Small molecule GLP-1 agonists

Abstract

Disclosed are compounds of formulae (I) and (I-a), and pharmaceutically acceptable salts thereof, which are useful as GLP-1R agonists. Also provided are pharmaceutical compositions comprising a compound of formula (I) or (I-a), or a pharmaceutically acceptable salt thereof, and methods involving use of the compounds or pharmaceutically acceptable salts thereof and compositions in the treatment of various GLP-1 -associated diseases, disorders, and conditions such as obesity.

Description

[0001] Attorney Docket No.: ABR-00125

[0002] SMALL MOLECULE GLP-1 AGONISTS

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 858,669, filed August 6, 2025; 63 / 750,578, filed January 28, 2025; and 63 / 750,572, filed January 28, 2025.

[0005] BACKGROUND

[0006] Glucagon-like peptide-1 (GLP-1) is an incretin metabolic hormone which plays a critical role in the regulation of glucose homeostasis. When food passes through the digestive tract, GLP-1 is secreted into the bloodstream by L cells of the small intestine. Binding of GLP-1 to glucagon-like peptide-1 receptors (GLP-1R) in the pancreas causes an increase in insulation secretion and a decrease in glucagon secretion, ultimately resulting in a reduction in blood sugar levels. GLP-1 production causes a variety of other physiological effects, such as decreasing gastric motility and increasing satiety. Synthetic GLP-1R agonists are effective therapeutic agents for the treatment of both diabetes and obesity because of their ability to decrease blood sugar levels and appetite. As GLP-1 has been shown to exert neuroprotective effects, GLP-1R agonists may also be used to treat neurodegenerative conditions such as Huntington’s disease. While GLP-1R agonists have demonstrated therapeutic value, the GLP-1R agonists developed to date have poor oral bioavailability and require invasive subcutaneous administration.

[0007] Thus, there remains a need for additional GLP-1R agonists which can be non-invasively administered and which will be suitable for various important therapeutic applications.

[0008] -1- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0009] SUMMARY

[0010] In certain aspects, provided herein are compounds of formula (I):

[0011]

[0012] or pharmaceutically acceptable salts thereof; wherein,

[0013] A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0014] B is –(alkylene)O(alkylene)–, alkylene, haloalkylene, alkenylene, –O(alkylene)–, –(alkylene)O–, –O(alkylene)O–,–O(alkylene)O(alkylene)–, –(alkylene)O(alkylene)O–,–S(alkylene)–, –(alkylene)S–, –(alkylene)S(alkylene)–, –S(alkylene)S–, –S(alkylene)S(alkylene)–, –(alkylene)S(alkylene)S– –NH(alkylene)–, –(alkylene)NH–, –(alkylene)NH(alkylene)–, –NH(alkylene)NH– –NH(alkylene)NH(alkylene)–, –(alkylene)NH(alkylene)NH–, –N(alkyl)(alkylene)–, –(alkylene)N(alkyl)–, or is a bond;

[0015] C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0016]

[0017] Ring Z is heterocycloalkylene or heteroarylene;

[0018] R1is independently for each occurrence alkyl, alkoxy, or halo; or two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring;

[0019] R2is independently for each occurrence alkyl, alkoxy, or halo;

[0020] R3is haloalkyl, unsubstituted cycloalkyl, cycloalkyl substituted with alkyl, cycloalkyl substituted with haloalkyl, cycloalkyl substituted with halo, unsubstituted heteroaryl, heteroaryl substituted with alkyl, heteroaryl substituted with halo, unsubstituted

[0021] FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0022] heterocycloalkyl, heterocycloalkyl substituted with alkyl, heterocycloalkyl substituted with halo, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0023] R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0024] R4is independently for each occurrence alkyl, alkoxy, or halo;

[0025] k is an integer selected from 0-2;

[0026] m is an integer selected from 0-6;

[0027] n is an integer selected from 0-4;

[0028] p is an integer selected from 0-4; and

[0029] q is an integer selected from 0-2.

[0030] In certain aspects, provided herein are pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0031] In certain aspects, provided herein are methods of inducing GLP-1R activity in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0032] In certain aspects, provided herein are methods of treating GLP-1 -associated diseases, disorders, or conditions in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0033] DETAILED DESCRIPTION

[0034] Provided herein are compounds of formula (I) and pharmaceutically acceptable salts thereof that are useful as GLP-1R agonists. The compounds of formula (I) are useful in the treatment or prevention of a disease or condition that would benefit from activation of GLP- 1R. For example, the disclosed GLP-1R agonists are useful in therapeutic methods and compositions suitable for use in treating obesity and diabetes.

