= 3.4, 11.3 Hz, 1H), 4.02 (s, 3H), 3.96 - 3.87 (m, 1H), 3.82 (dt, J = 6.3, 9.9 Hz, 1H), 2.47 - 2.41 (m, 1H), 2.40 - 2.28 (m, 1H), 1.96 (s, 3H), 1.42 (br s, 2H), 1.36 - 1.26 (m, 2H). Example 507: /V-(l-(3-Ethylnaphthalen-l-yl)cyclopropyl)-2-methyl-5-((l- methylazetidin-2-yl)methoxy)benzamide(Compound 516)

Compound 516

Compound 516 was synthesized according to an analogous procedure to the one described for compound 521. M + H ⁺ = 429.1 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 10.56 - 10.43 (m, 1H), 9.09 (s, 1H), 8.65 - 8.53 (m, 1H), 7.89 - 7.82 (m, 1H), 7.69 (d, J= 1.6 Hz, 1H), 7.61 (s, 1H), 7.52 - 7.44 (m, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.95 - 6.86 (m, 1H), 6.69 (br s, 1H), 4.60 (br d, J= 4.3 Hz, 1H), 4.36 - 4.26 (m, 1H), 4.24 - 4.16 (m, 1H), 3.98 (br s, 1H), 3.88 - 3.73 (m, 1H), 2.84 - 2.72 (m, 5H), 2.40 - 2.25 (m, 2H), 1.98 (s, 3H), 1.35 (br s, 2H), 1.32 - 1.25 (m, 3H), 1.22 - 1.14 (m, 2H).

Example 508: 2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(3-propyln aphthalen- 1-yl) cyclopropyl)benzamide (Compound 504)

Compound 504

Compound 504 was synthesized according to an analogous procedure to the one described for compound 521. M + H ⁺ = 443.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.45 - 10.35 (m, 1H), 9.08 (s, 1H), 8.64 - 8.56 (m, 1H), 7.89 - 7.82 (m, 1H), 7.69 (d, J= 1.6 Hz, 1H), 7.60 (s, 1H), 7.52 - 7.44 (m, 2H), 7.08 (d, J= 8.5 Hz, 1H), 6.90 (dd, J= 2.8, 8.4 Hz, 1H), 6.69 (d, J= 2.6 Hz, 1H), 4.67 - 4.55 (m, 1H), 4.36 - 4.26 (m, 1H), 4.24 - 4.17 (m, 1H), 4.05 - 3.94 (m, 1H), 3.84 (br dd, J= 6.5, 9.6 Hz, 1H), 2.81 (d, J= 5.1 Hz, 3H), 2.75 - 2.66 (m, 2H), 2.40 - 2.26 (m, 2H), 2.02 - 1.95 (m, 3H), 1.75 - 1.63 (m, 2H), 1.35 (br s, 2H), 1.17 (br s, 2H), 0.95 (t, J = 7.4 Hz, 3H). Example 509: (l?)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-( (l- methylazetidin-2-yl)methoxy)benzamide (Compound 558)

Compound 558

Compound 558 was synthesized according to an analogous procedure to the one described for compound 527. M + H ⁺ = 432.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.64 (br d, J= 8.6 Hz, 1H), 9.31 (s, 1H), 9.15 (d, J= 5.3 Hz, 1H), 7.95 (dd, J= 5.4, 8.5 Hz, 1H), 7.73 (d, J= 2.5 Hz, 1H), 7.55 (s, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.76 (d, J= 2.8 Hz, 1H), 4.62 (dt, J= 5.6, 8.0 Hz, 1H), 4.37 - 4.16 (m, 2H), 4.02 (s, 4H), 3.86 (d, J= 9.6 Hz, 1H), 2.82 (s, 3H), 2.43 - 2.27 (m, 2H), 1.94 (s, 3H), 1.41 (br s, 2H), 1.31 (br s, 2H). Example 510: 5-(((21?,45)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-A ^z -(l-(3- methoxynaphthalen-l-yl)cyclopropyl)-2-methylbenzamide(Compou nd 531)

Compound 531

Compound 531 was synthesized according to an analogous procedure to the one described for compound 528. M + H ⁺ = 463.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 11.30 - 11.07 (m, 1H), 9.13 (s, 1H), 8.54 (d, J= 8.3 Hz, 1H), 7.83 (d, J= 7.9 Hz, 1H), 7.50 - 7.34 (m, 3H), 7.24

(d, J= 2.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.92 (dd, J = 2.8, 8.4 Hz, 1H), 6.80 - 6.65 (m, 1H), 5.55 - 5.31 (m, 1H), 4.33 (br d, J= 5.1 Hz, 2H), 4.10 - 3.98 (m, 2H), 3.91 - 3.87 (m, 3H), 3.55 - 3.38 (m, 1H), 2.97 (d, J= 4.6 Hz, 3H), 2.49 - 2.37 (m, 1H), 2.22 - 2.03 (m, 1H), 1.97 (s, 3H), 1.34 (br s, 2H), 1.17 (br s, 2H). Example 511: 5-(((2»S,41?)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-/V- (l-(7- methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 532)

Compound 532

Compound 532 was synthesized according to an analogous procedure to the one described for compound 528. M + H ⁺ = 464.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.12 - 9.05 (m, 1H), 8.97 - 8.90 (m, 1H), 8.84 - 8.77 (m, 1H), 7.48 - 7.45 (m, 1H), 7.44 - 7.38 (m, 1H), 7.32 - 7.29 (m, 1H), 7.05 - 7.01 (m, 1H), 6.87 - 6.81 (m, 1H), 6.63 - 6.59 (m, 1H), 5.31 - 5.01 (m, 1H), 3.94 - 3.89 (m, 4H), 3.84 - 3.78 (m, 1H), 3.47 - 3.34 (m, 1H), 2.89 - 2.79 (m, 1H), 2.43 - 2.36 (m, 1H), 2.36 - 2.33 (m, 3H), 2.16 - 2.02 (m, 1H), 1.96 - 1.91 (m, 3H), 1.89 - 1.73 (m, 1H), 1.36 - 1.30 (m, 2H), 1.21 - 1.15 (m, 2H).

Example 512: 5-(((21?,45)-4-Fluoro-l-methylpyrrolidin-2-yl)methoxy)-A ^z -(l-(7- methoxyquinolin-5-yl)cyclopropyl)-2-methylbenzamide(Compound 557)

Compound 557

Compound 557 was synthesized according to an analogous procedure to the one described for compound 528. M + H ⁺ = 464.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.10 (s, 1H), 9.00

- 8.91 (m, 1H), 8.87 - 8.76 (m, 1H), 7.49 - 7.45 (m, 1H), 7.44 - 7.39 (m, 1H), 7.33 - 7.29 (m, 1H), 7.06 - 7.00 (m, 1H), 6.88 - 6.80 (m, 1H), 6.66 - 6.58 (m, 1H), 5.29 - 4.96 (m, 1H), 4.01

- 3.87 (m, 4H), 3.85 - 3.77 (m, 1H), 3.47 - 3.36 (m, 1H), 2.91 - 2.79 (m, 1H), 2.41 (br d, J = 11.6 Hz, 1H), 2.34 (s, 3H), 2.18 - 1.99 (m, 1H), 1.94 (s, 3H), 1.91 - 1.70 (m, 1H), 1.34 (br s, 2H), 1.24 - 1.13 (m, 2H). Example 513: ( )-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((l- methylpiperidin-2-yl)methoxy)benzamide (Compound 553)

Compound 553

Compound 553 was synthesized according to an analogous procedure to the one described for compound 528. M + H ⁺ = 460.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.69 (d, J = 8.4 Hz, 1H), 9.37 (s, 1H), 9.21 - 9.14 (m, 1H), 7.98 (dd, J= 5.4, 8.4 Hz, 1H), 7.73 (d, J= 2.5 Hz,

1H), 7.62 (d, J = 2.1 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.97 - 6.88 (m, 1H), 6.81 - 6.74 (m,

1H), 4.27 - 4.13 (m, 2H), 4.02 (s, 3H), 3.35 (br s, 1H), 3.28 - 3.18 (m, 1H), 3.09 - 3.01 (m,

1H), 2.78 - 2.68 (m, 3H), 1.96 (s, 3H), 1.94 - 1.86 (m, 1H), 1.80 - 1.66 (m, 4H), 1.57 - 1.44 (m, 1H), 1.42 (br s, 2H), 1.31 (br s, 2H).

Example 514: (l?)-5-(2-Aminopropoxy)-/V-(l-(7-methoxyquinolin-5-yl)cyclop ropyl)-2- methylbenzamide (Compound 535)

Compound 535

Compound 535 was synthesized according to an analogous procedure to the one described for compound 530. M + H ⁺ = 406.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.24 - 9.14 (m, 2H), 8.97 (br d, J= 4.38 Hz, 1H), 7.95 (br s, 3H), 7.63 (br dd, J= 8.19, 4.69 Hz, 1H), 7.57 (d, J= 2.38 Hz, 1H), 7.39 (d, J= 2.13 Hz, 1H), 7.09 (d, J= 8.50 Hz, 1H), 6.90 (dd, J= 8.38, 2.75 Hz, 1H), 6.69 (d, J= 2.63 Hz, 1H), 4.03 (dd, J= 10.26, 3.88 Hz, 1H), 3.96 (s, 3H), 3.86 (dd, J = 10.26, 7.25 Hz, 1H), 3.61 - 3.48 (m, 1H), 1.95 (s, 3H), 1.36 (br s, 2H), 1.29 - 1.17 (m, 5H). Example 515: (5)-5-(2-Aminopropoxy)-/V-(l-(7-methoxyisoquinolin-5-yl)cycl opropyl)-2- methylbenzamide (Compound 536)

Compound 536

Compound 536 was synthesized according to an analogous procedure to the one described for compound 530. M + H ⁺ = 406.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 89.45 (s, 1H), 9.22 (s, 1H), 8.63 (d, J= 6.13 Hz, 1H), 8.55 (d, J= 6.13 Hz, 1H), 7.96 (br s, 3H), 7.80 (d, J= 2.63 Hz, 1H), 7.63 (d, J= 2.25 Hz, 1H), 7.08 (d, J= 8.50 Hz, 1H), 6.89 (dd, J= 8.44, 2.69 Hz, 1H), 6.69 (d, J= 2.63 Hz, 1H), 4.02 (br d, J = 6.38 Hz, 1H), 3.95 (s, 3H), 3.85 (br d, J = 3.13 Hz, 1H), 3.58 - 3.51 (m, 1H), 1.94 (s, 3H), 1.40 - 1.31 (m, 2H), 1.22 (br d, J= 6.75 Hz, 5H).

Example 516: (l?)-5-(2-Aminopropoxy)-/V-(l-(7-methoxyisoquinolin-5-yl)cyc lopropyl)-2- methylbenzamide (Compound 537)

Compound 537

Compound 537 was synthesized according to an analogous procedure to the one described for compound 530. M + H ⁺ = 406.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.50 (s, 1H), 9.23 (s, 1H), 8.69 (d, J= 6.13 Hz, 1H), 8.59 (d, J= 6.25 Hz, 1H), 7.95 (br s, 3H), 7.84 (d, J= 2.38

Hz, 1H), 7.68 (d, J = 2.25 Hz, 1H), 7.09 (d, J= 8.51 Hz, 1H), 6.90 (dd, J= 8.38, 2.63 Hz, 1H), 6.70 (d, J= 2.63 Hz, 1H), 4.05 - 4.02 (m, 1H), 3.97 (s, 3H), 3.88 - 3.84 (m, 1H), 3.56 (br dd, J= 10.57, 5.69 Hz, 1H), 1.95 (s, 3H), 1.37 (br s, 2H), 1.28 - 1.19 (m, 5H). Example 517: (l?)-5-(2-Aminopropoxy)-2-methyl-/V-(l-(3-(thiophen-2-yl)nap hthalen-l- yl)cyclopropyl)benzamide (Compound 543)

Compound 543

Compound 543 was synthesized according to an analogous procedure to the one described for compound 539. M + H ⁺ = 457.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.21 (s, 1H), 8.71 - 8.59 (m, 1H), 8.16 (br s, 2H), 8.14 - 8.11 (m, 2H), 8.05 - 7.98 (m, 1H), 7.68 (dd, J= 3.61, 0.92 Hz, 1H), 7.64 (dd, J= 5.07, 0.92 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.23 (dd, J= 5.07, 3.61 Hz, 1H), 7.10 (d, J= 8.44 Hz, 1H), 6.91 (dd, J= 8.37, 2.63 Hz, 1H), 6.70 (d, = 2.57 Hz, 1H), 4.05 (dd, J= 10.27, 3.91 Hz, 1H), 3.91 (dd, J= 10.21, 7.03 Hz, 1H), 3.61 - 3.49 (m, 1H), 2.01 (s, 3H), 1.44 - 1.38 (m, 2H), 1.32 - 1.22 (m, 5H).

Example 518: (l?)-5-(2-Aminopropoxy)-/V-(l-(3-bromonaphthalen-l-yl)cyclop ropyl)-2- methylbenzamide (Compound 540)

Compound 540

Compound 540 was synthesized according to an analogous procedure to the one described for compound 541. M + H ⁺ = 453.0 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.22 (s, 1H), 8.64 (d, J= 8.25 Hz, 1H), 8.18 (br s, 2H), 8.15 (d, J= 1.38 Hz, 1H), 7.94 (d, J= 8.00 Hz, 1H), 7.88 (d, J= 1.88 Hz, 1H), 7.60 (dt, J= 19.76, 7.00 Hz, 2H), 7.08 (d, J= 8.38 Hz, 1H), 6.89 (dd, J= 8.38, 2.63 Hz, 1H), 6.68 (d, J= 2.50 Hz, 1H), 4.04 (dd, J= 10.26, 4.00 Hz, 1H), 3.90 (dd, J= 10.13, 7.13 Hz, 1H), 3.52 (br d, J= 4.75 Hz, 1H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.29 - 1.18 (m, 5H). Example 519: /V-(3-Fluorobenzyl)-l-(l-(2-isopropylphenyl)ethyl)piperidine -4- carboxamide (Compound 552)

Compound 552

Compound 552 was synthesized according to an analogous procedure to the one described for compound 549. M + H ⁺ = 383.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.80 (br dd, J = 1.8, 4.9 Hz, 1H), 8.62 - 8.48 (m, 1H), 7.83 - 7.71 (m, 1H), 7.53 - 7.26 (m, 4H), 7.12 - 6.94 (m, 3H), 4.72 (br t, J= 7.1 Hz, 1H), 4.33 - 4.22 (m, 2H), 3.90 (br d, J= 10.5 Hz, 1H), 3.39 - 3.35 (m, 1H), 3.21 - 3.08 (m, 1H), 2.95 (br d, J = 11.4 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.48 - 2.40 (m, 1H), 2.16 - 1.96 (m, 2H), 1.93 - 1.71 (m, 2H), 1.65 - 1.60 (m, 3H), 1.28 - 1.22 (m, 3H), 1.11 (d, J= 6.8 Hz, 3H).

Example 520: /V-(3-Fluorobenzyl)-l-(l-(7-methoxyquinolin-5-yl)ethyl)piper idine-4- carboxamide (Compound 593)

Compound 593

Compound 593 was synthesized according to an analogous procedure to the one described for compound 549. M + H ⁺ = 422.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 8.83 - 8.70 (m, 2H), 8.29 (br t, J= 5.9 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.27 (d, J= 2.3 Hz, 1H), 7.21 (d, J= 2.3 Hz, 1H), 7.08 - 6.95 (m, 3H), 4.24 (d, J= 5.4 Hz, 2H), 4.12 (q, J= 6.4 Hz, 1H), 3.90 (s, 3H), 2.98 (br d, J= 10.6 Hz, 1H), 2.78 (br d, J= 11.1 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.07 - 1.95 (m, 2H), 1.74 - 1.59 (m, 2H), 1.58 - 1.44 (m, 2H), 1.37 (d, J= 6.6 Hz, 3H). Example 521: /V-(3-Fluorobenzyl)-l-(l-(3-(thiophen-2-yl)naphthalen-l- yl)ethyl)piperidine-4-carboxamide (Compound 599)

Compound 599

Compound 599 was synthesized according to an analogous procedure to the one described for compound 549. M + H ⁺ = 473.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.03 - 9.87 (m, 1H), 8.51 (br t, J = 5.8 Hz, 1H), 8.45 - 8.33 (m, 2H), 8.27 (s, 1H), 8.11 - 8.05 (m, 1H), 7.82 (d, = 2.6 Hz, 1H), 7.68 - 7.57 (m, 3H), 7.40 - 7.31 (m, 1H), 7.26 - 7.20 (m, 1H), 7.11 - 6.98 (m, 3H), 5.46 - 5.28 (m, 1H), 4.31 - 4.24 (m, 2H), 4.02 (br d, J= 12.1 Hz, 1H), 3.29 - 3.14 (m, 1H), 3.11 - 3.00 (m, 1H), 2.96 - 2.85 (m, 1H), 2.47 - 2.40 (m, 1H), 2.13 - 2.01 (m, 2H), 1.85 - 1.77 (m, 5H).

Example 522: (l?)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-( 2-

(methylamino)propoxy)benzamide (Compound 573)

Compound 573

Compound 573 was synthesized according to an analogous procedure to the one described for compound 560. M + H ⁺ = 420.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.59 - 9.49 (m, 1H), 9.35 - 9.28 (m, 1H), 9.15 - 9.00 (m, 2H), 8.98 - 8.87 (m, 1H), 7.94 - 7.84 (m, 1H), 7.69 (br s, 1H), 7.62 - 7.54 (m, 1H), 7.09 (d, J= 8.50 Hz, 1H), 6.92 (dd, J= 8.38, 2.63 Hz, 1H), 6.74 (s, 1H), 4.16 - 4.11 (m, 1H), 4.07 - 4.03 (m, 1H), 4.01 (s, 3H), 3.53 - 3.46 (m, 1H), 2.58 - 2.52 (m, 3H), 1.96 (s, 3H), 1.44 - 1.36 (m, 2H), 1.33 - 1.24 (m, 5H). Example 523: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-(pyrid in-2- ylmethoxy)benzamide (Compound 562)

Compound 562

Compound 562 was synthesized according to an analogous procedure to the one described for compound 561. M + H ⁺ = 440.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.69 (d, J= 8.4 Hz, 1H), 9.33 (s, 1H), 9.20 (dd, J= 1.3, 5.4 Hz, 1H), 8.68 (d, J= 4.5 Hz, 1H), 8.11 (br t, J = 7.9 Hz, 1H), 7.99 (dd, J= 5.4, 8.4 Hz, 1H), 7.79 - 7.64 (m, 3H), 7.64 - 7.55 (m, 1H), 7.09 (d, J= 8.6 Hz, 1H), 6.97 (dd, J= 2.8, 8.4 Hz, 1H), 6.81 (d, J= 2.8 Hz, 1H), 5.26 (s, 2H), 4.02 (s, 3H), 1.98 (s, 3H), 1.46 - 1.39 (m, 2H), 1.35 - 1.29 (m, 2H).

Example 524: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7- (trifluoromethoxy) quinolin-5-yl)cyclopropyl)benzamide (Compound 579)

Compound 579

Compound 579 was synthesized according to an analogous procedure to the one described for compound 563. M + H ⁺ = 486.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.36 - 10.25 (m, 1H), 9.26 (s, 1H), 9.16 (d, J= 8.1 Hz, 1H), 9.03 (dd, J= 1.4, 4.2 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.72 (dd, J= 4.3, 8.5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.69 - 4.56 (m, 1H), 4.34 - 4.18 (m, 2H), 4.06 - 3.96 (m, 1H), 3.92 - 3.80 (m, 1H), 2.82 (d, J= 5.0 Hz, 3H), 2.36 - 2.23 (m, 2H), 1.94 (s, 3H), 1.40 (br s, 2H), 1.32 - 1.24 (m, 2H). Example 525: (3)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-vin ylquinolin-5- yl)cyclopropyl)benzamide (Compound 570)

Compound 570

Compound 570 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 428.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 11.08 (br d, J = 2.3 Hz, 1H), 9.62 (br d, J= 8.6 Hz, 1H), 9.36 (s, 1H), 9.19 (d, J= 4.4 Hz, 1H), 8.29 - 8.15 (m, 2H), 7.99 (br dd, J= 5.1, 8.3 Hz, 1H), 7.17 - 7.01 (m, 2H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.75 (d, J= 2.4 Hz, 1H), 6.23 (d, J= 17.5 Hz, 1H), 5.66 (d, J= 11.0 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.46 - 4.38 (m, 1H), 4.24 - 4.18 (m, 1H), 4.00 - 3.92 (m, 1H), 3.88 - 3.80 (m, 1H), 2.79 (d, J = 5.1 Hz, 3H), 2.41 - 2.23 (m, 2H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.35 (br s, 2H).

Example 526: (3)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(2- methylprop- l-en-l-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 603)

Compound 603

Compound 603 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 456.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.52 (br d, J= 1.3 Hz, 1H), 9.25 (br s, 1H), 9.14 (br s, 1H), 8.06 - 7.86 (m, 3H), 7.09 (d, J = 8.5 Hz, 1H), 6.92 (dd, J= 2.7, 8.4 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.55 (s, 1H), 4.61 (br dd, J = 2.8, 6.8 Hz, 1H), 4.36 - 4.16 (m, 2H), 4.02 (dt, J= 4.6, 9.7 Hz, 1H), 3.86 (q, J = 9.5 Hz, 1H), 2.90 - 2.73 (m, 3H), 2.46 - 2.29 (m, 2H), 2.09 - 1.90 (m, 9H), 1.41 (br s, 2H), 1.28 (br s, 2H). Example 527: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(3,3, 3- trifluoroprop-l-en-2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 650)

Compound 650

Compound 650 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 496.2 (LCMS); ¹ H NMR (400 MHz, DMSO- d ₆ ) 5 9.31 - 9.15 (m,

2H), 9.04 (br d, J= 3.8 Hz, 1H), 8.08 (br d, J= 5.6 Hz, 2H), 7.74 (br dd, J= 4.5, 8.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.92 (dd, J= 2.7, 8.3 Hz, 1H), 6.72 (d, J= 2.5 Hz, 1H), 6.42 (s, 1H), 6.32 (s, 1H), 4.70 - 4.55 (m, 1H), 4.35 - 4.17 (m, 2H), 4.09 - 3.94 (m, 1H), 3.93 - 3.81 (m, 1H), 2.69 (s, 3H), 2.34 - 2.28 (m, 2H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.30 (br s, 2H). Example 528: ( )-/V-(l-(7-(3-Chlorothiophen-2-yl)quinolin-5-yl)cyclopropyl) -2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 668)

Compound 668

Compound 668 was synthesized according to an analogous procedure to the one described for compound 568 M + H ⁺ = 518.2/520.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.72 - 10.46 (m, 1H), 9.44 - 9.23 (m, 2H), 9.10 (br s, 1H), 8.38 (br s, 1H), 8.26 (s, 1H), 7.90 (d, J =

5.4 Hz, 1H), 7.83 (br d, J= 3.6 Hz, 1H), 7.31 (d, = 5.4 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.7, 8.3 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 4.70 - 4.54 (m, 1H), 4.38 - 4.30 (m, 1H), 4.22 (br dd, J= 3.2, 11.2 Hz, 1H), 4.08 - 3.97 (m, 2H), 2.81 (d, J= 5.0 Hz, 3H), 2.39 - 2.23 (m, 2H), 1.99 (s, 3H), 1.44 (br s, 2H), 1.31 (br s, 2H). Example 529: (3)-/V-(l-(7-(4-Chlorothiophen-2-yl)quinolin-5-yl)cyclopropy l)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 632)

Compound 632

Compound 632 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 518.2/520.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.71 - 10.56 (m, 1H), 9.39 (br d, J= 8.6 Hz, 1H), 9.30 (s, 1H), 9.12 (d, J= 3.6 Hz, 1H), 8.32 (s, 1H), 8.28 (d, J= 1.6 Hz, 1H), 7.93 (d, J= 1.4 Hz, 1H), 7.85 (dd, J= 4.6, 8.5 Hz, 1H), 7.80 (d, J = 1.4 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.74 (d, J= 2.8 Hz, 1H), 4.68 - 4.55 (m, 1H), 4.35 (dd, J= 7.9, 11.3 Hz, 1H), 4.21 (dd, J = 3.1, 11.3 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.87 - 3.83 (m, 1H), 2.81 (d, J= 5.0 Hz, 3H), 2.39 - 2.24 (m, 2H), 1.97 (s, 3H), 1.41 (br d, J= 12.6 Hz, 4H).

Example 530: (3)-/V-(l-(7-(5-Chlorothiophen-2-yl)quinolin-5-yl)cyclopropy l)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 623)

Compound 623

Compound 623 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 518.2/520.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.89 - 9.77 (m, 1H), 9.17 (s, 1H), 9.04 (br d, J= 8.4 Hz, 1H), 8.94 (d, J = 4.0 Hz, 1H), 8.10 (d, J= 8.9 Hz, 2H), 7.69 (d, J= 3.9 Hz, 1H), 7.60 (dd, J = 4.6, 8.1 Hz, 1H), 7.27 (d, J= 3.9 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 4.63 - 4.53 (m, 1H), 4.26 - 4.15 (m, 2H), 4.07 - 3.96 (m, 1H), 3.91 - 3.79 (m, 1H), 2.83 (d, J= 4.9 Hz, 3H), 2.39 - 2.28 (m, 2H), 1.96 (s, 3H), 1.42 - 1.29 (m, 4H). Example 531: /V-(l-(7-(Furan-2-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-( (l- methylazetidin -2-yl)methoxy)benzamide (Compound 604)

Compound 604

Compound 604 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 4.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.50 (br d, J = 8.4 Hz, 1H), 9.29 (s, 1H), 9.20 - 9.12 (m, 1H), 8.37 (d, J= 1.4 Hz, 1H), 8.32 (s, 1H), 7.97 (d, J= 1.5 Hz, 1H), 7.92 (dd, J= 4.9, 8.6 Hz, 1H), 7.42 (d, J= 3.4 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.98 - 6.88 (m, 1H), 6.79 - 6.75 (m, 1H), 6.74 (d, = 2.6 Hz, 1H), 4.70 - 4.56 (m, 1H), 4.33 - 4.17 (m, 2H), 4.01 (dt, J= 4.6, 9.6 Hz, 1H), 3.86 (q, J = 9.5 Hz, 1H), 2.84 - 2.68 (m, 3H), 2.42 - 2.22 (m, 2H), 1.95 (s, 3H), 1.48 - 1.33 (m, 4H).

Example 532: ( S)- \-( l-(7-( l//-I’yr:izol-4-yl)qiiiiioliii-5-yl)cyclopropyl)-2-methyl- 5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 652)

Compound 652

Compound 652 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 468.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.21 - 9.04 (m, 2H), 8.94 (d, J= 4.1 Hz, 1H), 8.31 (br s, 2H), 8.19 - 8.06 (m, 2H), 7.67 - 7.49 (m, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.69 - 4.53 (m, 1H), 4.22 (br d, J= 3.0 Hz, 2H), 4.06 - 3.99 (m, 1H), 3.94 - 3.85 (m, 1H), 2.88 - 2.79 (m, 3H), 2.48 - 2.43 (m, 1H), 2.35 (br s, 1H), 1.98 (s, 3H), 1.50 - 1.25 (m, 4H). Example 533: (S)-2-Methyl-\-(l-(7-( 1 -methyl- l//-pyr:izol-4-yl)quinolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 670)

Compound 670

Compound 670 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ =482.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.45 - 10.28 (m, 1H), 9.46 - 9.33 (m, 1H), 9.25 (s, 1H), 9.08 (br d, J= 2.1 Hz, 1H), 8.50 (s, 1H), 8.20 (br d, J= 18.0 Hz, 2H), 8.13 (s, 1H), 7.86 - 7.77 (m, 1H), 7.14 - 7.07 (m, 1H), 6.92 (dd, J= 2.7, 8.3 Hz, 1H), 6.74 (d, J= 2.5 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.36 - 4.19 (m, 2H), 4.06 - 3.98 (m, 1H), 3.95 (s, 3H), 3.86 (br dd, J = 6.5, 9.6 Hz, 1H), 2.82 (d, J = 4.9 Hz, 3H), 2.34 - 2.26 (m, 2H), 1.98 (s, 3H), 1.40 (br d, J= 16.6 Hz, 4H).

Example 534: ( l-(7-( l//-I’yr:izol-3-yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-( (l- methylazetidin-2-yl)methoxy)benzamide (Compound 633)

Compound 633

Compound 633 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 468.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.59 - 10.39 (m, 1H), 9.45 (br d, J= 5.5 Hz, 1H), 9.28 (s, 1H), 9.17 - 9.02 (m, 1H), 8.49 (br d, J= 17.9 Hz, 2H), 7.95 - 7.77 (m, 2H), 7.17 - 7.06 (m, 1H), 6.99 (d, J= 2.1 Hz, 1H), 6.92 (dd, J = 2.8, 8.4 Hz, 1H), 6.81 - 6.67 (m, 1H), 4.72 - 4.55 (m, 1H), 4.39 - 4.27 (m, 1H), 4.26 - 4.15 (m, 1H), 4.03 - 3.96 (m, 1H), 3.85 (br dd, J= 6.7, 9.7 Hz, 1H), 2.81 (d, J= 4.9 Hz, 3H), 2.42 - 2.34 (m, 1H), 2.32 - 2.22 (m, 1H), 1.97 (s, 3H), 1.44 (br s, 2H), 1.35 (br s, 2H). Example 535: (.S)-2-Methyl- \-(l-(7-(5-methyl-l//-pyrazol-3-yl)quinolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 651)

Compound 651

Compound 651 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 482.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 12.73 (s, 1H), 9.11 (s, 1H), 9.04 (br d, J= 8.4 Hz, 1H), 8.94 - 8.85 (m, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.52 (dd, J= 4.3, 8.5 Hz, 1H), 7.02 (d, J= 8.5 Hz, 1H), 6.83 (dd, J= 2.8, 8.3 Hz, 1H), 6.66 (s, 1H), 6.61 (d, J= 2.6 Hz, 1H), 3.86 (d, J= 5.4 Hz, 2H), 3.27 - 3.16 (m, 2H), 2.76 - 2.66 (m, 1H),

2.32 (s, 3H), 2.23 - 2.17 (m, 3H), 1.98 - 1.92 (m, 4H), 1.88 - 1.80 (m, 1H), 1.39 (br s, 2H),

1.33 - 1.20 (m, 2H).

Example 536: (S)-2-Methyl-\-(l-(7-( 1 -methyl- l//-pyr:izol-3-yl)quinolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 582)

Compound 582

Compound 582 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 482.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.64 (br d, J= 8.8 Hz, 1H), 9.36 - 9.29 (m, 1H), 9.20 (d, J= 4.9 Hz, 1H), 8.56 (d, J= 1.4 Hz, 1H), 8.48 (s, 1H), 7.99 (dd, J= 5.1, 8.4 Hz, 1H), 7.90 (d, J= 2.3 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 2.6, 8.4 Hz, 1H), 6.75 (d, J = 2.6 Hz, 1H), 4.62 (br dd, J = 2.9, 7.8 Hz, 1H), 4.39 - 4.28 (m, 1H), 4.25 - 4.18 (m, 1H), 4.04 - 3.95 (m, 4H), 3.85 (d, J= 9.8 Hz, 1H), 2.84 - 2.68 (m, 3H), 2.36 (br s, 2H), 1.96 (s, 3H), 1.46 (br s, 2H), 1.35 (br s, 2H). Example 537: CS)- \-( 1 -( 7-( 1 -( Di 11 uoromel Iiy 1 )- 1 //-py razol-3-y 1 )qu inol in-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (Compound 644)

Compound 644

Compound 644 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 518.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.47 (br d, J= 8.4 Hz, 1H), 9.29 (s, 1H), 9.18 - 9.10 (m, 1H), 8.55 (s, 2H), 8.44 (d, J= 2.8 Hz, 1H), 8.15 - 7.78 (m, 2H), 7.32 (d, J= 2.6 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.74 (d, J= 2.8 Hz, 1H), 4.62 (br dd, J= 3.3, 7.7 Hz, 1H), 4.37 - 4.17 (m, 2H), 4.00 (td, J= 4.9, 9.5 Hz, 1H), 3.94 - 3.79 (m, 1H), 2.88 - 2.67 (m, 3H), 2.39 - 2.28 (m, 2H), 1.96 (s, 3H), 1.45 (br s, 2H), 1.34 (br s, 2H).

Example 538: (.S)-2-Methyl-5-((l-methyl:izetidin-2-yl)methoxy)- \-( l-(7-( 1 -phenyl- 1//- pyrazol-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 659)

Compound 659

Compound 659 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 544.3 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.15 (d, J = 8.5 Hz, 1H), 8.89 (dd, J= 1.5, 4.3 Hz, 1H), 8.65 (d, J= 1.6 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J= 2.5 Hz, 1H), 7.93 (d, J= 7.8 Hz, 2H), 7.60 (dd, J= 4.3, 8.5 Hz, 1H), 7.54 (t, J = 8.0 Hz, 2H), 7.40 - 7.33 (m, 1H), 7.15 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.88 (dd, J= 2.8, 8.4 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 4.06 - 3.97 (m, 2H), 3.85 (br d, J= 1.1 Hz, 1H), 3.62 (td, J= 3.9, 7.9 Hz, 1H), 3.28 - 3.21 (m, 1H), 2.54 (s, 3H), 2.25 - 2.14 (m, 2H), 2.02 (s, 3H), 1.57 - 1.52 (m, 2H), 1.48 - 1.40 (m, 2H). Example 539: (5)-/V-(l-(7-(Cyclopent-l-en-l-yl)quinolin-5-yl)cyclopropyl) -2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 609)

Compound 609

Compound 609 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 468.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.29 - 9.16 (m, 2H), 9.06 - 8.97 (m, 1H), 8.22 - 8.16 (m, 1H), 7.90 (br d, J= 5.8 Hz, 1H), 7.65 (br d, J= 1.3 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.97 - 6.87 (m, 1H), 6.72 - 6.69 (m, 1H), 6.67 - 6.64 (m, 1H), 4.65 - 4.50 (m, 1H), 4.33 - 4.17 (m, 2H), 4.06 - 3.94 (m, 1H), 3.90 - 3.75 (m, 2H), 2.85 - 2.75 (m, 5H), 2.62 - 2.57 (m, 2H), 2.37 - 2.25 (m, 2H), 2.12 - 2.01 (m, 2H), 1.95 (s, 3H), 1.38 (br s, 2H), 1.31 - 1.23 (m, 2H).

Example 540: (5)-/V-(l-(7-(Benzo[b]thiophen-2-yl)quinolin-5-yl)cyclopropy l)-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 621)

Compound 621

Compound 621 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 534.2 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.90 (br d, J= 8.3 Hz, 1H), 9.43 (br s, 1H), 9.22 (br d, J= 5.5 Hz, 1H), 8.80 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H), 8.18 - 8.08 (m, 1H), 7.97 (dd, J= 3.2, 6.0 Hz, 2H), 7.46 (dd, J = 3.1, 6.1 Hz, 2H), 7.14 (d, J= 8.4 Hz, 1H), 6.98 (dd, J= 2.7, 8.3 Hz, 1H), 6.88 (s, 1H), 4.74 - 4.65 (m, 1H), 4.38 - 4.14 (m, 3H), 4.02 - 3.88 (m, 1H), 2.95 (s, 3H), 2.62 - 2.48 (m, 2H), 2.07 (s, 3H), 1.66 (br s, 2H), 1.59 - 1.52 (m, 2H). Example 541: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-pheny lquinolin- 5-yl)cyclopropyl)benzamide (Compound 594)

Compound 594

Compound 594 was synthesized according to an analogous procedure to the one described for compound 568. M + H ⁺ = 478.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.50 (br d, J= 8.0 Hz, 1H), 9.29 (s, 1H), 9.19 - 9.11 (m, 1H), 8.39 - 8.27 (m, 2H), 7.97 - 7.84 (m, 3H), 7.66 - 7.58 (m, 2H), 7.55 - 7.49 (m, 1H), 7.18 - 7.05 (m, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.81 - 6.71 (m, 1H), 4.68 - 4.56 (m, 1H), 4.34 - 4.17 (m, 2H), 4.01 (dt, J= 4.6, 9.6 Hz, 1H), 3.85 (q, J= 9.3 Hz, 1H), 2.84 - 2.69 (m, 3H), 2.40 - 2.28 (m, 2H), 1.97 (s, 3H), 1.48 - 1.36 (m, 4H). Example 542: (l?)-5-(2-(Dimethylamino)propoxy)-/V-(l-(7-methoxyquinolin-5 - yl)cyclopropyl)-2-methylbenzamide (Compound 574)

Compound 574

Compound 574 was synthesized according to an analogous procedure to the one described for compound 575. M + H ⁺ = 434.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.87 - 10.59 (m, 1H), 9.77 (d, J= 8.51 Hz, 1H), 9.42 (m, 1H), 9.20 (m, 1H), 8.00 (m, 1H), 7.84 - 7.61 (m, 2H),

7.09 (d, J= 8.50 Hz, 1H), 6.93 (m, 1H), 6.80 (d, J= 2.63 Hz, 1H), 4.20 (m, 2H), 4.02 (m, 3H), 3.74 - 3.68 (m, 1H), 2.76 - 2.69 (m, 6H), 1.97 (m, 3H), 1.43 (m, 2H), 1.31 (d, J = 6.75 Hz, 5H). Example 543: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7- phenoxyquinolin-5-yl)cyclopropyl)benzamide (Compound 592)

Compound 592

Compound 592 was synthesized according to an analogous procedure to the one described for compound 581. M + H ⁺ = 494.2. 'H NMR (400 MHz, DMSO-t/e) 8 9.15 (s, 1H), 9.07 - 8.95 (m, 1H), 8.88 - 8.75 (m, 1H), 7.76 - 7.61 (m, 1H), 7.55 - 7.43 (m, 3H), 7.35 - 7.13 (m, 4H), 7.09 - 6.98 (m, 1H), 6.91 - 6.77 (m, 1H), 6.69 - 6.56 (m, 1H), 3.95 - 3.78 (m, 2H), 3.26 - 3.19 (m, 2H), 2.76 - 2.69 (m, 1H), 2.24 - 2.18 (m, 3H), 2.03 - 1.90 (m, 4H), 1.88 - 1.79 (m, 1H), 1.42 - 1.29 (m, 2H), 1.25 - 1.20 (m, 2H). Example 544: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(thia zol-2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 590)

Compound 590

Compound 590 was synthesized according to an analogous procedure to the one described for compound 588. M + H ⁺ = 485.1 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 8 10.59 - 10.41 (m, 1H), 9.38 - 9.24 (m, 2H), 9.09 (d, J = 3.3 Hz, 1H), 8.58 - 8.46 (m, 2H), 8.08 (d, J = 3.1 Hz,

1H), 7.97 (d, J= 3.3 Hz, 1H), 7.80 (dd, J= 4.3, 8.5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 4.69 - 4.54 (m, 1H), 4.39 - 4.19 (m, 2H), 4.04 - 3.93 (m, 1H), 3.88 - 3.81 (m, 1H), 2.81 (d, J= 4.9 Hz, 3H), 2.40 - 2.25 (m, 2H), 1.97 (s, 3H), 1.45 (br s, 2H), 1.32 (br s, 2H). Example 545: ( )-/V-(l-(7-(2-Methoxyethoxy)quinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 591)

Compound 591

Compound 591 was synthesized according to an analogous procedure to the one described for compound 598. M + H ⁺ = 476.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.48 - 10.28 (m, 1H), 9.39 (br dd, J= 2.5, 4.8 Hz, 1H), 9.30 - 9.20 (m, 1H), 9.05 (br d, J= 4.3 Hz, 1H), 7.85 - 7.72 (m, 1H), 7.62 (s, 1H), 7.50 - 7.43 (m, 1H), 7.14 - 7.06 (m, 1H), 6.98 - 6.89 (m, 1H), 6.72 (s, 1H), 4.67 - 4.55 (m, 1H), 4.36 - 4.27 (m, 3H), 4.26 - 4.19 (m, 1H), 4.03 - 3.96 (m, 1H), 3.90 - 3.84 (m, 1H), 3.79 - 3.76 (m, 2H), 2.82 (d, J= 5.0 Hz, 3H), 2.72 - 2.63 (m, 2H), 2.42 - 2.24 (m, 3H), 1.95 (s, 3H), 1.42 - 1.36 (m, 2H), 1.28 (br s, 2H).