[0035] Definitions

[0036] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0037] -3- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0038] The term “heteroatom” is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

[0039] The term “alkyl” as used herein is a term of art and refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, alkyl substituted cycloalkyl groups, and (cycloalkyl)alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, or 10 or fewer. In certain embodiments, the term “alkyl” refers to a Ci-C10 alkyl group. In certain embodiments, the term “alkyl” refers to a Ci-Ce alkyl group, for example a Ci-Ce straight-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C12 branched-chain alkyl group. In certain embodiments, the term “alkyl” refers to a C3-C8 branched-chain alkyl group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0040] The term “cycloalkyl” means mono- or bicyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Certain cycloalkyls have from 5-12 carbon atoms in their ring structure, and may have 6-10 carbons in the ring structure. Preferably, cycloalkyl is (C3-C7)cycloalkyl, which represents a monocyclic saturated carbocyclic ring, having from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems include bridged bicyclic rings, fused bicyclic rings, and spiro bicyclic rings. Bridged bicyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH₂)w-, where w is 1, 2, or 3). Representative examples of bridged bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycloalkyl, a monocyclic heterocycloalkenyl, or a monocyclic heteroaryl. Spiro bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring that shares only one ring atom in common with a second ring. The second ring may be a monocyclic cycloalkyl or a monocyclic heterocycloalkyl. The bridged, fused, or spiro bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon -4- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0041] atom contained within the monocyclic cycloalkyl ring. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocycloalkyl, a 5 or 6 membered monocyclic heterocycloalkenyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted.

[0042] The term “cycloalkylene” as used herein refers to a divalent cycloalkyl group. In some embodiments, a cycloalkylene may be fused to an arylene or heteroarylene group; i.e., a cycloalkylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the cycloalkylene is saturated at all atoms except the atoms that are fused to the arylene group.

[0043] The term “(cycloalkyl)alkyl” as used herein refers to an alkyl group substituted with one or more cycloalkyl groups. An example of (cycloalkyl)alkyl is cyclohexylmethyl group.

[0044] The term “cycloalkenyl” as used herein refers to a cycloalkyl group as defined above that additionally contains at least one carbon-carbon double bond. In certain embodiments, the cycloalkenyl is a mono- or bicyclic carbocyclic ring having at least one carbon-carbon double bond and containing from 3 to 12 carbon atoms. For avoidance of doubt, a cycloalkenyl group is not aromatic. Representative examples of cycloalkenyl include, but are not limited to, cyclohexenyl and cyclopentenyl.

[0045] The term “cycloalkynyl” as used herein refers to a cycloalkyl group as defined above that additionally contains at least one carbon-carbon triple bond. In certain embodiments, the cycloalkynyl is a mono- or bicyclic carbocyclic ring having at least one carbon-carbon triple bond and containing from 3 to 12 carbon atoms. For avoidance of doubt, a cycloalkynyl group is not aromatic.

[0046] The term “cycloalkenylene” as used herein refers to a divalent cycloalkenyl group. In some embodiments, a cycloalkenylene may be fused to an arylene or heteroarylene group; i.e., a cycloalkenylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the cycloalkenylene contains at least one saturated carbon atom and at least one carbon-carbon double bond in addition to the atoms that are fused to the arylene group.

[0047] The term “heterocycloalkyl” as used herein refers to a radical of a non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, and tricyclic rings, which can be completely saturated or which can contain one or more units of unsaturation, wherein for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system, and -5- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0048] having 3 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur. Bicyclic heterocycloalkyl ring systems include bridged bicyclic rings, fused bicyclic rings, and spiro bicyclic rings. For purposes of exemplification, which should not be construed as limiting the scope of this invention, the following are examples of heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl, diazetidinyl, dioxetanyl, dithietanyl, dioxalanyl, azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, trithianyl, tropanyl, 2-azobicyclo[3.1.0]hexane, and 2-oxa-6-azaspiro[3.3]heptane. A heterocycloalkyl group may be optionally substituted by one or more substituents as described below. In certain embodiments, the heterocycloalkyl is attached to the rest of the molecule through a carbon atom in the heterocycloalkyl group, i.e., not through a heteroatom, such as a nitrogen atom, in the heterocycloalkyl group. In certain embodiments, “heterocycloalkyl” is used interchangeably with “heterocyclyl.”

[0049] The term “heterocycloalkylene” as used herein refers to a divalent heterocycloalkyl group. In some embodiments, a heterocycloalkylene may be fused to an arylene or heteroarylene group; i.e., a heterocycloalkylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the heterocycloalkylene is saturated at all atoms except the atoms that are fused to the arylene group. In certain embodiments, “heterocycloalkylene” is used interchangeably with “heterocyclylene.”

[0050] The term “heterocycloalkenyl” as used herein refers to a heterocycloalkyl group, as defined above, that additionally contains at least one carbon-carbon double bond. For avoidance of doubt, a heterocycloalkenyl group is not aromatic.