Example 546: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-vinylquinolin-5 - yl)cyclopropyl)benzamide (Compound 612)

Compound 612

Compound 612 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 414.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.27 (d, J= 8.5 Hz, 1H), 9.19 (s, 1H), 9.04 (dd, J= 1.2, 4.4 Hz, 1H), 8.14 (d, J= 1.4 Hz, 1H), 8.00 (s, 1H), 7.75 (dd, J= 4.6, 8.6 Hz, 1H), 7.12 - 6.98 (m, 2H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.70 (d, J= 2.8 Hz, 1H), 6.15 (d, J= 17.6 Hz, 1H), 5.56 (d, J= 11.0 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.28 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 3.99 - 3.79 (m, 2H), 2.44 - 2.30 (m, 2H), 1.96 (s, 3H), 1.39 (br s, 2H), 1.31 (br s, 2H). Example 547: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(prop-l-en-2-yl )quinolin- 5-yl)cyclopropyl)benzamide (Compound 613)

Compound 613

Compound 613 was synthesized according to an analogous procedure to the one described for compound 608. M + H+ = 428.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.32 (d, J = 8.5 Hz, 1H), 9.19 (s, 1H), 9.07 (dd, J= 1.4, 4.6 Hz, 1H), 8.20 (d, J= 1.6 Hz, 1H), 8.04 (s, 1H), 7.79 (dd, J = 4.6, 8.6 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.70 (d, = 2.8 Hz, 1H), 5.79 (s, 1H), 5.42 (s, 1H), 4.65 (dq, J = 3.4, 7.8 Hz, 1H), 4.27 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 3.96 - 3.88 (m, 1H), 3.82 (dt, J= 6.3, 10.0 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.37 - 2.31 (m, 1H), 2.27 (s, 3H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.31 (br s, 2H).

Example 548: (5',£')-5-(Azetidin-2-ylmethoxy)-A-(l-(7-(2-cyclopropylviny l)quinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 667)

Compound 667

Compound 667 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 454.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 9.23 (br d, J= 6.1 Hz, 2H), 9.00 - 8.74 (m, 3H), 7.96 (br d, J= 3.9 Hz, 1H), 7.80 (s, 1H), 7.69 - 7.57 (m, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.78 - 6.66 (m, 2H), 6.24 - 6.09 (m, 1H), 4.73 - 4.60 (m, 1H), 4.26 - 4.09 (m, 2H), 3.92 (br d, J= 6.1 Hz, 1H), 3.85 - 3.81 (m, 1H), 2.46 - 2.30 (m, 2H), 1.97 (s, 3H), 1.76 - 1.64 (m, 1H), 1.41 - 1.23 (m, 4H), 0.92 - 0.85 (m, 2H), 0.70 - 0.60 (m, 2H). Example 549: ( ',£')-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(3- methylstyryl)quinolin-5-yl)cyclopropyl)benzamide (Compound 704)

Compound 704

Compound 704 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 504.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.48 (d, J= 8.3 Hz, 1H), 9.02 (dd, J= 1.3, 4.8 Hz, 1H), 8.51 (d, J= 1.3 Hz, 1H), 8.09 (s, 1H), 7.83 (dd, J = 4.9, 8.5 Hz, 1H), 7.65 - 7.57 (m, 1H), 7.55 - 7.42 (m, 3H), 7.31 (t, J= 7.7 Hz, 1H), 7.18 (br d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 2.7, 8.5 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 4.80 - 4.75 (m, 1H), 4.26 - 4.19 (m, 2H), 4.09 - 3.94 (m, 2H), 2.65 - 2.52 (m, 2H), 2.41 (s, 3H), 2.04 (s, 3H), 1.60 - 1.51 (m, 2H), 1.50 - 1.43 (m, 2H).

Example 550: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-methylthioph en-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 640)

Compound 640

Compound 640 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 484.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.21 - 9.10 (m, 2H), 8.97 (dd, J= 1.3, 4.3 Hz, 1H), 8.95 - 8.69 (m, 2H), 8.26 - 8.17 (m, 2H), 7.91 (d, J= 1.5 Hz, 1H), 7.64 (dd, J = 4.3, 8.6 Hz, 1H), 7.47 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.70 (d, J= 2.8 Hz, 1H), 4.70 - 4.61 (m, 1H), 4.27 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 3.98 - 3.87 (m, 2H), 2.55 (d, J= 0.8 Hz, 3H), 2.44 - 2.29 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.37 - 1.31 (m, 2H). Example 551: (5)-/V-(l-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)cyclopropy l)-5-(azetidin- 2-ylmethoxy)-2-methylbenzamide (Compound 643)

Compound 643

Compound 643 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 512.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 9.19 (s, 1H), 9.08 (d, J = 8.7 Hz, 1H), 8.98 (dd, J = 1.6, 4.1 Hz, 1H), 8.82 - 8.75 (m, 1H), 8.32 (d, J= 1.4 Hz, 1H), 8.21 (d, J= 1.9 Hz, 1H), 8.05 (d, J= 4.0 Hz, 1H), 7.93 (d, J= 4.0 Hz, 1H), 7.65 (dd, J= 4.3, 8.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.70 (d, J= 2.8 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.26 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 3.96 - 3.88 (m, 1H), 3.86 - 3.79 (m, 1H), 2.69 - 2.65 (m, 1H), 2.59 (s, 3H), 2.34 - 2.31 (m, 1H), 1.98 (s, 3H), 1.43 - 1.38 (m, 2H), 1.35 (br s, 2H).

Example 552: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(5-cyanothiophen-2-yl)qu inolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 658)

Compound 658

Compound 658 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 495.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.20 (s, 1H), 9.08 (d, J= 8.6 Hz, 1H), 8.99 (dd, J= 1.4, 4.2 Hz, 1H), 8.89 - 8.71 (m, 2H), 8.33 (d, J= 1.5 Hz, 1H), 8.17 (d, J= 1.9 Hz, 1H), 8.10 (d, J= 4.0 Hz, 1H), 7.98 (d, J= 4.0 Hz, 1H), 7.66 (dd, J= 4.2, 8.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.70 (d, J= 2.6 Hz, 1H), 4.70 - 4.57 (m, 1H), 4.28 - 4.18 (m, 1H), 4.17 - 4.09 (m, 1H), 3.98 - 3.78 (m, 2H), 2.48 - 2.42 (m, 1H), 2.48 - 2.40 (m, 2H), 2.24 (s, 1H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.35 (br s, 2H). Example 553: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-methyl-l,3 ,4-thiadiazol-

2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 673)

Compound 673

Compound 673 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 486.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.23 (s, 1H), 9.16 (d, J= 8.5 Hz, 1H), 9.03 (dd, J = 1.4, 4.1 Hz, 1H), 9.00 - 8.73 (m, 2H), 8.48 (d, J= 1.8 Hz, 1H), 8.42 (d, J= l.l Hz, 1H), 7.72 (dd, J= 4.2, 8.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.72 (d, J = 2.6 Hz, 1H), 4.65 (br d, J= 5.1 Hz, 1H), 4.28 - 4.19 (m, 1H), 4.18 - 4.09 (m, 1H), 3.96 - 3.89 (m, 1H), 3.86 - 3.80 (m, 1H), 2.84 (s, 3H), 2.48 - 2.28 (m, 2H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.31 (br s, 2H).

Example 554: (3)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(furan-3-yl)quinolin-5 - yl)cyclopropyl)-2-methylbenzamide (Compound 645)

Compound 645

Compound 645 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 454.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.25 - 9.09 (m, 2H), 9.03 - 8.71 (m, 3H), 8.48 (s, 1H), 8.27 - 8.06 (m, 2H), 7.86 (t, J= 1.6 Hz, 1H), 7.65 (dd, J = 4.3, 8.5 Hz, 1H), 7.18 (d, J = 1.1 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.65 (br d, J= 4.0 Hz, 1H), 4.23 (br dd, J = 7.1, 11.2 Hz, 2H), 4.13 (br dd, J = 3.3, 11.2 Hz, 2H), 2.45 - 2.24 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.35 (br s, 2H). Example 555: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(2,5-dimethylfuran-3-yl) quinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 641)

Compound 641

Compound 641 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 482.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.21 - 9.09 (m, 2H), 8.96 (br d, J= 4.0 Hz, 1H), 8.87 - 8.71 (m, 2H), 8.03 (s, 1H), 7.93 (s, 1H), 7.63 (br dd, J = 3.9, 8.0 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.71 (d, J= 2.8 Hz, 1H), 6.51 (s, 1H), 4.71 - 4.60 (m, 1H), 4.27 - 4.19 (m, 1H), 4.16 - 4.10 (m, 1H), 3.96 - 3.87 (m, 1H), 3.86 - 3.77 (m, 1H), 2.54 (s, 3H), 2.39 - 2.32 (m, 2H), 2.31 (s, 3H), 1.99 (s, 3H), 1.39 (br s, 2H), 1.32 - 1.25 (m, 2H).

Example 556: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-methylfuran- 2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 646)

Compound 646

Compound 646 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 468.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.17 (s, 1H), 9.09 (br d, J= 8.3 Hz, 1H), 9.00 - 8.64 (m, 3H), 8.24 - 8.05 (m, 2H), 7.60 (dd, J= 4.3, 8.5 Hz, 1H), 7.15 (d, J= 3.1 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 6.32 (dd, J = 0.9, 3.2 Hz, 1H), 4.74 - 4.57 (m, 1H), 4.31 - 4.18 (m, 1H), 4.17 - 4.06 (m, 1H), 4.00 - 3.87 (m, 1H), 3.86 - 3.77 (m, 1H), 2.43 (s, 3H), 2.40 - 2.21 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.30 (br s, 2H). Example 557 : (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(oxazol-2-yl) quinolin-5- yl)cyclopropyl)benzamide (Compound 694)

Compound 694

Compound 694 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 455.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.22 (s, 1H), 9.14 (d, J= 7.9 Hz, 1H), 9.02 (dd, J = 1.5, 4.1 Hz, 1H), 8.95 - 8.77 (m, 2H), 8.50 (s, 2H), 8.36 (s, 1H), 7.70 (dd, J= 4.2, 8.6 Hz, 1H), 7.51 (s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 2.7, 8.3 Hz, 1H), 6.72 (d, J= 2.8 Hz, 1H), 4.67 - 4.63 (m, 1H), 4.23 (dd, J= 7.1, 11.2 Hz, 1H), 4.17 - 4.11 (m, 1H), 3.97 - 3.77 (m, 2H), 2.48 - 2.41 (m, 1H), 2.39 - 2.29 (m, 1H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.29 (br s, 2H).

Example 558: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(2-methyloxaz ol-5- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 698)

Compound 698

Compound 698 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 469.2 (LCMS); 'H NMR (400 MHz, DMSO4) 6 9.24 - 9.17 (m, 2H), 9.01 (dd, J= 1.2, 4.3 Hz, 1H), 8.20 (s, 2H), 7.86 (s, 1H), 7.72 (dd, J = 4.4, 8.6 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J = 2.6, 8.4 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H), 4.70 - 4.53 (m, 1H), 4.27 - 4.18 (m, 1H), 4.16 - 4.08 (m, 1H), 3.98 - 3.88 (m, 1H), 3.86 - 3.77 (m, 1H), 2.56 (s, 3H), 2.47 - 2.30 (m, 2H), 1.95 (s, 3H), 1.45 - 1.37 (m, 2H), 1.35 - 1.29 (m, 2H), 1.65 - 1.67 (m, 1H). Example 559: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-methyl-l,3 ,4-oxadiazol-

2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 680)

Compound 680

Compound 680 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 470.3 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.23 (s, 1H), 9.15 (d, J= 8.3 Hz, 1H), 9.05 (dd, J= 1.4, 4.1 Hz, 1H), 8.90 - 8.77 (m, 2H), 8.48 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 7.74 (dd, J= 4.1, 8.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.65 (br d, J= 5.5 Hz, 1H), 4.28 - 4.19 (m, 1H), 4.18 - 4.11 (m, 1H), 4.00 - 3.87 (m, 2H), 2.66 (s, 3H), 2.46 (br s, 1H), 2.37 - 2.29 (m, 1H), 1.95 (s, 3H), 1.43 (br s, 2H), 1.29 (br s, 2H).

Example 560: (5)-/V-(l-(7-(lZ/-Pyrazol-3-yl)quinolin-5-yl)cyclopropyl)-5- (azetidin-2- ylmethoxy)-2-methylbenzamide (Compound 636)

Compound 636

Compound 636 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 454.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.23 - 9.15 (m, 2H), 8.99 (d, J= 3.5 Hz, 1H), 8.88 - 8.71 (m, 2H), 8.43 (s, 1H), 8.35 (s, 1H), 7.86 (d, J= 1.8 Hz, 1H), 7.67 (dd, J= 4.5, 8.6 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.97 (d, J= 2.3 Hz, 1H), 6.91 (dd, J= 2.5, 8.5 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.71 - 4.60 (m, 1H), 4.23 (dd, J= 6.9, 11.1 Hz, 1H), 4.16 - 4.11 (m, 1H), 3.96 - 3.86 (m, 2H), 2.44 - 2.29 (m, 2H), 1.97 (s, 3H), 1.41 (br s, 2H), 1.31 (br s, 2H). Example 561: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(5-methyl-lH-py razol-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 635)

Compound 635

Compound 635 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 468.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.40 (d, J= 8.5 Hz, 1H), 9.22 (s, 1H), 9.09 (dd, J= 1.3, 4.8 Hz, 1H), 8.47 (d, J= 1.4 Hz, 1H), 8.35 (s, 1H), 7.83 (dd, J= 4.8, 8.6 Hz, 1H), 7.09 (d, J= 8.6 Hz, 1H), 6.91 (dd, J= 2.7, 8.4 Hz, 1H), 6.76 - 6.68 (m, 2H), 4.65 (dq, J= 3.2, 7.8 Hz, 1H), 4.28 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 3.98 - 3.88 (m, 1H), 3.82 (dt, J = 6.3, 10.0 Hz, 1H), 2.47 - 2.41 (m, 1H), 2.39 - 2.29 (m, 4H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.32 (br s, 2H).

Example 562: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(l-methyl-lH-py razol-5- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 649)

Compound 649

Compound 649 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 468.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.22 (s, 1H), 9.18 - 9.11 (m, 1H), 9.05 - 8.98 (m, 1H), 8.95 - 8.77 (m, 2H), 8.15 - 8.02 (m, 2H), 7.78 - 7.65 (m, 1H), 7.61 - 7.52 (m, 1H), 7.16 - 7.05 (m, 1H), 6.97 - 6.87 (m, 1H), 6.78 - 6.69 (m, 1H), 6.67 - 6.59 (m, 1H), 4.76 - 4.58 (m, 1H), 4.28 - 4.19 (m, 1H), 4.17 - 4.09 (m, 1H), 4.00 (s, 3H), 3.97 - 3.81 (m, 2H), 2.47 - 2.41 (m, 1H), 2.39 - 2.31 (m, 1H), 1.97 (s, 3H), 1.40 (br s, 2H), 1.32 (br s, 2H). Example 563: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(l-methyl-lH- pyrazol-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 634)

Compound 634

Compound 634 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 468.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.21 - 9.14 (m, 2H), 8.98 (dd, J= 1.4, 4.4 Hz, 1H), 8.88 - 8.78 (m, 1H), 8.43 (d, J= 1.5 Hz, 1H), 8.31 (s, 1H), 7.85 (d, J= 2.1 Hz, 1H), 7.65 (dd, J= 4.4, 8.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.91 (dd, J= 2.7, 8.4 Hz, 1H), 6.71 (d, J= 2.7 Hz, 1H), 4.71 - 4.60 (m, 1H), 4.28 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 3.97 (s, 3H), 3.88 - 3.78 (m, 2H), 2.45 - 2.30 (m, 2H), 1.98 (s, 3H), 1.41 (br s, 2H), 1.29 (br s, 2H).

Example 564: (5)-5-(Azetidin-2-ylmethoxy)-A-( l-(7-(l-(difluoromethyl)-lZ/-pyrazol-3- yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 656)

Compound 656

Compound 656 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 504.1 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.19 (s, 1H), 9.14 (d, J= 8.4 Hz, 1H), 8.98 (dd, J= 1.5, 4.3 Hz, 1H), 8.88 - 8.73 (m, 2H), 8.48 - 8.43 (m, 2H), 8.40 (d, J= 2.8 Hz, 1H), 8.13 - 7.80 (m, 1H), 7.65 (dd, J = 4.2, 8.6 Hz, 1H), 7.32 (d, J= 2.8 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.70 (d, J = 2.8 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.23 (dd, J= 7.1, 11.3 Hz, 2H), 4.13 (br dd, J = 3.3, 11.1 Hz, 2H), 2.45 - 2.28 (m, 2H), 1.97 (s, 3H), 1.41 (br s, 2H), 1.30 (br s, 2H). Example 565: (.S)-5-(Azetidin-2-ylmethoxy)-2-methyl- \-(l-(7-( 1 -phenyl- l//-pyrazol-3- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 664)

Compound 664

Compound 664 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 530.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.24 - 9.15 (m, 2H), 9.00 (dd, J= 1.4, 4.3 Hz, 1H), 8.96 - 8.72 (m, 2H), 8.68 (d, J= 2.5 Hz, 1H), 8.53 (d, J= 1.6 Hz, 1H), 8.48 (s, 1H), 8.04 - 7.95 (m, 2H), 7.67 (dd, J= 4.3, 8.6 Hz, 1H), 7.58 (t, J = 8.0 Hz, 2H), 7.43 - 7.34 (m, 1H), 7.32 (d, J= 2.6 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J = 2.6, 8.4 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 4.65 (br d, J= 3.4 Hz, 1H), 4.27 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 4.00 - 3.89 (m, 2H), 2.45 - 2.28 (m, 2H), 1.99 (s, 3H), 1.44 (br s, 2H), 1.34 (br s, 2H).

Example 566: (5)-/V-(l-(7-(lH-Pyrazol-4-yl)quinolin-5-yl)cyclopropyl)-5-( azetidin-2- ylmethoxy)-2-methylbenzamide (Compound 642)

Compound 642

Compound 642 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 454.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.24 - 9.08 (m, 2H), 8.98 - 8.91 (m, 1H), 8.85 - 8.69 (m, 2H), 8.32 (br s, 2H), 8.21 - 8.10 (m, 2H), 7.67 - 7.54 (m, 1H), 7.17 - 7.02 (m, 1H), 6.96 - 6.87 (m, 1H), 6.75 - 6.65 (m, 1H), 4.72 - 4.58 (m, 1H), 4.25 (s, 1H), 4.17 - 4.11 (m, 1H), 3.94 - 3.90 (m, 1H), 3.86 - 3.80 (m, 1H), 2.47 - 2.42 (m, 1H), 2.33 (br s, 1H), 1.98 (s, 3H), 1.43 - 1.32 (m, 4H). Example 567: (.S)-5-(Azetidin-2-ylmethoxy)-2-methyl-\-(l-(7-( 1 -methyl- l//-pyrazol-4- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 665)

Compound 665

Compound 665 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 468.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.19 - 9.07 (m, 2H), 8.95 (dd, J= 1.4, 4.4 Hz, 1H), 8.93 - 8.75 (m, 2H), 8.44 (s, 1H), 8.13 - 8.08 (m, 3H), 7.62 (dd, J= 4.4, 8.5 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.70 (d, J= 2.8 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.23 (dd, J= 7.1, 11.2 Hz, 2H), 4.13 (br dd, = 3.3, 11.3 Hz, 2H), 3.93 (s, 3H), 2.48 - 2.29 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.36 - 1.29 (m, 2H).

Example 568: (5)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(benzo[b]thiophen-2-yl )quinolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 695)

Compound 695

Compound 695 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 520.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.21 (s, 1H), 9.09 (d, J= 7.7 Hz, 1H), 8.98 (dd, J = 1.3, 4.1 Hz, 1H), 8.89 - 8.67 (m, 2H), 8.34 (d, J= 1.9 Hz, 1H), 8.28 - 8.14 (m, 2H), 8.09 - 8.01 (m, 1H), 7.96 (dd, J= 1.8, 6.5 Hz, 1H), 7.64 (dd, J= 4.2, 8.6 Hz, 1H), 7.50 - 7.37 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 6.97 - 6.87 (m, 1H), 6.71 (d, J = 2.8 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.28 - 4.20 (m, 1H), 4.18 - 4.11 (m, 1H), 3.94 - 3.88 (m, 1H), 3.83 (br dd, = 5.3, 10.5 Hz, 1H), 2.46 - 2.25 (m, 2H), 2.00 (s, 3H), 1.42 (br s, 2H), 1.37 (br s, 2H). Example 569: (5)-5-(Azetidin-2-ylmethoxy)-N-(l-(7-(benzo[d]oxazol-2-yl)qu inolin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 711)

Compound 711

Compound 711 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 505.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.26 (s, 1H), 9.18 (d, J= 8.3 Hz, 1H), 9.07 (dd, J= 1.5, 4.1 Hz, 1H), 8.94 - 8.76 (m, 2H), 8.73 (s, 1H), 8.69 (d, J = 1.8 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.75 (dd, = 4.1, 8.5 Hz, 1H), 7.49 (dquin, J= 1.5, 7.3 Hz, 2H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J = 2.6, 8.4 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.71 - 4.58 (m, 1H), 4.28 - 4.19 (m, 1H), 4.18 - 4.11 (m, 1H), 3.96 - 3.77 (m, 2H), 2.48 - 2.40 (m, 1H), 2.38 - 2.28 (m, 1H), 1.98 (s, 3H), 1.46 (br s, 2H), 1.34 (br s, 2H).

Example 570: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(cyclohex-l-en-l-yl)quin olin-5- yl)cyclopropyl)-2-methylbenzamide (Compound 662)

Compound 662

Compound 662 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 468.2 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.24 - 9.11 (m, 2H), 9.02 - 8.96 (m, 1H), 8.95 - 8.76 (m, 2H), 8.11 (d, J= 1.6 Hz, 1H), 7.89 (s, 1H), 7.68 (dd, J = 4.5, 8.5 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 2.7, 8.3 Hz, 1H), 6.69 (d, J= 2.8 Hz, 1H), 6.54 (br s, 1H), 4.72 - 4.60 (m, 1H), 4.27 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 4.02 - 3.81 (m, 4H), 2.44 - 2.18 (m, 4H), 1.97 (s, 3H), 1.86 - 1.77 (m, 2H), 1.72 - 1.63 (m, 2H), 1.37 (br s, 2H), 1.28 (br s, 2H). Example 571: (3)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(4-fluorophenyl)quinol in-5- yl)cyclopropyl)-2-methylbenzamide (Compound 675)

Compound 675

Compound 675 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 482.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.23 - 9.12 (m, 2H), 8.99 (br d, J= 3.9 Hz, 1H), 8.90 - 8.74 (m, 2H), 8.20 (s, 2H), 7.94 (dd, J = 5.5, 8.6 Hz, 2H), 7.66 (dd, J= 4.2, 8.5 Hz, 1H), 7.40 (t, J= 8.8 Hz, 2H), 7.10 (d, J= 8.4 Hz, 1H), 6.91 (dd, J= 2.4, 8.4 Hz, 1H), 6.70 (d, J= 2.4 Hz, 1H), 4.65 (br d, J= 4.3 Hz, 1H), 4.23 (br dd, J= 7.2, 11.1 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.95 - 3.89 (m, 1H), 3.85 - 3.79 (m, 1H), 2.47 - 2.28 (m, 2H), 1.98 (s, 3H), 1.38 (br d, J= 15.4 Hz, 4H).

Example 572: (3)-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(3-chloro-4-fluorophen yl)quinolin- 5-yl)cyclopropyl)-2-methylbenzamide (Compound 666)

Compound 666

Compound 666 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 516.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.23 - 9.13 (m, 2H), 9.00 (dd, J= 1.5, 4.3 Hz, 1H), 8.97 - 8.76 (m, 2H), 8.26 (d, J= 1.4 Hz, 1H), 8.20 (d, J= 1.9 Hz, 1H), 8.13 (dd, J= 2.3, 7.1 Hz, 1H), 7.92 (ddd, J= 2.4, 4.7, 8.6 Hz, 1H), 7.68 (dd, J= 4.3, 8.5 Hz, 1H), 7.61 (t, J = 8.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.65 (br d, J= 6.3 Hz, 1H), 4.23 (dd, J= 7.2, 11.2 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.97 - 3.78 (m, 2H), 2.48 - 2.26 (m, 2H), 1.98 (s, 3H), 1.40 (br s, 4H). Example 573: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(6-oxo-l,6- dihydropyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 674)

Compound 674

Compound 674 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 481.2 (LCMS); ^X H NMR (400 MHz, DMSO4) 6 9.19 - 9.09 (m, 2H), 8.97 (dd, J= 1.3, 4.3 Hz, 1H), 8.95 - 8.71 (m, 2H), 8.16 - 7.94 (m, 4H), 7.64 (dd, J= 4.4, 8.5 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.69 (d, J= 2.6 Hz, 1H), 6.53 (d, J= 9.5 Hz, 1H), 4.65 (br d, J= 4.8 Hz, 1H), 4.30 - 4.18 (m, 1H), 4.17 - 4.08 (m, 1H), 3.99 - 3.73 (m, 2H), 2.47 - 2.42 (m, 1H), 2.38 - 2.28 (m, 1H), 1.98 (s, 3H), 1.37 (br s, 4H). Example 574: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(pyridin-3-yl )quinolin-5- yl)cyclopropyl)benzamide (Compound 637)

Compound 637

Compound 637 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 465.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.28 - 9.16 (m, 3H), 9.07 - 9.01 (m, 1H), 8.78 (dd, J= 1.3, 5.1 Hz, 1H), 8.63 - 8.56 (m, 1H), 8.38 (d, J= 1.6

Hz, 1H), 8.27 (d, J= 1.6 Hz, 1H), 7.82 (dd, J = 5.2, 7.8 Hz, 1H), 7.73 (dd, J = 4.3, 8.5 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.65 (br dd, J = 2.7, 8.0 Hz, 1H), 4.27 - 4.18 (m, 1H), 4.16 - 4.09 (m, 1H), 3.97 - 3.77 (m, 2H), 2.41 - 2.25 (m, 2H), 1.96 (s, 3H), 1.41 (br s, 4H). Example 575: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(pyrimidin-2- yl)quinolin- 5-yl)cyclopropyl)benzamide (Compound 682)

Compound 682

Compound 682 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 466.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 9.26 - 9.13 (m, 2H), 9.08 - 9.01 (m, 3H), 9.00 - 8.92 (m, 2H), 8.90 - 8.71 (m, 2H), 7.71 (dd, J= 4.2, 8.6 Hz, 1H), 7.57 (t, J= 4.8 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.3 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.71 - 4.59 (m, 1H), 4.27 - 4.19 (m, 1H), 4.17 - 4.10 (m, 1H), 4.18 - 4.10 (m, 1H), 3.96 - 3.88 (m, 1H), 3.86 - 3.78 (m, 1H), 2.47 - 2.29 (m, 2H), 1.98 (s, 3H), 1.45 (br s, 2H), 1.30 (br s, 2H).

Example 576: (3)-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-(2-(piperidin -l- yl)pyrimidin-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 688)

Compound 688

Compound 688 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 549.5 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.21 - 9.10 (m, 2H), 8.99 - 8.96 (m, 1H), 8.90 (s, 2H), 8.88 - 8.70 (m, 2H), 8.18 (dd, J = 1.6, 19.5 Hz, 2H), 7.64 (dd, J= 4.4, 8.5 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J = 2.7, 8.3 Hz, 1H), 6.70 (d, J= 2.8 Hz, 1H), 4.70 - 4.61 (m, 1H), 4.21 (br d, J= 7.3 Hz, 1H), 4.15 (br d, J= 3.4 Hz, 1H), 3.97 - 3.88 (m, 2H), 3.86 - 3.83 (m, 4H), 2.48 - 2.40 (m, 1H), 2.40 - 2.27 (m, 1H), 1.98 (s, 3H), 1.72 - 1.64 (m, 2H), 1.57 (br d, J= 3.9 Hz, 4H), 1.39 (br s, 4H). Example 577: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(imidazo[l,2-a]pyridin-6 - yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 686)

Compound 686

Compound 686 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 504.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.54 (s, 1H), 9.25 (s, 1H), 9.12 (d, J= 8.7 Hz, 1H), 9.02 (dd, J= 1.5, 4.0 Hz, 1H), 8.97 - 8.77 (m, 2H), 8.51 (dd, J= 1.3, 9.6 Hz, 1H), 8.43 - 8.37 (m, 2H), 8.30 - 8.22 (m, 2H), 8.15 - 8.09 (m, 1H), 7.74 - 7.66 (m, 1H), 7.12 (s, 1H), 6.95 - 6.89 (m, 1H), 6.72 - 6.67 (m, 1H), 4.66 (br d, J= 6.1 Hz, 1H), 4.27 - 4.20 (m, 1H), 4.16 - 4.10 (m, 1H), 3.95 - 3.90 (m, 1H), 3.85 - 3.81 (m, 1H), 2.47 - 2.41 (m, 1H), 2.39 - 2.31 (m, 1H), 1.97 (s, 3H), 1.45 - 1.36 (m, 4H).

Example 578: (5)-N-(l-(7-([l,2,4]Triazolo[l,5-a]pyridin-6-yl)quinolin-5-y l)cyclopropyl)- 5-(azetidin-2-ylmethoxy)-2-methylbenzamide (Compound 685)

Compound 685

Compound 685 was synthesized according to an analogous procedure to the one described for compound 608. M + H ⁺ = 505.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.60 (s, 1H), 9.20 (s, 1H), 9.16 (d, J = 8.3 Hz, 1H), 9.01 (dd, J= 1.3, 4.2 Hz, 1H), 8.94 - 8.73 (m, 2H), 8.61 (s, 1H), 8.39 (d, J= 1.4 Hz, 1H), 8.30 (d, J= 1.8 Hz, 1H), 8.27 - 8.23 (m, 1H), 8.08 - 8.01 (m, 1H), 7.71 - 7.64 (m, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 4.68 - 4.62 (m, 1H), 4.26 - 4.20 (m, 1H), 4.16 - 4.10 (m, 1H), 3.93 - 3.79 (m, 2H), 2.49 - 2.41 (m, 1H), 2.38 - 2.27 (m, 1H), 1.98 (s, 3H), 1.43 (br d, J= 14.2 Hz, 4H). Example 579: ( )-/V-(l-(7-Ethynyl-2-methylquinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 822)

Compound 822

Compound 822 was synthesized according to an analogous procedure to the one described for compound 620. M + H ⁺ = 440.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.44 - 10.12 (m, 1H), 9.33 - 9.16 (m, 2H), 8.11 (s, 1H), 7.92 (s, 1H), 7.80 (br d, J = 8.1 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.99 - 6.90 (m, 1H), 6.82 - 6.68 (m, 1H), 4.62 (br s, 2H), 4.31 - 4.20 (m, 2H), 4.03 - 3.98 (m, 1H), 3.88 - 3.85 (m, 1H), 2.86 - 2.78 (m, 6H), 2.41 - 2.27 (m, 2H), 1.96 (s, 3H), 1.38 (br s, 2H), 1.27 (br s, 2H). Example 580: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(7-vinylquinolin-5- yl)cyclopropyl)benzamide (Compound 615)

Compound 615

Compound 615 was synthesized according to an analogous procedure to the one described for compound 630. M + H ⁺ = 402.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.47 - 9.42 (m, 1H), 9.27 - 9.24 (m, 1H), 9.18 - 9.03 (m, 1H), 8.25 - 8.15 (m, 1H), 8.12 - 8.00 (m, 1H), 7.96

- 7.79 (m, 1H), 7.12 - 6.99 (m, 2H), 6.93 - 6.87 (m, 1H), 6.71 - 6.67 (m, 1H), 6.19 (d, J= 17.5 Hz, 1H), 5.62 (d, J = 11.0 Hz, 1H), 4.13 (t, J = 5.0 Hz, 2H), 3.25 (t, J = 4.9 Hz, 2H), 2.58 (s, 3H), 1.95 (s, 3H), 1.40 (br s, 2H), 1.33 (br s, 2H). Example 581: 2-Methyl-5-(2-(methylamino)ethoxy)-/V-(l-(7-(prop-l-en-2-yl) quinolin-5- yl)cyclopropyl)benzamide (Compound 616)

Compound 616

Compound 616 was synthesized according to an analogous procedure to the one described for compound 630. M + H ⁺ = 416.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.62 - 9.50 (m, 1H), 9.34 - 9.26 (m, 1H), 9.22 - 9.14 (m, 1H), 8.31 - 8.25 (m, 1H), 8.19 - 8.13 (m, 1H), 8.02 - 7.93 (m, 1H), 7.14 - 7.06 (m, 1H), 6.95 - 6.86 (m, 1H), 6.77 - 6.65 (m, 1H), 5.84 (s, 1H), 5.49 (s, 1H), 4.15 (t, J = 5.0 Hz, 2H), 3.26 (br t, J= 4.9 Hz, 2H), 2.58 (s, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.34 (br s, 2H). Example 582: 2-Methyl-\-(l-(7-( 1 -methyl- l//-pyrazol-5-yl)quinolin-5-yl)cyclopropyl)-5-

(2-(methylamino)ethoxy)benzamide (Compound 639)

Compound 639

Compound 639 was synthesized according to an analogous procedure to the one described for compound 630. M + H ⁺ = 456.2 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 89.22 (s, 1H), 9.15 (br d, J= 8.5 Hz, 1H), 9.02 (d, J= 4.1 Hz, 1H), 8.11 (d, J= 1.0 Hz, 1H), 8.06 (d, J= 1.5 Hz, 1H), 7.71 (dd, J= 4.2, 8.6 Hz, 1H), 7.57 (d, J= 1.9 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.90 (dd, J= 2.8, 8.4 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.64 (d, J= 1.8 Hz, 1H), 4.12 (t, J= 4.9 Hz, 2H), 4.00 (s, 3H), 3.27 (br t, J= 4.7 Hz, 2H), 2.60 (s, 3H), 1.97 (s, 3H), 1.39 (br s, 2H), 1.32 (br s, 2H). Example 583: 2-Methyl-/V-(l-(7-( 1 -methyl- l//-py razol-3-yl )quinolin-5-yl )cyclopropyl)-5- (2-(methylamino)ethoxy)benzamide (Compound 647)

Compound 647

Compound 647 was synthesized according to an analogous procedure to the one described for compound 630. M + H ⁺ = 456.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.46 - 9.32 (m, 1H), 9.26 (s, 1H), 9.08 (br d, J= 3.5 Hz, 1H), 8.76 (br dd, J= 1.3, 7.4 Hz, 2H), 8.48 (s, 1H), 8.39 (s, 1H), 7.88 (d, J= 2.3 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.15 (t, J = 4.9 Hz, 2H), 3.99 (s, 3H), 3.27 (br d, J= 5.3 Hz, 2H), 2.59 (t, J= 5.4 Hz, 3H), 1.98 (s, 3H), 1.43 (br s, 2H), 1.32 (br s, 2H).

Example 584: (3)-/V-(l-(2,7-Dimethylquinolin-5-yl)cyclopropyl)-2-methyl-5 -((l- methylazetidin-2-yl)methoxy)benzamide (Compound 802)

Compound 802

Compound 802 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 430.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.48 (d, J= 8.8

Hz, 1H), 9.22 (s, 1H), 7.96 - 7.79 (m, 3H), 7.09 (br d, J= 8.5 Hz, 1H), 6.92 (dd, J = 2.4, 8.4 Hz, 1H), 6.72 (d, J= 2.4 Hz, 1H), 4.66 - 4.56 (m, 1H), 4.21 (br d, J= 5.1 Hz, 2H), 4.03 (dt, J = 4.6, 9.5 Hz, 1H), 3.86 (br d, J= 9.6 Hz, 1H), 2.85 (d, J= 16.0 Hz, 6H), 2.60 (s, 3H), 2.43 - 2.28 (m, 2H), 1.94 (s, 3H), 1.39 (br s, 2H), 1.27 (br s, 2H). Example 585: ( )-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(7-vin ylquinolin- 5-yl)cyclopropyl)benzamide (Compound 717)

Compound 717

Compound 717 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 442.1 (LCMS^H NMR (400 MHz, DMSO-t/e) 8 9.64 - 9.49 (m, 1H), 9.36 - 9.28 (m, 1H), 9.18 (br s, 1H), 8.25 (s, 1H), 8.13 (br s, 1H), 8.04 - 7.84 (m, 1H), 7.13 - 6.98 (m, 2H), 6.92 (dd, J= 2.7, 8.3 Hz, 1H), 6.74 (d, J= 2.3 Hz, 1H), 6.23 (d, J= 17.6 Hz, 1H), 5.66 (br d, J = 10.8 Hz, 1H), 4.29 - 4.16 (m, 2H), 3.80 - 3.64 (m, 1H), 3.60 - 3.55 (m, 1H), 3.14 - 3.04 (m, 1H), 2.89 (s, 3H), 2.28 - 2.14 (m, 1H), 2.06 - 1.85 (m, 5H), 1.81 - 1.72 (m, 1H), 1.43 (br s, 2H), 1.34 (br s, 2H).