[0051] The term “(heterocycloalkyl)alkyl” or (heterocyclyl)alkyl” as used herein refers to an alkyl group substituted with one or more heterocycloalkyl (i.e., heterocyclyl) groups.

[0052] The term “heterocycloalkynyl” as used herein refers to a heterocycloalkyl group, as defined above, that additionally contains at least one carbon-carbon triple bond. For avoidance of doubt, a heterocycloalkynyl group is not aromatic.

[0053] The term “heterocycloalkenylene” as used herein refers to a divalent

[0054] -6- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0055] heterocycloalkenyl group. In some embodiments, a heterocycloalkenylene may be fused to an arylene or heteroarylene group; i.e., a heterocycloalkenylene may be bonded at two adjacent positions to an arylene or heteroarylene group. In such embodiments, the heterocycloalkenylene contains at least one carbon-carbon double bond in addition to the atoms that are fused to the arylene group.

[0056] The term “alkenyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2 -propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l -heptenyl, and 3 -decenyl. The unsaturated bond(s) of the alkenyl group can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0057] The term “alkynyl” as used herein means a straight or branched chain hydrocarbon radical containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0058] The term “alkylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkyl group, as defined above. In certain embodiments an alkylene refers to a disubstituted alkane, i.e., an alkane substituted at two positions with substituents such as those described below. That is, in certain embodiments, a “substituted alkyl” is an “alkylene”.

[0059] The term “alkenylene” is art-recognized, and as used herein pertains to a diradical obtained by removing two hydrogen atoms of an alkenyl group, as defined above.

[0060] The term “amino” is a term of art and as used herein refers to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

[0061] R r\a |

[0062] - hX - N— Rb

[0063]

[0064] wherein Ra, Rb, and Rceach independently represent a hydrogen, -(CH₂)x-Rd, -C(O)-alkyl, -C(O)-alkenyl, where the alkyl or alkenyl may be optionally substituted, or optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, alkoxyalkyl, or haloalkyl; or Raand Rb, taken together with the N atom to -7- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0065] which they are attached form a heterocycle having from 4 to 8 atoms in the ring structure, which may be optionally substituted; Rd represents optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclyl; and x is zero or an integer in the range of 1 to 8. In certain embodiments, only one of Raor Rb contains a carbonyl adjacent to the N atom, e.g., Ra, Rb, and the nitrogen together do not form an imide. In other embodiments, Raand Rb (and optionally Rc) each independently represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or -(CH2)x-Rd. In certain embodiments, the term “amino” refers to -NH2.

[0066] In certain embodiments, the term “alkylamino” refers to -NH(alkyl).

[0067] In certain embodiments, the term “dialkylamino” refers to -N(alkyl)2.

[0068] The term “amido”, as used herein, means -NHC(=O)-, wherein the amido group is bound to the parent molecular moiety through the nitrogen or through the carbonyl carbon. Examples of amido include -C(O)NH2, -C(O)NH(methyl), and alkylamido such as CH3C(=O)N(H)- and CH3CH2C(=O)N(H)-.

[0069] The term “acyl” is a term of art and as used herein refers to any group or radical of the form RC(O)- where R is any organic group, e.g., alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl. Representative acyl groups include acetyl, benzoyl, and malonyl.

[0070] The term “aminoalkyl” as used herein refers to an alkyl group substituted with one or more one amino groups. In certain embodiments, the term “aminoalkyl” refers to an aminomethyl group, i.e., -CH2NH2.

[0071] The term “aminoacyl” is a term of art and as used herein refers to an acyl group substituted with one or more amino groups.

[0072] The term “aminothionyl” is a term of art and as used herein refers to any group or radical of the form RC(S)-, wherein R is any organic group, e.g., alkyl, aryl, heteroaryl, arylalkyl, and heteroaryl alkyl.

[0073] The term “phosphoryl” is a term of art and as used herein may in general be represented by the formula:

[0074] Q50

[0075] - p II> - O IR59

[0076] wherein Q50 represents S or O, and R59 represents hydrogen, optionally substituted (Ci-Ce) alkyl or optionally substituted aryl; for example, -P(O)(OMe)- or -P(O)(OH)2. When used to

[0077] -8- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0078] substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:

[0079] Q50 Q50

[0080] - Q51 - j! - o - - Q51— P-OR59

[0081] OR I59 OR I59

[0082] wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N; for example, -O-P(O)(OH)OMe or -NH-P(0)(0H)2. When Q50 is S, the phosphoryl moiety is a “phosphorothioate.”

[0083] The term “aminophosphoryl” as used herein refers to a phosphoryl group substituted with at least one amino group, as defined herein; for example, -P(0)(0H)NMe2.

[0084] The term “azide” or “azido”, as used herein, means an -N3 group.

[0085] The term “carbonyl” as used herein refers to -C(=O)-.