Example 586: (5)-2-Methyl-N-(l-(2-methyl-7-vinylquinolin-5-yl)cyclopropyl )-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 813)

Compound 813

Compound 813 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 442.3 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 3 10.92 (br d, J =

3.4 Hz, 1H), 9.63 - 9.23 (m, 2H), 8.35 - 7.76 (m, 3H), 7.15 - 7.00 (m, 2H), 6.92 (dd, J= 2.7,

8.4 Hz, 1H), 6.83 - 6.73 (m, 1H), 6.20 (d, J= 17.6 Hz, 1H), 5.65 (br d, J= 11.0 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.40 (dd, J= 8.2, 11.2 Hz, 1H), 4.22 (dd, J= 3.1, 11.3 Hz, 1H), 4.05 - 3.93 (m, 1H), 3.91 - 3.77 (m, 1H), 2.92 (s, 3H), 2.83 - 2.66 ( m, 3H), 2.40 - 2.26 (m, 2H), 1.98 (s, 3H), 1.42 (br s, 2H), 1.33 (br s, 2H). Example 587 : ( )-2-Methyl-5-((l-methylpyrrolidin-2-yl)methoxy)-/V-(l-(7-(pr op-l-en-2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 719)

Compound 719

Compound 719 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 456.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.44 - 9.33 (m, 1H), 9.27 - 9.19 (m, 1H), 9.13 - 9.03 (m, 1H), 8.26 - 8.19 (m, 1H), 8.09 - 8.04 (m, 1H), 7.88

- 7.78 (m, 1H), 7.12 - 7.05 (m, 1H), 6.98 - 6.88 (m, 1H), 6.77 - 6.67 (m, 1H), 5.86 - 5.73 (m, 1H), 5.52 - 5.28 (m, 1H), 4.27 - 4.10 (m, 2H), 3.84 - 3.69 (m, 1H), 3.16 - 3.03 (m, 1H), 2.92

- 2.84 (m, 3H), 2.29 - 2.16 (m, 4H), 2.10 - 1.69 (m, 7H), 1.44 - 1.38 (m, 2H), 1.34 - 1.27 (m, 2H).

Example 588: (5',£')-N-(l-(7-(2-Cyclopropylvinyl)quinolin-5-yl)cycloprop yl)-2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 684)

Compound 684

Compound 684 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 468.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.04 - 9.84 (m, 1H), 9.22 - 9.09 (m, 2H), 8.99 - 8.90 (m, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.63 (dd, J= 4.4, 8.5 Hz, 1H), 7.11 (d, J= 8.6 Hz, 1H), 7.00 - 6.87 (m, 1H), 6.80 - 6.67 (m, 2H), 6.17 (dd, J= 9.4, 15.8 Hz, 1H), 4.65 - 4.58 (m, 1H), 4.23 (br d, J= 5.7 Hz, 2H), 4.03 - 3.99 (m, 1H), 3.89 - 3.84 (m, 1H), 2.94 - 2.76 (m, 3H), 2.40 - 2.31 (m, 2H), 1.97 (s, 3H), 1.76 - 1.64 (m, 1H), 1.41 - 1.22 (m, 3H), 0.93 - 0.84 (m, 2H), 0.69 - 0.62 (m, 2H). Example 589: (5',£')-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-A ^z -(l-(7-(3- methylstyryl)quinolin-5-yl)cyclopropyl)benzamide (Compound 690)

Compound 690

Compound 690 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 518.3 (LCMS); ^X HNMR (400 MHz, DMSO-tL) 8 10.59 - 10.46 (m, 1H), 9.43 - 9.34 (m, 1H), 9.27 (s, 1H), 9.08 (br d, J= 3.9 Hz, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.81 (br dd, J= 3.3, 7.5 Hz, 1H), 7.61 (s, 1H), 7.57 (s, 2H), 7.57 - 7.53 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.17 (d, J= 7.7 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.92 (dd, J= 2.5, 8.3 Hz, 1H), 6.74 (d, J= 2.6 Hz, 1H), 4.66 - 4.58 (m, 1H), 4.33 (dd, J= 7.8, 11.3 Hz, 1H), 4.25 - 4.19 (m, 1H), 4.03 - 3.98 (m, 1H), 3.88 - 3.84 (m, 1H), 2.81 (d, J= 5.1 Hz, 3H), 2.41 - 2.25 (m, 5H), 1.98 (s, 3H), 1.43 (br s, 2H), 1.40 - 1.35 (m, 2H).

Example 590: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(prop -l-yn-l- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 721)

Compound 721

Compound 721 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 440.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.10 - 9.89 (m, 1H), 9.16 (s, 1H), 9.09 (br d, J= 8.4 Hz, 1H), 8.96 (br d, J= 3.4 Hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.65 (dd, J= 4.3, 8.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 2.3, 8.4 Hz, 1H), 6.77 - 6.67 (m, 1H), 4.60 (br d, J= 5.3 Hz, 1H), 4.22 (br d, J = 5.1 Hz, 2H), 4.08 - 3.97 (m, 1H), 3.86 (br dd, J= 5.6, 9.1 Hz, 1H), 2.88 - 2.68 (m, 3H), 2.43 - 2.25 (m, 2H), 2.14 (s, 3H), 1.94 (s, 3H), 1.35 (br s, 2H), 1.24 (br s, 2H). Example 591: ( )-/V-(l-(7-(5-Acetylthiophen-2-yl)quinolin-5-yl)cyclopropyl) -2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 657)

Compound 657

Compound 657 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 526.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.91 (br s, 1H), 9.23 - 9.16 (m, 1H), 9.09 (d, J = 8.6 Hz, 1H), 8.98 (dd, J = 1.4, 4.1 Hz, 1H), 8.32 (d, J= 1.5 Hz, 1H), 8.22 (d, J= 1.9 Hz, 1H), 8.05 (d, J= 4.0 Hz, 1H), 7.93 (d, J= 4.0 Hz, 1H), 7.65 (dd, J= 4.3, 8.5 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.92 (dd, J= 2.7, 8.4 Hz, 1H), 6.77 - 6.68 (m, 1H), 4.60 (br d, J = 4.4 Hz, 1H), 4.25 - 4.20 (m, 2H), 3.87 (br dd, J= 3.1, 9.4 Hz, 2H), 2.83 (d, J= 4.9 Hz, 3H), 2.59 (s, 3H), 2.42 - 2.27 (m, 2H), 1.97 (s, 3H), 1.45 - 1.31 (m, 4H).

Example 592: (5)-/V-(l-(7-(5-Cyanothiophen-2-yl)quinolin-5-yl)cyclopropyl )-2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 754)

Compound 754

Compound 754 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 509.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.67 (br d, J = 4.0 Hz, 1H), 9.33 - 9.23 (m, 2H), 9.08 (d, J= 3.3 Hz, 1H), 8.39 (s, 1H), 8.24 (d, J= 1.8 Hz, 1H), 8.11 (d, J= 4.0 Hz, 1H), 8.01 (d, = 4.0 Hz, 1H), 7.79 (dd, J= 4.4, 8.5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.8, 8.4 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.69 - 4.56 (m, 1H), 4.42 - 4.30 (m, 1H), 4.21 (dd, J = 3.2, 11.3 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.89 - 3.80 (m, 1H), 2.80 (d, J= 5.0 Hz, 3H), 2.38 - 2.26 (m, 2H), 1.96 (s, 3H), 1.45 - 1.40 (m, 2H), 1.37 (br s, 2H). Example 593: (3)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(2- methylthiazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 764)

Compound 764

Compound 764 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 499.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 1.31 - 1.44 (m, 4H), 1.91 - 1.97 (m, 3H), 2.27 - 2.40 (m, 2H), 2.72 - 2.76 (m, 3H), 2.79 - 2.84 (m, 3H), 3.81 - 3.89 (m, 1H), 3.97 - 4.06 (m, 1H), 4.17 - 4.24 (m, 2H), 4.53 - 4.67 (m, 1H), 6.68 - 6.73 (m, 1H), 6.89 - 6.94 (m, 1H), 7.05 - 7.13 (m, 1H), 7.72 - 7.79 (m, 1H), 8.13 (s, 1H), 8.20 (s, 1H), 8.33 (s, 1H), 8.95 - 9.08 (m, 1H), 9.25 (br d, J= 9.4 Hz, 1H). Example 594: (3)-2-Methyl-/V-(l-(7-(5-methyl-l,3,4-thiadiazol-2-yl)quinol in-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 691)

Compound 691

Compound 691 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 500.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.03 - 9.83 (m, 1H), 9.22 (s, 1H), 9.14 (d, J= 8.5 Hz, 1H), 9.02 (dd, J= 1.4, 4.1 Hz, 1H), 8.48 (d, J= 1.8 Hz,

1H), 8.41 (d, J= 1.3 Hz, 1H), 7.71 (dd, J = 4.2, 8.6 Hz, 1H), 7.10 (d, J= 8.6 Hz, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 4.60 (br d, J= 4.0 Hz, 1H), 4.27 - 4.17 (m, 2H), 4.08 - 3.99 (m, 1H), 3.93 - 3.82 (m, 1H), 2.86 - 2.80 (m, 6H), 2.41 - 2.28 (m, 2H), 1.96 (s, 3H), 1.43 (br s, 2H), 1.31 (br s, 2H). Example 595: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5-me thylfuran- 2-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 654)

Compound 654

Compound 654 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 482.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.63 - 10.46 (m, 1H), 9.39 (br d, = 4.3 Hz, 1H), 9.28 (s, 1H), 9.09 (br d, J= 4.8 Hz, 1H), 8.25 (d, J= 11.5 Hz, 2H), 7.92 - 7.72 (m, 1H), 7.27 (d, J= 2.8 Hz, 1H), 7.17 - 7.02 (m, 1H), 6.92 (dd, J= 2.5, 8.4 Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 6.38 (d, J = 3.0 Hz, 1H), 4.68 - 4.58 (m, 1H), 4.37 - 4.28 (m, 1H), 4.26 - 4.18 (m, 1H), 3.99 (br dd, J= 4.6, 9.0 Hz, 1H), 3.88 - 3.81 (m, 1H), 2.81 (d, J = 5.0 Hz, 3H), 2.44 (s, 3H), 2.37 - 2.29 (m, 2H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.35 (br s, 2H).

Example 596: (5)-/V-(l-(7-(Furan-3-yl)quinolin-5-yl)cyclopropyl)-2-methyl -5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 655)

Compound 655

Compound 655 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 468.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.70 (br d, J= 8.4 Hz, 1H), 9.36 (s, 1H), 9.22 (d, J= 5.1 Hz, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.05 (dd, J= 5.3, 8.5 Hz, 1H), 7.91 (s, 1H), 7.17 (s, 1H), 7.14 - 7.03 (m, 1H), 6.92 (dd, J= 2.6, 8.3 Hz, 1H), 6.75 (d, J= 2.6 Hz, 1H), 4.62 (br dd, J= 2.9, 7.4 Hz, 1H), 4.40 - 4.26 (m, 1H), 4.25 - 4.14 (m, 1H), 4.01 (dt, J= 4.4, 9.6 Hz, 1H), 3.85 (q, J = 9.7 Hz, 1H), 2.81 (s, 3H), 2.42 - 2.23 (m, 2H), 1.96 (s, 3H), 1.45 (br s, 2H), 1.42 (br s, 2H). Example 597: ( )-/V-(l-(7-(2,5-Dimethylfuran-3-yl)quinolin-5-yl)cyclopropyl )-2-methyl- 5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 671)

Compound 671

Compound 671 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 496.1 (LCMS); 'H NMR (400 MHz, CD ₃ OD) 8 9.60 (d, J= 8.5 Hz, 1H), 9.07 (dd, J= 1.3, 5.1 Hz, 1H), 8.37 (d, J= 1.5 Hz, 1H), 8.06 (s, 1H), 7.91 (dd, J= 5.1, 8.5 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.97 (dd, J= 2.6, 8.3 Hz, 1H), 6.80 (d, = 2.6 Hz, 1H), 6.47 (s, 1H), 4.74 - 4.61 (m, 1H), 4.31 - 4.26 (m, 1H), 4.24 - 4.14 (m, 2H), 4.00 - 3.90 (m, 1H), 2.95 (s, 3H), 2.61 (s, 3H), 2.57 - 2.51 (m, 2H), 2.34 (s, 3H), 2.03 (s, 4H), 1.60 - 1.53 (m, 2H), 1.48 - 1.41 (m, 2H).

Example 598: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(2- methyloxazol-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 716)

Compound 716

Compound 716 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 483.4 (LCMS); ^X H NMR (400 MHz, DMSO-tZ ₆ ) 5 11.19 - 11.07 (m, 1H), 9.83 - 9.63 (m, 1H), 9.47 - 9.39 (m, 1H), 9.24 (d, J= 4.3 Hz, 1H), 8.57 - 8.28 (m, 2H), 8.13 - 7.96 (m, 2H), 7.21 - 7.03 (m, 1H), 6.91 (dd, J = 2.6, 8.3 Hz, 1H), 6.77 (d, J = 2.6 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.43 (br dd, J= 8.3, 11.2 Hz, 1H), 4.23 - 4.19 (m, 1H), 3.83 (br d, J = 6.9 Hz, 2H), 2.84 - 2.65 (m, 3H), 2.59 (s, 3H), 2.39 - 2.25 (m, 1H), 2.42 - 2.17 (m, 2H), 2.10 - 1.90 (m, 3H), 1.60 - 1.24 (m, 4H). Example 599: ( )-2-Methyl-/V-(l-(7-(5-methyl-l,3,4-oxadiazol-2-yl)quinolin- 5-yl) cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 693)

Compound 693

Compound 693 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 484.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.95 - 9.82 (m, 1H), 9.27 - 9.18 (m, 1H), 9.16 (s, 1H), 9.05 (dd, J = 1.5, 4.1 Hz, 1H), 8.48 (s, 1H), 8.44 (d, J = 1.8 Hz, 1H), 7.74 (dd, J= 4.1, 8.6 Hz, 1H), 7.19 - 7.07 (m, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.81- 6.70 (m, 1H), 4.66 - 4.53 (m, 1H), 4.42 - 4.36 (m, 1H), 4.27 - 4.18 (m, 2H), 4.07 - 3.97 (m, 1H), 3.86 (br dd, J= 6.3, 9.5 Hz, 1H), 2.84 (d, J= 4.9 Hz, 3H), 2.66 (s, 3H), 2.42 - 2.26 (m, 2H), 1.95 (s, 3H), 1.43 (br s, 2H), 1.30 (br s, 2H), 1.22 - 1.25 (m, 1H).

Example 600: ( )-2-Methyl-/V-(l-(2-methyl-7-(l-methyl-lH-pyrazol-4-yl)quino lin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 820)

Compound 820

Compound 820 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 496.3 (LCMS); 'H NMR(400 MHz, DMSO-tL) 8 9.41 (d, J= 8.8 Hz, 1H), 9.32 - 9.15 (m, 1H), 8.49 (s, 1H), 8.22 (d, J= 0.9 Hz, 1H), 8.13 (d, J= 4.6 Hz, 2H), 7.83 (d, J= 8.8 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 7.02 - 6.87 (m, 1H), 6.80 - 6.68 (m, 1H), 4.67 - 4.56 (m, 1H), 4.23 (d, J= 5.3 Hz, 2H), 4.04 (dt, J= 4.8, 9.5 Hz, 1H), 3.95 (s, 3H), 3.91 - 3.84 (m, 1H), 2.85 (d, J = 10.6 Hz, 6H), 2.41 - 2.30 (m, 2H), 1.97 (s, 3H), 1.48 - 1.31 (m, 4H). Example 601: (5)-/V-(l-(7-(Benzo[d]oxazol-2-yl)quinolin-5-yl)cyclopropyl) -2-methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 718)

Compound 718

Compound 718 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 519.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.49 - 9.24 (m, 2H), 9.16 (d, J= 3.4 Hz, 1H), 8.82 (s, 1H), 8.74 (s, 1H), 7.98 - 7.82 (m, 3H), 7.60 - 7.36 (m, 2H), 7.16 - 7.00 (m, 1H), 6.92 (dd, J= 2.7, 8.3 Hz, 1H), 6.75 (d, J= 2.6 Hz, 1H), 4.66 - 4.54 (m, 1H), 4.35 - 4.17 (m, 2H), 4.00 (td, J =4.8, 9.5 Hz, 1H), 3.85 (q, J = 9.5 Hz, 1H), 2.86 - 2.68 (m, 3H), 2.42 - 2.21 (m, 2H), 1.97 (s, 3H), 1.48 (br s, 2H), 1.35 (br s, 2H). Example 602: (5)-/V-(l-(7-(Imidazo[l,5-a]pyridin-l-yl)quinolin-5-yl)cyclo propyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 736)

Compound 736

Compound 736 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ =518.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.93 - 9.80 (m, 1H), 9.34 - 9.26 (m, 1H), 9.26 - 9.21 (m, 1H), 9.05 (br d, J= 4.5 Hz, 1H), 8.66 (s, 2H), 8.52

(d, J = 7.0 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H), 7.78 - 7.69 (m, 1H), 7.19 - 7.07 (m, 2H), 6.97 - 6.84 (m, 2H), 6.76 (d, J= 2.8 Hz, 1H), 4.61 (br d, J= 4.3 Hz, 1H), 4.24 - 4.21 (m, 2H), 4.05 - 4.01 (m, 1H), 3.87 (br dd, J = 6.4, 9.4 Hz, 1H), 2.84 (d, J = 4.9 Hz, 3H), 2.38 - 2.28 (m, 2H), 1.99 (s, 3H), 1.45 (br s, 2H), 1.34 (br s, 2H). Example 603: ( )-/V-(l-(7-(Cyclohex-l-en-l-yl)quinolin-5-yl)cyclopropyl)-2- methyl-5- ((l-methylazetidin-2-yl)methoxy)benzamide (Compound 663)

Compound 663

Compound 663 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 482.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.77 - 10.37 (m, 1H), 9.53 - 9.38 (m, 1H), 9.25 (br s, 1H), 9.16 - 9.04 (m, 1H), 8.20 (br s, 1H), 8.03 (br s, 1H),

7.92 - 7.80 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 2.6, 8.4 Hz, 1H), 6.73 (d, J= 2.4

Hz, 1H), 6.63 (br s, 1H), 4.66 - 4.55 (m, 1H), 4.38 - 4.28 (m, 1H), 4.21 (dd, J= 3.1, 11.2 Hz, 1H), 4.03 - 3.94 (m, 1H), 3.91 - 3.75 (m, 2H), 2.81 (d, J= 4.9 Hz, 3H), 2.70 - 2.65 (m, 1H),

2.37 - 2.28 (m, 4H), 1.96 (s, 3H), 1.86 - 1.78 (m, 2H), 1.72 - 1.64 (m, 2H), 1.41 (br s, 2H),

1.31 (br s, 2H).

Example 604: ( )-/V-(l-(7-(4-Fluorophenyl)quinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 678)

Compound 678

Compound 678 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 496.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.94 (br s, 1H), 9.23 - 9.13 (m, 2H), 9.01 (dd, J= 1.5, 4.4 Hz, 1H), 8.21 (s, 2H), 7.99 - 7.89 (m, 2H), 7.68 (dd, J= 4.3, 8.6 Hz, 1H), 7.46 - 7.36 (m, 2H), 7.13 - 7.07 (m, 1H), 6.97 - 6.88 (m, 1H), 6.77 - 6.70 (m, 1H), 4.60 (br d, J= 4.6 Hz, 1H), 4.22 (d, J= 5.5 Hz, 2H), 4.01 (dt, J = 5.0, 9.6 Hz, 1H), 3.91 - 3.85 (m, 1H), 2.87 - 2.69 (m, 3H), 2.41 - 2.29 (m, 2H), 1.97 (s, 3H), 1.39 (br d, J= 14.3 Hz, 4H). Example 605: ( )-/V-(l-(7-(3-Chloro-4-fluorophenyl)quinolin-5-yl)cyclopropy l)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 687)

Compound 687

Compound 687 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 530.3/532.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.88 - 9.80 (m, 1H), 9.20 - 9.16 (m, 1H), 9.11 (d, J = 8.9 Hz, 1H), 8.98 (dd, J= 1.5, 4.1 Hz, 1H), 8.25 (d, J= 1.4 Hz, 1H), 8.18 (d, J= 1.8 Hz, 1H), 8.13 (dd, J= 2.3, 7.1 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.68 - 7.57 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 2.7, 8.3 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 4.65 - 4.53 (m, 1H), 4.25 - 4.17 (m, 2H), 4.07 - 3.94 (m, 1H), 3.90 - 3.77 (m, 1H), 2.83 (d, J= 4.9 Hz, 3H), 2.29 (s, 2H), 1.97 (s, 3H), 1.39 (s, 4H).

Example 606: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(6-ox o-l,6- dihydropyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 672)

Compound 672

Compound 672 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 495.2 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 8 9.95 - 9.77 (m,

1H), 9.24 - 9.05 (m, 2H), 9.01 - 8.90 (m, 1H), 8.19 - 7.93 (m, 4H), 7.62 (dd, J= 4.3, 8.8 Hz, 1H), 7.19 - 7.04 (m, 1H), 7.00 - 6.87 (m, 1H), 6.77 - 6.65 (m, 1H), 6.53 (d, J= 9.7 Hz, 1H), 4.66 - 4.52 (m, 1H), 4.25 - 4.15 (m, 2H), 4.08 - 3.99 (m, 1H), 3.86 (br dd, J= 6.3, 9.7 Hz, 1H), 2.83 (d, J= 5.0 Hz, 3H), 2.44 - 2.30 (m, 2H), 1.97 (s, 3H), 1.37 (br s, 4H). Example 607: (3)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(py rimidin-2- yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 681)

Compound 681

Compound 681 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 480.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.97 - 9.82 (m, 1H), 9.26 - 9.13 (m, 2H), 9.07 - 9.00 (m, 3H), 8.99 - 8.92 (m, 2H), 7.70 (dd, J= 4.1, 8.5 Hz, 1H), 7.56 (t, J = 4.9 Hz, 1H), 7.15 - 7.06 (m, 1H), 6.99 - 6.87 (m, 1H), 6.79 - 6.68 (m, 1H), 4.61 (br dd, J= 3.3, 6.1 Hz, 1H), 4.29 - 4.16 (m, 2H), 4.08 - 3.96 (m, 1H), 3.86 (br dd, J= 6.1, 9.5 Hz, 1H), 2.88 - 2.65 (m, 3H), 2.42 - 2.26 (m, 2H), 1.97 (s, 3H), 1.44 (br s, 2H), 1.29 (br s, 2H).

Example 608: (3)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(2- (piperidin-l- yl)pyrimidin-5-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 701)

Compound 701

Compound 701 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 563.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.32 - 11.16 (m, 1H), 9.89 - 9.76 (m, 1H), 9.52 - 9.44 (m, 1H), 9.30 (d, J= 4.4 Hz, 1H), 8.94 (s, 2H), 8.50 (s, 1H), 8.41 (d, J= 1.5 Hz, 1H), 8.11 (dd, J = 5.3, 8.6 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.91 (dd, J = 2.7, 8.4 Hz, 1H), 6.78 (d, J= 2.6 Hz, 1H), 4.69 - 4.59 (m, 1H), 4.45 (dd, J = 8.4, 11.3 Hz, 1H), 4.21 (dd, J= 3.Q, 11.1 Hz, 1H), 4.03 - 3.92 (m, 1H), 3.90 - 3.86 (m, 4H), 3.85 - 3.78 (m, 1H), 2.79 (d, J= 5.0 Hz, 3H), 2.41 - 2.21 (m, 2H), 2.01 - 1.97 (m, 3H), 1.71 - 1.64 (m, 2H), 1.62 - 1.53 (m, 4H), 1.53 - 1.41 (m, 4H). Example 609: (3)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5- morpholinopyridin-3-yl)quinolin-5-yl)cyclopropyl)benzamide (Compound 699)

Compound 699

Compound 699 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 564.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.09 - 9.89 (m, 1H), 9.28 - 9.19 (m, 1H), 9.15 (d, J= 8.5 Hz, 1H), 9.02 (dd, J = 1.4, 4.1 Hz, 1H), 8.66 (s, 1H), 8.48 (br d, J= 2.0 Hz, 1H), 8.43 (s, 1H), 8.22 (d, J= 1.7 Hz, 1H), 8.14 - 8.06 (m, 1H), 7.69 (dd, J= 4.2, 8.6 Hz, 1H), 7.14 - 7.06 (m, 1H), 6.96 - 6.88 (m, 1H), 6.72 (d, J= 2.6 Hz, 1H), 4.65 - 4.57 (m, 1H), 4.25 - 4.19 (m, 2H), 4.07 - 3.99 (m, 1H), 3.93 - 3.85 (m, 1H), 3.84 - 3.79 (m, 4H), 3.51 - 3.40 (m, 4H), 2.85 (br d, J= 4.4 Hz, 3H), 2.39 - 2.27 (m, 2H), 1.96 (s, 3H), 1.42 (br s, 4H).

Example 610: (5)-/V-(l-(7-(Imidazo[l,2-a]pyridin-6-yl)quinolin-5-yl)cyclo propyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 702)

Compound 702

Compound 702 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 518.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.84 - 10.70 (m, 1H), 9.59 (s, 1H), 9.37 - 9.33 (m, 1H), 9.26 (br d, J= 8.8 Hz, 1H), 9.11 - 9.07 (m, 1H), 8.56 - 8.51 (m, 1H), 8.44 (dd, J= 1.4, 9.5 Hz, 2H), 8.33 - 8.27 (m, 2H), 8.15 (d, J = 9.2 Hz, 1H), 7.83

- 7.74 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.92 (dd, J= 2.6, 8.3 Hz, 1H), 6.73 (d, J = 2.9 Hz, 1H), 4.69 - 4.57 (m, 1H), 4.37 (dd, J= 8.1, 11.4 Hz, 1H), 4.21 (dd, J= 3.2, 11.3 Hz, 1H), 4.03

- 3.95 (m, 1H), 3.81 (s, 1H), 2.80 (d, J= 5.0 Hz, 3H), 2.34 - 2.27 (m, 2H), 1.96 (s, 3H), 1.45 - 1.40 (m, 4H). Example 611: (5)-/V-(l-(7-([l,2,4]Triazolo[l,5-a]pyridin-6-yl)quinolin-5- yl)cyclopropyl)-

2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 700)

Compound 700

Compound 700 was synthesized according to an analogous procedure to the one described for compound 653. M + H ⁺ = 519.2 (LCMS); ^X H NMR (400 MHz, DMSO-tZ ₆ ) 5 11.19 - 10.91 (m, 1H), 9.85 - 9.63 (m, 2H), 9.54 - 9.39 (m, 1H), 9.35 - 9.24 (m, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 8.50 (s, 1H), 8.26 - 8.21 (m, 1H), 8.14 - 8.06 (m, 2H), 7.12 - 7.07 (m, 1H), 6.94 - 6.89 (m, 1H), 6.77 (d, J = 2.8 Hz, 1H), 4.65 - 4.61 (m, 1H), 4.42 (dd, J = 8.3, 11.4 Hz, 1H), 4.21 (dd, J = 3.2, 11.1 Hz, 1H), 4.02 - 3.93 (m, 1H), 3.89 - 3.76 (m, 1H), 2.79 (d, J= 4.8 Hz, 3H), 2.39 - 2.21 (m, 2H), 2.01 - 1.96 (m, 3H), 1.57 - 1.50 (m, 2H), 1.47 (br s, 2H).

Example 612: (3)-2-Methyl-5-(2-(methylamino)propoxy)-/V-(l-(7-vinylquinol in-5- yl)cyclopropyl)benzamide (Compound 661)

Compound 661

Compound 661 was synthesized according to an analogous procedure to the one described for compound 660. M + H ⁺ = 416.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.54 (br d, J= 6.1 Hz, 1H), 9.32 (s, 1H), 9.23 - 9.05 (m, 2H), 9.03 - 8.89 (m, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.96 (br d, J= 5.5 Hz, 1H), 7.14 - 7.01 (m, 2H), 6.91 (dd, J= 2.7, 8.3 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 6.21 (d, J= 17.6 Hz, 1H), 5.64 (d, J= 10.9 Hz, 1H), 4.16 - 4.11 (m, 1H), 4.04 (br dd, J= 6.2, 10.7 Hz, 1H), 3.51 (br d, J= 4.1 Hz, 1H), 2.56 - 2.52 (m, 3H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.34 (br s, 2H), 1.28 (d, J= 6.8 Hz, 3H). Example 613: (5) -5-(2-Aminopropoxy)-2-methyl-/V-(l-(7-vinylquinolin-5- yl)cyclopropyl)benzamide (Compound 735)

Compound 735

Compound 735 was synthesized according to an analogous procedure to the one described for compound 660. M + H ⁺ = 402.3 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.57 (br d, J= 8.4 Hz, 1H), 9.33 (s, 1H), 9.18 (d, J= 4.0 Hz, 1H), 8.28 - 8.10 (m, 5H), 7.97 (dd, J= 5.0, 8.5 Hz, 1H), 7.15 - 7.00 (m, 2H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.73 (d, J= 2.6 Hz, 1H), 6.22 (d, J= 17.6 Hz, 1H), 5.65 (d, J= 10.9 Hz, 1H), 4.07 - 4.02 (m, 1H), 3.95 - 3.89 (m, 1H), 3.60 - 3.46 (m, 2H), 1.98 (s, 3H), 1.51 - 1.30 (m, 4H), 1.26 (d, J= 6.7 Hz, 3H). Example 614: ( )-5-(2-Aminopropoxy)-2-methyl-/V-(l-(7-(prop-l-en-2-yl)quino lin-5- yl)cyclopropyl)benzamide (Compound 734)

Compound 734

Compound 734 was synthesized according to an analogous procedure to the one described for compound 660. M + H ⁺ = 432.1 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 8 9.59 (br d, J= 8.4 Hz, 1H), 9.32 (s, 1H), 9.20 (d, J= 4.1 Hz, 1H), 8.32 - 8.19 (m, 6H), 7.98 (dd, J= 5.0, 8.5 Hz, 1H), 7.08 (d, J= 8.5 Hz, 1H), 6.90 (dd, J = 2.8, 8.4 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 5.91 - 5.73 (m, 1H), 5.49 (s, 1H), 4.07 - 4.03 (m, 1H), 3.95 - 3.91 (m, 1H), 3.57 - 3.44 (m, 2H), 2.27 (s, 3H), 1.97 (s, 4H), 1.45 - 1.39 (m, 2H), 1.34 (br s, 2H), 1.25 (d, J= 6.8 Hz, 4H). Example 615: A (l-(7-(5-((((15',3^)-3-Hydroxycyclopentyl)amino)methyl) thiophen-2-yl) quinolin-5-yl)cyclopropyl)-2-methyl-5-(((5)-l-methylazetidin -2-yl)methoxy)benzamide

(Compound 751)

Compound 751

Compound 751 was synthesized according to an analogous procedure to the one described for compound 669. M + H ⁺ = 597.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.49 - 10.38 (m, 1H), 9.26 (s, 1H), 9.21 - 9.12 (m, 3H), 9.00 (d, J= 4.0 Hz, 1H), 8.25 - 8.17 (m, 2H), 7.78 (d, J= 3.5 Hz, 1H), 7.69 (dd, J = 4.3, 8.3 Hz, 1H), 7.43 (d, J= 3.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.97 - 6.87 (m, 1H), 6.76 - 6.68 (m, 1H), 4.67 - 4.56 (m, 1H), 4.44 (br t, J= 5.0 Hz, 2H), 4.36 - 4.27 (m, 1H), 4.24 - 4.18 (m, 1H), 4.12 (quin, J = 5.1 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.91 - 3.80 (m, 1H), 2.81 (d, J= 5.0 Hz, 3H), 2.73 - 2.64 (m, 1H), 2.36 - 2.27 (m, 2H), 2.23 - 2.18 (m, 1H), 2.25 - 2.16 (m, 1H), 2.26 - 2.16 (m, 1H), 1.74 - 1.63 (m, 1H), 1.77 - 1.61 (m, 3H), 1.43 - 1.39 (m, 1H), 1.41 (br s, 1H), 1.32 (br s, 2H).

Example 616: (3)-/V-(l-(7-(5-((Dimethylamino)methyl)thiophen-2-yl)quinoli n-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (Compound 756)

Compound 756

Compound 756 was synthesized according to an analogous procedure to the one described for compound 669. M + H ⁺ = 541.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.96 - 10.58 (m, 1H), 9.47 - 9.26 (m, 2H), 9.10 (br s, 1H), 8.45 - 8.18 (m, 2H), 7.99 - 7.75 (m, 2H), 7.50 (br s, 1H), 7.17 - 7.03 (m, 1H), 6.99 - 6.87 (m, 1H), 6.75 (s, 1H), 4.60 (br d, J= 5.1 Hz, 2H), 4.42 - 4.34 (m, 1H), 4.21 (br dd, J = 2.9, 11.3 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.91 - 3.79 (m, 2H), 2.84 - 2.72 (m, 9H), 2.36 - 2.27 (m, 2H), 1.96 (s, 3H), 1.50 - 1.30 (m, 3H). Example 617: (3)-/V-(l-(7-(5-((3,3-Difluoropyrrolidin-l-yl)methyl)thiophe n-2- yl)quinolin-5-yl)cyclopropyl)-2-methyl-5-((l-methylazetidin- 2-yl)methoxy)benzamide (Compound 805)

Compound 805

Compound 805 was synthesized according to an analogous procedure to the one described for compound 669. M + H ⁺ = 603.5 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.14 (s, 1H), 9.03 (d, J= 8.3 Hz, 1H), 8.93 - 8.88 (m, 1H), 8.11 (s, 2H), 7.63 (d, J = 3.5 Hz, 1H), 7.55 (sxt, J= 4.2 Hz, 1H), 7.09 (d, J= 3.6 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.83 (dd, J= 2.6, 8.4 Hz, 1H), 6.61 (d, J= 2.8 Hz, 1H), 3.90 (s, 2H), 3.86 (d, J= 5.4 Hz, 2H), 3.26 - 3.16 (m, 2H), 2.98 (t, J = 13.3 Hz, 2H), 2.80 (t, J= 7.2 Hz, 2H), 2.75 - 2.64 (m, 2H), 2.34 - 2.27 (m, 2H), 2.20 (s, 3H), 1.95 (s, 3H), 1.90 - 1.79 (m, 1H), 1.42 - 1.36 (m, 2H), 1.32 - 1.26 (m, 2H).

Example 618: (3)-/V-(l-(7-(5-((Cyclopentylamino)methyl)thiophen-2-yl)quin olin-5- yl)cyclopropyl)-2-methyl-5-((l-methylazetidin-2-yl)methoxy)b enzamide (Compound 752)

Compound 752

Compound 752 was synthesized according to an analogous procedure to the one described for compound 669. M + H ⁺ = 581.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.74 - 10.50 (m, 1H), 9.43 - 9.27 (m, 3H), 9.23 (br s, 1H), 9.04 (br s, 1H), 8.25 (br d, J= 9.1 Hz, 2H), 7.80 (d, J = 3.5 Hz, 1H), 7.74 (br d, J= 4.5 Hz, 1H), 7.46 (d, J = 3.0 Hz, 1H), 7.16 - 7.04 (m, 1H), 6.97 - 6.86 (m, 1H), 6.73 (d, J= 2.6 Hz, 1H), 4.72 - 4.57 (m, 1H), 4.50 - 4.40 (m, 2H), 4.40 - 4.29 (m, 1H), 4.22 (dd, J= 3.1, 11.3 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.91 - 3.81 (m, 1H), 2.85 - 2.79 (m, 1H), 2.82 (d, J= 5.0 Hz, 2H), 2.44 - 2.23 (m, 2H), 2.02 - 1.94 (m, 4H), 1.80 - 1.67 (m, 4H), 1.65 - 1.50 (m, 2H), 1.43 (br s, 2H), 1.34 (br s, 2H). Example 619: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(5- (morpholinomethyl)thiophen-2-yl)quinolin-5-yl)cyclopropyl)be nzamide (Compound 793)

Compound 793

Compound 793 was synthesized according to an analogous procedure to the one described for compound 669. M + H ⁺ =583.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.92 - 11.64 (m, 1H), 11.31 - 10.99 (m, 1H), 9.56 (br s, 1H), 9.40 (br s, 1H), 9.20 (br s, 1H), 8.44 (br s, 1H), 8.34 (br s, 1H), 8.02 - 7.86 (m, 2H), 7.56 (d, J= 3.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.76 (d, J= 2.5 Hz, 1H), 4.6 - 4.61 (m, 3H), 4.42 (br dd, J= 8.6, 10.8 Hz, 1H), 4.21 (br dd, J= 3.1, 11.3 Hz, 1H), 3.99 - 3.94 (m, 4H), 3.84 (br dd, J= 6.3, 9.6 Hz, 4H), 3.35 (br d, J= 11.9 Hz, 2H), 2.79 (d, J= 5.0 Hz, 3H), 2.36 - 2.23 (m, 2H), 1.98 - 1.93 (m, 3H), 1.46 (br s, 2H), 1.38 (br s, 2H).

Example 620: ( )-2-Methyl-/V-(l-(7-(methyl(2,2,2-trifluoroethyl)amino)quino lin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 781)

Compound 781

Compound 781 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 513.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 811.23 (br s, 1H), 9.66 - 9.56 (m, 1H), 9.41 - 9.31 (m, 1H), 9.00 (d, J = 5.5 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.76 (dd, J= 5.6, 8.3 Hz, 1H), 7.37 (d, J= 1.9 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.77 (d, J= 2.6 Hz, 1H), 4.65 (q, J= 9.1 Hz, 3H), 4.49 - 4.39 (m, 1H), 4.23 (dd, J= 3.1, 11.2 Hz, 1H), 4.04 - 3.92 (m, 1H), 3.91 - 3.80 (m, 1H), 3.37 (br s, 2H), 3.27 (s, 3H), 2.80 (d, J= 4.8 Hz, 3H), 2.40 - 2.26 (m, 2H), 2.02 - 1.96 (m, 3H), 1.48 - 1.31 (m, 4H). Example 621: ( )-2-Methyl-/V-(l-(2-methyl-7-((2,2,2-trifluoroethyl)amino)qu inolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 807)

Compound 807

Compound 807 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 527.3 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 11.20 - 10.89 (m, 1H), 9.42 (br d, J= 8.4 Hz, 1H), 9.28 (s, 1H), 7.80 (br s, 1H), 7.63 (br d, J= 8.4 Hz, 1H), 7.32 (br s, 1H), 7.10 (br d, J= 8.3 Hz, 1H), 6.95 - 6.90 (m, 1H), 6.75 (br s, 1H), 4.69 - 4.54 (m, 3H), 4.48 - 4.38 (m, 1H), 4.27 - 4.19 (m, 1H), 4.05 - 3.93 (m, 1H), 3.90 - 3.80 (m, 1H), 3.25 (s, 3H), 2.92 - 2.76 (m, 6H), 2.40 - 2.26 (m, 2H), 1.99 (s, 3H), 1.47 - 1.27 (m, 4H). Example 622: (5)-/V-(l-(7-(Dipropylamino)quinolin-5-yl)cyclopropyl)-2-met hyl-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 771)

Compound 771

Compound 771 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 501.5 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.05 - 9.93 (m, 1H), 9.30 (br d, J= 7.5 Hz, 1H), 9.16 (s, 1H), 8.84 (d, J= 4.6 Hz, 1H), 7.72 (d, J= 2.0 Hz,

1H), 7.54 (dd, J= 5.8, 8.1 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.76 (d, J= 2.5 Hz, 1H), 4.67 - 4.57 (m, 1H), 4.24 (d, J= 5.3 Hz, 2H), 4.03 (br d, J= 4.4 Hz, 1H), 3.93 - 3.83 (m, 1H), 3.53 - 3.48 (m, 4H), 2.85 (br s, 3H), 2.43 - 2.28 (m, 2H), 1.97 (s, 3H), 1.74 - 1.63 (m, 4H), 1.38 (br s, 2H), 1.28 (br s, 2H), 0.97 (t, J= 13 Hz, 6H). Example 623: (5)-/V-(l-(7-(Azetidin-l-yl)quinolin-5-yl)cyclopropyl)-5-(az etidin-2- ylmethoxy)-2-methylbenzamide (Compound 722)

Compound 722

Compound 722 was synthesized according to an analogous procedure to the one described for compound 683. 1H NMR (400 MHz, DMSO-t/e) 8 = 9.37 - 9.27 (m, 1H), 9.16 (s, 1H), 9.00 - 8.80 (m, 3H), 7.58 - 7.52 (m, 1H), 7.28 (d, J= 2.0 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.95 - 6.90 (m, 1H), 6.73 (d, J= 2.6 Hz, 1H), 6.57 - 6.51 (m, 1H), 4.72 - 4.59 (m, 1H), 4.29 - 4.21 (m, 1H), 4.21 - 4.12 (m, 5H), 4.02 - 3.91 (m, 1H), 3.87 - 3.77 (m, 1H), 2.48 - 2.29 (m, 4H), 1.98 (s, 3H), 1.40 - 1.24 (m, 3H). Example 624: ( )-/V-(l-(7-(Azetidin-l-yl)quinolin-5-yl)cyclopropyl)-2-methy l-5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 723)

Compound 723

Compound 723 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 457.4. (LCMS); 'H NMR (400 MHz, DMSO-t/e) 5 11.01 - 10.13 (m, 1H), 9.10 (s, 1H), 8.85 (br d, J= 7.9 Hz, 1H), 8.68 (dd, J= 1.4, 4.3 Hz, 1H), 7.22 (dd, J=

4.3, 8.4 Hz, 1H), 7.15 (d, J= 2.1 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.91 (dd, J= 2.6, 8.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.66 - 6.62 (m, 1H), 4.64 - 4.47 (m, 1H), 4.31 (br dd, J= 9.1, 10.1 Hz, 1H), 4.24 - 4.13 (m, 1H), 3.99 (brt, = 7.3 Hz, 4H), 3.95 - 3.87 (m, 1H), 3.86 - 3.72 (m, 1H), 2.76 (br s, 3H), 2.44 - 2.23 (m, 4H), 1.99 (s, 3H), 1.32 (br s, 2H), 1.18 (br s, 2H). Example 625: ( )-/V-(l-(7-(3-Methoxyazetidin-l-yl)-2-methylquinolin-5-yl)cy clopropyl)-

2-methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 811)

Compound 811

Compound 811 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 501.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 15.81 (br d, J = 2.1 Hz, 1H), 11.43 - 11.03 (m, 1H), 9.38 - 9.32 (m, 1H), 9.30 - 9.26 (m, 1H), 7.49 (d, J= 8.5 Hz, 1H), 7.25 (d, J= 1.8 Hz, 1H), 7.14 - 7.07 (m, 1H), 6.92 (dd, J = 2.6, 8.4 Hz, 1H), 6.83 - 6.73 (m, 2H), 4.70 - 4.58 (m, 1H), 4.49 - 4.41 (m, 2H), 4.39 - 4.32 (m, 2H), 4.22 (dd, J= 3.1, 11.2 Hz, 1H), 4.03 - 3.94 (m, 3H), 3.85 (br dd, J= 6.8, 9.3 Hz, 1H), 3.31 (s, 3H), 2.82 (s, 3H), 2.80 (d, J= 4.9 Hz, 3H), 2.38 - 2.26 (m, 1H), 2.40 - 2.26 (m, 1H), 2.00 (s, 3H), 1.37 (br s, 2H), 1.27 (br s, 2H).

Example 626: ( )-2-Methyl-/V-(l-(2-methyl-7-(3-(trifluoromethyl)azetidin-l- yl) quinolin-5-yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy )benzamide (Compound 810)

Compound 810

Compound 810 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 539.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 15.90 - 15.51 (m, 1H), 11.29 - 10.82 (m, 1H), 9.43 - 9.33 (m, 1H), 9.30 - 9.22 (m, 1H), 7.59 - 7.53 (m, 1H), 7.33 - 7.25 (m, 1H), 7.13 - 7.06 (m, 1H), 6.95 - 6.89 (m, 1H), 6.83 - 6.72 (m, 2H), 4.75 - 4.55 (m, 1H), 4.49 - 4.36 (m, 3H), 4.27 - 4.16 (m, 3H), 4.06 - 3.96 (m, 1H), 3.93 - 3.82 (m, 2H), 2.88 - 2.65 (m, 6H), 2.43 - 2.20 (m, 2H), 2.06 - 1.93 (m, 3H), 1.43 - 1.24 (m, 4H). Example 627: ( )-/V-(l-(7-(3-Fluoroazetidin-l-yl)-2-methylquinolin-5-yl)cyc lopropyl)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 816)

Compound 816

Compound 816 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 489.2 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.32 (br d, J =

8.5 Hz, 1H), 9.25 - 9.21 (m, 1H), 9.23 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.28 (d, J= 1.9 Hz, 1H), 7.12 (d, J= 8.5 Hz, 1H), 7.02 - 6.91 (m, 1H), 6.84 - 6.72 (m, 1H), 6.67 (s, 1H), 5.79 - 5.46 (m, 1H), 4.68 - 4.58 (m, 1H), 4.57 - 4.43 (m, 2H), 4.37 - 4.20 (m, 4H), 4.03 (dt, J= 4.6,

9.5 Hz, 1H), 3.87 (q, J= 9.3 Hz, 1H), 2.84 (s, 3H), 2.80 (s, 3H), 2.41 - 2.28 (m, 2H), 1.98 (s, 3H), 1.37 (br s, 2H), 1.29 (br s, 2H).

Example 628: ( )-2-Methyl-/V-(l-(2-methyl-7-((2,2,2-trifluoroethyl)amino)qu inolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 826)

Compound 826

Compound 826 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 513.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 15.89 (br s, 1H), 11.25 (br d, J= 4.1 Hz, 1H), 9.39 - 9.29 (m, 2H), 8.12 (br t, J = 6.6 Hz, 1H), 7.66 (d, J= 2.0 Hz, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.21 (d, J= 1.0 Hz, 1H), 7.09 (d, J= 8.5 Hz, 1H), 6.92 (dd, J = 2.7, 8.4 Hz, 1H), 6.77 (d, J= 2.6 Hz, 1H), 4.72 - 4.59 (m, 1H), 4.46 (dd, J= 8.4, 11.2 Hz, 1H), 4.24 (br d, J= 3.3 Hz, 1H), 4.02 - 3.77 (m, 4H), 2.84 (s, 3H), 2.80 (d, J = 5.0 Hz, 3H), 2.38 - 2.23 (m, 2H), 2.02 - 1.96 (m, 3H), 1.38 (br s, 2H), 1.22 (br s, 2H). Example 629: ( )-5-(Azetidin-2-ylmethoxy)-2-methyl-/V-(l-(7-morpholinoquino lin-5- yl)cyclopropyl)benzamide (Compound 712)

Compound 712

Compound 712 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 473.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.29 (br d, J= 7.8 Hz, 1H), 9.16 (s, 1H), 8.94 - 8.89 (m, 2H), 8.88 - 8.80 (m, 1H), 7.85 (d, J= 2.1 Hz, 1H), 7.62 (dd, J= 5.3, 8.3 Hz, 1H), 7.16 (d, J= 2.1 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 6.92 (dd, J= 2.7, 8.5 Hz, 1H), 6.71 (d, J= 2.6 Hz, 1H), 4.70 - 4.64 (m, 1H), 4.29 - 4.19 (m, 2H), 4.16 - 4.12 (m, 1H), 3.93 (br d, J= 7.4 Hz, 1H), 3.89 - 3.74 (m, 8H), 2.40 - 2.27 (m, 2H), 1.98 (s, 3H), 1.36 (br s, 2H), 1.32 (br s, 2H).

Example 630: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7- morpholinoquinolin-5-yl)cyclopropyl)benzamide (Compound 740)

Compound 740

Compound 740 was synthesized according to an analogous procedure to the one described for compound 683. M + H ⁺ = 487.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.78 - 10.66 (m, 1H), 9.49 (br d, J= 7.9 Hz, 1H), 9.26 (s, 1H), 8.96 (d, J= 4.6 Hz, 1H), 7.91 (d, J= 2.1 Hz, 1H), 7.73 (dd, J= 5.6, 8.3 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 2.6, 8.4 Hz, 1H), 6.82 - 6.72 (m, 1H), 4.68 - 4.57 (m, 1H), 4.37 (dd, J= 7.9, 11.4 Hz, 1H), 4.22 (dd, J= 3.3, 11.4 Hz, 1H), 4.05 - 3.95 (m, 1H), 3.88 - 3.80 (m, 5H), 3.53 - 3.50 (m, 4H), 2.85 - 2.79 (m, 3H), 2.39 - 2.27 (m, 2H), 1.98 (s, 3H), 1.39 (br s, 2H), 1.34 (br s, 2H). Example 631: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(isoxazol-4-yl)quinolin- 5- yl)cyclopropyl)-2-methylbenzamide (Compound 714)

Compound 714

Compound 714 was synthesized according to an analogous procedure to the one described for compound 689. M + H ⁺ = 455.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 = 9.76 - 9.67 (m, 1H), 9.46 - 9.35 (m, 1H), 9.27 - 9.19 (m, 1H), 9.16 - 9.10 (m, 1H), 9.04 - 8.95 (m, 1H), 8.32 - 8.27 (m, 1H), 8.22 - 8.15 (m, 1H), 7.71 - 7.62 (m, 1H), 7.13 - 7.05 (m, 1H), 6.96 - 6.86 (m, 1H), 6.68 (d, J = 2.6 Hz, 1H), 4.71 - 4.59 (m, 1H), 4.26 - 4.17 (m, 1H), 4.16 - 4.08 (m, 1H), 3.98 - 3.76 (m, 2H), 2.48 - 2.30 (m, 2H), 2.00 - 1.92 (m, 3H), 1.43 - 1.32 (m, 4H). Example 632: ( )-5-(Azetidin-2-ylmethoxy)-/V-(l-(7-(imidazo[l,5-a]pyridin-l - yl)quinolin-5-yl)cyclopropyl)-2-methylbenzamide (Compound 733)

Compound 733

Compound 733 was synthesized according to an analogous procedure to the one described for compound 689. M + H ⁺ =504.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.48 - 9.40 (m, 1H), 9.26 (s, 1H), 9.13 (br d, J= 3.9 Hz, 1H), 8.91 - 8.76 (m, 2H), 8.73 - 8.67 (m, 2H), 8.54

(d, = 7.0 Hz, 1H), 8.48 (s, 1H), 8.17 (d, J= 9.3 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.23 - 7.15 (m, 1H), 7.11 (d, J= 8.5 Hz, 1H), 6.94 - 6.87 (m, 2H), 6.75 (d, J= 2.5 Hz, 1H), 4.65 (br d, J= 5.9 Hz, 1H), 4.27 - 4.21 (m, 1H), 4.14 (br dd, J = 3.4, 11.1 Hz, 1H), 3.96 - 3.90 (m, 2H), 2.47 - 2.27 (m, 2H), 1.99 (s, 3H), 1.47 (br s, 2H), 1.35 (br s, 2H). Example 633: (5)-2-Methyl-/V-(l-(7-(prop-l-en-2-yl)quinolin-5-yl)cyclopro pyl)-5- (pyrrolidin-2-ylmethoxy)benzamide (Compound 715)

Compound 715

Compound 715 was synthesized according to an analogous procedure to the one described for compound 713. M + H ⁺ = 442.1 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 9.36 - 9.27 (m, 1H), 9.23 - 9.16 (m, 1H), 9.10 - 9.01 (m, 1H), 8.23 - 8.18 (m, 1H), 8.05 - 8.00 (m, 1H), 7.83 - 7.74 (m, 1H), 7.12 - 7.05 (m, 1H), 6.95 - 6.86 (m, 1H), 6.73 - 6.61 (m, 1H), 5.83 - 5.75 (m, 1H), 5.45 - 5.39 (m, 1H), 4.22 - 4.10 (m, 1H), 4.03 - 3.93 (m, 1H), 3.88 - 3.77 (m, 1H), 3.23 - 3.13 (m, 2H), 2.30 - 2.22 (m, 3H), 2.14 - 2.03 (m, 1H), 1.99 - 1.84 (m, 5H), 1.73 - 1.61 (m, 1H), 1.43 - 1.37 (m, 2H), 1.33 - 1.26 (m, 2H).

Example 634: ( )-2-Methyl-/V-(l-(2-methyl-7-(prop-l-yn-l-yl)quinolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 824)

Compound 824

Compound 824 was synthesized according to an analogous procedure to the one described for compound 721. M + H ⁺ = 454.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.35 - 9.96 (m, 1H), 9.17 (s, 1H), 9.11 (br d, J= 8.6 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J= 1.3 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.97 - 6.87 (m, 1H), 6.80 - 6.63 (m, 1H), 4.61 (br d, J = 5.4 Hz, 1H), 4.31 - 4.19 (m, 2H), 4.03 (br dd, J= 4.6, 8.9 Hz, 1H), 3.87 (br dd, J= 6.1, 9.6 Hz, 1H), 2.84 (br d, J= 4.4 Hz, 3H), 2.74 (s, 3H), 2.43 - 2.29 (m, 2H), 2.15 (s, 3H), 1.95 (s, 3H), 1.35 (br s, 2H), 1.23 (br s, 2H). Example 635: ( )-2-Methyl-/V-(l-(7-(methylamino)quinolin-5-yl)cyclopropyl)- 5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 763)

Compound 763

Compound 763 was synthesized according to an analogous procedure to the one described for compound 729. M + H ⁺ = 431.3 (LCMS); ^X H NMR (400 MHz, DMSO-tL) 8 10.09 - 9.88 (m, 1H), 9.26 (br d, J = 8.3 Hz, 1H), 9.15 (s, 1H), 8.79 (d, J= 5.1 Hz, 1H), 7.78 - 7.65 (m, 1H), 7.57 (d, J= 1.8 Hz, 1H), 7.52 (dd, J= 5.6, 8.0 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 6.93 (dd, J= 2.6, 8.6 Hz, 1H), 6.76 (d, J= 2.5 Hz, 1H), 6.66 (s, 1H), 4.68 - 4.55 (m, 1H), 4.24 (d, J= 5.3 Hz, 2H), 4.09 - 3.99 (m, 1H), 3.88 (br d, J= 9.9 Hz, 1H), 2.91 - 2.81 (m, 6H), 2.42 - 2.29 (m, 2H), 1.97 (s, 3H), 1.36 (br s, 2H), 1.20 (br s, 2H).

Example 636: ( )-2-Methyl-4-(methylamino)-5-((l-methylazetidin-2-yl)methoxy )-/V-(l- (7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 745)

Compound 745

Compound 745 was synthesized according to an analogous procedure to the one described for compound 737. M + H ⁺ = 457.4 (LCMS); 'H NMR (400 MHz, DMSO ) 6 10.81 - 10.58 (m, 1H), 9.76 - 9.61 (m, 1H), 9.17 (d, J = 4.6 Hz, 1H), 9.00 (s, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 7.96 (dd, J= 5.0, 8.3 Hz, 1H), 7.15 - 6.99 (m, 1H), 6.87 - 6.73 (m, 1H), 6.41 (br s, 1H), 6.26 - 6.15 (m, 1H), 5.65 (d, J= 11.0 Hz, 1H), 4.68 - 4.59 (m, 1H), 4.33 (br dd, J= 5.7, 11.6 Hz, 1H), 4.19 (br dd, J= 2.5, 12.0 Hz, 1H), 4.10 - 4.02 (m, 2H), 2.82 (s, 3H), 2.73 (s, 3H), 2.41 - 2.34 (m, 2H), 2.08 (s, 3H), 1.42 (br s, 2H), 1.37 - 1.30 (m, 2H). Example 637: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-((2,2 ,2- trifluoroethyl)amino)quinolin-5-yl)cyclopropyl)benzamide (Compound 759)

Compound 759

Compound 759 was synthesized according to an analogous procedure to the one described for compound 743. M + H ⁺ = 499.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 89.05 (s, 1H), 8.85 - 8.73 (m, 1H), 8.66 (d, J = 2.9 Hz, 1H), 7.44 (d, J= 2.1 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.90 - 6.80 (m, 2H), 6.60 (d, J = 2.5 Hz, 1H), 4.14 - 4.00 (m, 2H), 3.86 (d, J= 5.4 Hz, 2H), 3.27 - 3.21 (m, 2H), 2.77 - 2.69 (m, 1H), 2.21 (s, 3H), 1.97 (s, 3H), 1.95 - 1.79 (m, 2H), 1.31 (br s, 2H), 1.16 - 1.10 (m, 2H).

Example 638: ( )-/V-(l-(7-(Benzylamino)quinolin-5-yl)cyclopropyl)-2-methyl- 5-((l- methylazetidin-2-yl)methoxy)benzamide (Compound 747)

Compound 747

Compound 747 was synthesized according to an analogous procedure to the one described for compound 743. M + H ⁺ = 507.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 11.02 - 10.84 (m, 1H), 9.43 - 9.35 (m, 1H), 9.31 - 9.21 (m, 1H), 8.80 - 8.73 (m, 1H), 8.49 - 8.32 (m, 1H), 7.71 (d, J= 2.0 Hz, 1H), 7.56 (dd, J = 5.8, 8.2 Hz, 1H), 7.46 - 7.35 (m, 4H), 7.32 - 7.25 (m, 1H), 7.13 - 7.07 (m, 1H), 6.96 - 6.90 (m, 1H), 6.85 - 6.80 (m, 1H), 6.77 (d, J= 2.8 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.50 - 4.37 (m, 3H), 4.22 (dd, J = 3.1, 11.1 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.93 - 3.77 (m, 1H), 2.81 (d, J = 4.6 Hz, 3H), 2.40 - 2.24 (m, 2H), 1.99 (s, 3H), 1.38 (br s, 2H), 1.21 (br s, 2H). Example 639: (5)-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-4-(methylsul fonamido)-

/V-(l-(7-vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 760)

Compound 760

Compound 760 was synthesized according to an analogous procedure to the one described for compound 746. M + H ⁺ = 521.4 (LCMS); 'H NMR (400 MHz, DMSO- d ₆ ) 5 10.84 (br s, 1H), 9.62 (br d, J= 8.5 Hz, 1H), 9.47 - 9.29 (m, 1H), 9.27 - 9.13 (m, 2H), 8.25 (d, J= 1.3 Hz, 1H), 8.17 (s, 1H), 7.97 (dd, J= 5.0, 8.5 Hz, 1H), 7.16 - 7.00 (m, 2H), 6.97 - 6.83 (m, 1H), 6.22 (d, J= 17.6 Hz, 1H), 5.65 (d, J= 11.0 Hz, 1H), 4.68 (br dd, J= 3.4, 8.7 Hz, 1H), 4.39 (dd, J= 5.8, 11.6 Hz, 1H), 4.24 (br dd, J= 2.6, 11.6 Hz, 1H), 4.06 - 4.01 (m, 1H), 3.85 (br d, J= 3.1 Hz, 1H), 2.99 (s, 3H), 2.83 (d, J= 5.0 Hz, 3H), 2.40 - 2.33 (m, 2H), 1.98 (s, 3H), 1.44 (br s, 2H), 1.35 (br s, 2H).

Example 640: ( )-4-Hydroxy-2-methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-( l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 755)

Compound 755

Compound 755 was synthesized according to an analogous procedure to the one described for compound 750. M + H ⁺ = 444.2 (LCMS); ¹ H NMR (400 MHz, DMSO-tL) 5 9.11 - 9.03 (m, 1H), 8.93 - 8.84 (m, 2H), 8.06 - 8.00 (m, 1H), 7.94 - 7.89 (m, 1H), 7.59 - 7.50 (m, 1H), 7.05 - 6.92 (m, 1H), 6.77 - 6.71 (m, 1H), 6.55 - 6.51 (m, 1H), 6.12 - 6.03 (m, 1H), 5.51 - 5.44 (m, 1H), 3.97 - 3.66 (m, 3H), 2.90 - 2.82 (m, 1H), 2.25 - 2.22 (m, 3H), 2.18 - 1.92 (m, 6H), 1.39 - 1.32 (m, 2H), 1.27 - 1.20 (m, 2H). Example 641: /V-(l-(7-(5-(l-Hydroxyethyl)thiophen-2-yl)quinolin-5-yl)cycl opropyl) -2- methyl-5-(((5)-l-methylazetidin-2-yl)methoxy)benzamide (Compound 762)

Compound 762

Compound 762 was synthesized according to an analogous procedure to the one described for compound 753. M + H ⁺ = 528.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.35 - 10.20 (m, 1H), 9.30 - 9.20 (m, 2H), 9.03 (br d, J= 3.6 Hz, 1H), 8.20 (br d, J= 18.0 Hz, 2H), 7.77- 7.69 (m, 1H), 7.66 (d, J= 3.6 Hz, 1H), 7.12 - 7.08 (m, 1H), 7.05 (d, J= 3.9 Hz, 1H), 6.94 - 6.89 (m, 1H), 6.73 (d, J= 2.6 Hz, 1H), 5.00 (q, J = 6.0 Hz, 1H), 4.65 - 4.57 (m, 1H), 4.35 - 4.26 (m, 1H), 4.25 - 4.18 (m, 1H), 4.03 - 3.95 (m, 1H), 3.87- 3.80 (m, 1H), 2.82 (d, J= 5.0 Hz, 3H), 2.72 - 2.62 (m, 1H), 2.37 - 2.27 (m, 2H), 1.97 (s, 3H), 1.48 (d, J= 6.4 Hz, 3H), 1.41 (br s, 2H), 1.37 - 1.31 (m, 2H).

Example 642: 2-Methyl-5-((l?)-l-((5)-l-methylazetidin-2-yl)ethoxy)-A ^z -(l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 758)

Compound 758

Compound 758 was synthesized according to an analogous procedure to the one described for compound 757 M + H ⁺ =442.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.91 - 10.63 (m, 1H), 9.47 (br s, 1H), 9.27 (s, 1H), 9.12 (br d, J= 2.3 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.94 - 7.83 (m, 1H), 7.11 - 7.01 (m, 2H), 6.96 (dd, J = 2.6, 8.4 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.20 (d, J= 17.6 Hz, 1H), 5.62 (d, J= 10.9 Hz, 1H), 4.95 - 4.81 (m, 1H), 4.44 - 4.31 (m, 1H), 3.98 - 3.92 (m, 1H), 3.82 (br dd, J= 6.8, 9.5 Hz, 1H), 2.78 (d, J= 4.9 Hz, 3H), 2.39 - 2.32 (m, 1H), 2.28 - 2.20 (m, 1H), 1.97 (s, 3H), 1.42 (br s, 2H), 1.33 (br s, 2H), 1.07 (d, J= 6.1 Hz, 3H). Example 643: (l?)-/V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-( (5-methyl-5- azaspiro[2.4]heptan-6-yl)methoxy)benzamide (Compound 774)

Compound 774

Compound 774 was synthesized according to an analogous procedure to the one described for compound 775. M + H+ = 472.3 (LCMS); ^X HNMR (400 MHz, DMSO-t/e) 89.10 (s, 1H), 8.95 (d, J= 8.3 Hz, 1H), 8.81 (dd, J= 1.4, 4.2 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.31 (d, J= 2.5 Hz, 1H), 7.03 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 2.7, 8.3 Hz, 1H), 6.61 (d, J= 2.6 Hz, 1H), 4.02 - 3.85 (m, 4H), 3.78 (dd, J = 6.1, 9.6 Hz, 1H), 2.80 - 2.68 (m, 1H), 2.61 (s, 1H), 2.44 (d, J= 8.8 Hz, 1H), 2.30 (s, 3H), 2.03 - 1.84 (m, 4H), 1.52 (dd, J= 7.6, 12.6 Hz, 1H), 1.33 (br s, 2H), 1.19 (br s, 2H), 0.61 - 0.34 (m, 4H).

Example 644: (3)-2-Methyl-5-((l-(methyl-</3)azetidin-2-yl)methoxy)-/V- (l-(7- vinylquinolin-5-yl)cyclopropyl)benzamide (Compound 788)

Compound 788

Compound 788 was synthesized according to an analogous procedure to the one described for compound 782. M + H ⁺ = 431.3 (LCMS); ¹ HNMR (400 MHz, DMSO-tfj 8 10.45 - 10.30 (m, 1H), 9.34 - 9.27 (m, 1H), 9.22 (s, 1H), 9.05 (br d, J= 3.8 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.77 (br dd, J= 4.8, 8.5 Hz, 1H), 7.13 - 6.99 (m, 2H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.15 (d, J= 17.6 Hz, 1H), 5.57 (d, J= 10.9 Hz, 1H), 4.67 - 4.56 (m, 1H), 4.38 - 4.18 (m, 2H), 4.05 - 3.95 (m, 1H), 3.90 - 3.81 (m, 1H), 2.41 - 2.26 (m, 2H), 1.96 (s, 3H), 1.40 (br s, 2H), 1.31 (br s, 2H). Example 645: ( )-/V-(l-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl)-2-meth yl-5-((l- (methyl-d3)azetidin-2-yl)methoxy)benzamide (Compound 798)

Compound 798

Compound 798 was synthesized according to an analogous procedure to the one described for compound 782. M + H ⁺ = 449.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.24 - 9.96 (m, 1H), 9.36 - 9.12 (m, 2H), 7.68 (br d, J= 8.1 Hz, 1H), 7.58 (d, J= 2.0 Hz, 1H), 7.40 (d, J= 2.0 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.97 - 6.87 (m, 1H), 6.81 - 6.69 (m, 1H), 4.74 - 4.55 (m, 1H), 4.23 (d, J= 5.3 Hz, 2H), 4.10 - 4.01 (m, 1H), 3.97 (s, 3H), 3.87 (br dd, J = 6.1, 9.7 Hz, 1H), 2.81 (s, 3H), 2.44 - 2.27 (m, 2H), 1.96 (s, 3H), 1.36 (br s, 2H), 1.26 (br s, 2H). Example 646: ( )-2-Methyl-5-((l-methylazetidin-2-yl)methoxy)-/V-(l-(7-(N- methylmethylsulfonamido)quinolin-5-yl)cyclopropyl)benzamide (Compound 818)

Compound 818

Compound 818 was synthesized according to an analogous procedure to the one described for compound 786. M + H ⁺ = 509.2 (LCMS); 'H NMR (400 MHz, DMSO ) 6 9.99 - 9.75 (m, 1H), 9.22 - 9.16 (m, 1H), 9.09 (d, J= 8.4 Hz, 1H), 8.97 (dd, J= 1.4, 4.2 Hz, 1H), 8.02 (d, J=

2.3 Hz, 1H), 7.92 (d, = 2.0 Hz, 1H), 7.65 (dd, J= 4.3, 8.5 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.92 (dd, J= 2.8, 8.4 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 4.66 - 4.55 (m, 1H), 4.24 - 4.18 (m, 2H), 4.06 - 4.00 (m, 1H), 3.89 (br s, 1H), 3.41 (s, 3H), 3.06 (s, 3H), 2.84 (d, J = 5.0 Hz, 3H), 2.43 - 2.24 (m, 2H), 1.97 (s, 3H), 1.39 (br s, 2H), 1.30 - 1.15 (m, 2H). Example 647 : ( )-2-Methyl-/V-(l-(2-methyl-7-(methylsulfonamido)quinolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 825)

Compound 825

Compound 825 was synthesized according to an analogous procedure to the one described for compound 786. M + H ⁺ = 509.4 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.83 - 10.49 (m, 1H), 10.06 - 9.74 (m, 1H), 9.18 (s, 2H), 7.84 (s, 1H), 7.74 (br s, 1H), 7.69 - 7.58 (m, 1H), 7.11 (d, J= 8.6 Hz, 1H), 6.93 (dd, J = 2.8, 8.4 Hz, 1H), 6.80 - 6.69 (m, 1H), 4.67 - 4.58 (m, 1H), 4.23 (d, J= 4.9 Hz, 2H), 4.12 - 3.97 (m, 1H), 3.92 - 3.84 (m, 1H), 3.20 (s, 3H), 2.85 (d, J = 4.8 Hz, 3H), 2.78 - 2.70 (m, 3H), 2.42 - 2.29 (m, 2H), 1.96 (s, 3H), 1.39 (br s, 2H), 1.20 (br s, 2H).

Example 648: (3)-2-Methyl-/V-(l-(2-methyl-7-(N-methylmethylsulfonamido)qu inolin-5- yl)cyclopropyl)-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 819)

Compound 819

Compound 819 was synthesized according to an analogous procedure to the one described for compound 786. M + H ⁺ = 523.2 (LCMS); 'H NMR(400 MHz, DMSO-tL) 5 9.21 - 9.15 (m, 2H), 8.02 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.13 - 7.07 (m, 1H), 6.92 (dd, J= 2.6, 8.4 Hz, 1H), 6.71 (d, J= 2.8 Hz, 1H), 4.68 - 4.57 (m, 1H), 4.26 - 4.16 (m, 2H), 4.02 (dt, J= 4.4, 9.7 Hz, 1H), 3.86 (q, J= 9.7 Hz, 1H), 3.40 (s, 3H), 3.08 (s, 3H), 2.83 (s, 3H), 2.76 (s, 3H), 2.41 - 2.29 (m, 2H), 1.94 (s, 3H), 1.39 (br s, 2H), 1.25 (br s, 2H). Example 649: (5)-A ^z -(l-(7-Methoxy-2-methylquinolin-5-yl)cyclopropyl-2,2,3 ,3-^)-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 804)

Compound 804

Compound 804 was synthesized according to an analogous procedure to the one described for compound 794. M + H ⁺ = 450.3 (LCMS); 'H NMR (400 MHz, DMSO-tL) 8 10.20 - 9.95 (m, 1H), 9.35 (br d, J = 8.6 Hz, 1H), 9.18 (s, 1H), 7.75 (br d, J= 8.4 Hz, 1H), 7.62 (br d, J= 1.4 Hz, 1H), 7.42 (s, 1H), 7.11 (br d, J = 8.5 Hz, 1H), 6.93 (dd, J= 2.4, 8.2 Hz, 1H), 6.80 - 6.69 (m, 1H), 4.67 - 4.59 (m, 1H), 4.24 (br d, J= 5.3 Hz, 2H), 4.08 - 3.97 (m, 4H), 3.94 - 3.84 (m, 1H), 2.92 - 2.80 (m, 6H), 2.44 - 2.28 (m, 2H), 1.96 (s, 3H). Example 650: ( )-/V-(l-(7-(Fluoromethoxy)-2-methylquinolin-5-yl)cyclopropyl )-2- methyl-5-((l-methylazetidin-2-yl)methoxy)benzamide (Compound 823)

Compound 823

Compound 823 was synthesized according to an analogous procedure to the one described for compound 795. M + H ⁺ = 464.4 (LCMS); ^X H NMR (400 MHz, D SO-tfj 8 11.13 - 10.71 (m, 1H), 9.52 (br d, J= 8.1 Hz, 1H), 9.35 (s, 1H), 7.96 - 7.83 (m, 2H), 7.78 (d, J = 2.1 Hz, 1H),

7.47 (d, J = 8.0 Hz, 1H), 7.14 - 7.06 (m, 1H), 7.00 - 6.89 (m, 1H), 6.83 - 6.72 (m, 1H), 6.17 (s, 1H), 6.04 (s, 1H), 4.71 - 4.57 (m, 1H), 4.39 (dd, J = 8.1, 11.3 Hz, 1H), 4.22 (dd, J = 3.2, 11.2 Hz, 1H), 4.05 - 3.94 (m, 1H), 3.91 - 3.81 (m, 1H), 2.92 (s, 3H), 2.83 - 2.65 (m, 3H), 2.42 - 2.27 (m, 2H), 1.98 (s, 3H), 1.42 (br s, 2H), 1.31 (br s, 2H). Example 651: /V-(l-(7-Methoxyquinolin-5-yl)cyclopropyl)-2-methyl-5-((2-me thyl-l,2,3,4- tetrahydroisoquinolin-l-yl)methoxy)benzamide (Compound 801)

Compound 801

Compound 801 was synthesized according to an analogous procedure to the one described for compound 799. M + H ⁺ = 508.3 (LCMS); 'H NMR (400 MHz, DMSO-t/e) 89.08 (s, 1H), 8.93 (d, J= 8.3 Hz, 1H), 8.79 (dd, J= 1.6, 4.3 Hz, 1H), 7.45 (d, J= 2.6 Hz, 1H), 7.35 (dd, J= 4.3, 8.5 Hz, 1H), 7.30 (d, J= 2.5 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.18 - 7.10 (m, 3H), 7.02 (d, J = 8.5 Hz, 1H), 6.84 (dd, J= 2.8, 8.4 Hz, 1H), 6.60 (d, = 2.6 Hz, 1H), 4.16 (dd, J= 5.8, 10.1 Hz, 1H), 3.97 (dd, J= 4.6, 10.2 Hz, 1H), 3.92 (s, 3H), 3.80 (t, J= 4.9 Hz, 1H), 3.06 (ddd, J= 4.9, 7.1, 11.9 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.74 - 2.66 (m, 1H), 2.63 - 2.56 (m, 1H), 2.44 (s, 3H), 1.94 (s, 3H), 1.40 - 1.29 (m, 2H), 1.22 - 1.14 (m, 2H).

ADDITIONAL BIOLOGICAL DATA

List of Abbreviations

Example 652: Evaluation of in vitro inhibitory activity of compounds against SARS- CoV-2 Papain-like Protease Test compounds were assayed at 10 concentrations from lOpM, in duplicate for the IC50 determination. The assay buffer contained 50 mM HEPES (pH 7.5), 0.01% Triton-X 100, O.lmg/ml BSA and 5mM DTT. The final concentrations of the PLpro protein and substrate in the assay were 6.25 nM and 25 pM, respectively.

Compounds were 3 folds serially diluted to 10 concentrations and added to an assay plate (384w format) using ECHO, in duplicate wells. The final concentrations are 10 pM, 3.33 pM, 1.11 pM, 0.37 pM, 0.123 pM, 0.041 pM, 0.014 pM, 0.0046 pM, 0.0015 pM and 0.00051 pM.

20 pL of 7.8 nM of PLpro protein were added to an assay plate containing compounds using a Multidrop. The compounds and PLpro protein were pre-incubated at room temperature for 30 min. Then 5 pL of 125 pM of substrate were added to an assay plate using a Multidrop. The final concentrations of PLpro and substrate were 6.25 nM and 25 pM, respectively. For 100% inhibition control (HPE, hundred percent effect), high concentration of positive compound was added. For no inhibition control (ZPE, zero percent effect), no compound was added. The final DMSO concentration is 1%

After 60 min incubation at 25°C, the fluorescence signal (RFU) was detected using a microplate reader SpectraMax M2e (Molecular Devices) at Ex/Em=360nm/460nm.

The inhibitory activity (Inhibition%) was calculated using the formula below, IC50 values were calculated using the Inhibition% data.

Inhibition% =[ (Sample- Average ZPE )/(Average HPE-Average ZPE)] * 100% ^#

^# HEP: Hundred percent effect controls. Containing substrate + assay buffer, no compound. ZPE: Zero percent effective controls. Containing enzyme + substrate, no compound.

Sample: Compound activity testing wells. Containing compound + enzyme + substrate.

For more potent compounds, the following PLpro enzymatic assay was used: PLpro enzyme: 20 pL of 1.25 nM, 1 nM final concentration

Substrate: 5 pL of 125 pM, 25 pM final concentration

Incubation time: 120 min

Certain compounds having a relatively greater potency were not tested at a top concentration of 10 pM. IC50 values of compounds were calculated with the GraphPad Prism software using the nonlinear regression model of log(inhibitor) vs. response — Variable slope (four parameters). IC50 values are provided in the table below, wherein A represents an IC50 value of < 0.1 pM; B represents an IC50 value of 0.1 to <1 pM; C represents an IC50 value of 1 to <5 pM; and D represents an IC50 value of > 5 pM.

¹ US provisional application No. 63/352,580, to which the present application claims priority, contained a typographical error in the corresponding column heading, where the IC50 data were incorrectly presented as millimolar (mM) concentrations instead of micromolar (pM) concentrations. The column heading has been corrected in the current version of the table.

Incorporation by Reference

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

Equivalents

Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.