[0086] The term “thiocarbonyl” as used herein refers to -C(=S)-.

[0087] The term “alkylphosphoryl” as used herein refers to a phosphoryl group substituted with at least one alkyl group, as defined herein; for example, -P(O)(OH)Me.

[0088] The term “alkylthio” as used herein refers to alkyl-S-. The term “(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthio group.

[0089] The term “carboxyl”, as used herein, means a -CO2H group.

[0090] The term “aryl” is a term of art and as used herein refers to includes monocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, for example, benzene, naphthalene, anthracene, and pyrene. Typically, an aryl group contains from 6-10 carbon ring atoms (i.e., (C6-Cio)aryl). The aromatic ring may be optionally substituted at one or more ring positions with one or more substituents as described below. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic hydrocarbon, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, heterocyclyls, heterocycloalkenyls, and / or heterocycloalkynyls. In certain embodiments, the term “aryl” refers to a phenyl group. The term “arylene” means a diradical obtained by removing two hydrogen atoms of an aryl group, as defined above. Arylene includes, without limitation, 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene, as depicted below:

[0091] -9- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0092]

[0093] Arylene groups may be optionally substituted at one or more ring positions with one or more substituents, valency permitting, such as the exemplary substituents described below.

[0094] The term “heteroaryl” is a term of art and as used herein refers to a monocyclic, bicyclic, or polycyclic aromatic group having 3 to 12 total atoms including one or more heteroatoms such as nitrogen, oxygen, or sulfur in the ring structure. Exemplary heteroaryl groups include azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotri azolyl, benzoxadiazolyl, furanyl, l,3-dihydro-2H-imidazol-2-one, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, or triazine, and the like. The “heteroaryl” may be optionally substituted at one or more ring positions with one or more substituents as described below. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is an aromatic group having one or more heteroatoms in the ring structure, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, heterocyclyls, heterocycloalkenyls, and / or

[0095] heterocy cl oalky ny 1 s.

[0096] The term “heteroarylene” as used herein pertains to a diradical obtained by removing two hydrogen atoms of a heteroaryl group, as defined above. Heteroarylene includes, without limitation, the divalent heteroarylene groups depicted below:

[0097]

[0098] Heteroarylene groups may be optionally substituted at one or more ring positions with one or more substituents, valency permitting, such as the exemplary substituents described below.

[0099] The term “aralkyl” or “arylalkyl” is a term of art and as used herein refers to an alkyl group substituted with an aryl group, wherein the moiety is appended to the parent molecule through the alkyl group.

[0100] -10- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0101] The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and as used herein refers to an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein, appended to the parent molecular moiety through the alkyl group.

[0102] The term “alkoxy” as used herein refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tertbutoxy, pentyloxy, and hexyloxy.

[0103] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, wherein some or all of the hydrogens of the alkyl group are replaced with halogen atoms, as defined herein. Representative examples of haloalkoxy include, but are not limited to, -OCF3.

[0104] The term “alkoxyalkyl” as used herein refers to an alkyl group, as defined herein, substituted by an alkoxy group as defined herein.

[0105] The term “alkoxycarbonyl” as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of alkoxy carbonyl include, but are not limited to, methoxy carbonyl, ethoxy carbonyl, and / c / V-butoxy carbonyl.

[0106] The term “alkylcarbonyl”, as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1 -oxopropyl, 2,2-dimethyl-l -oxopropyl, 1 -oxobutyl, and 1 -oxopentyl.

[0107] The term “arylcarbonyl”, as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, represented by -C(=O)-, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

[0108] The term “alkylcarbonyloxy” and “aryl carbonyl oxy”, as used herein, means an alkylcarbonyl or arylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butyl carbonyl oxy. Representative examples of aryl carbonyl oxy include, but are not limited to phenyl carbonyl oxy.

[0109] The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenoxyl include, but are not limited to, 2-propen-l-oxyl (i.e., CH2=CH-CH2-O-) and vinyloxy (i.e., CH2=CH-O-).

[0110] -11- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0111] The term “aryloxy” as used herein means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0112] The term “heteroaryloxy” as used herein means a heteroaryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0113] The term “carbocyclyl” as used herein means a monocyclic or multi cyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3 to 12 carbon atoms that is completely saturated or has one or more unsaturated bonds, and for the avoidance of doubt, the degree of unsaturation does not result in an aromatic ring system (e.g., phenyl).

[0114] Examples of carbocyclyl groups include 1 -cyclopropyl, 1 -cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1 -cyclohexenyl and 2-cyclopentenylmethyl.

[0115] The term “cyano” is a term of art and as used herein refers to -CN.

[0116] The term “halo” is a term of art and as used herein refers to -F, -Cl, -Br, or -I.

[0117] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, wherein some or all of the hydrogens are replaced with halogen atoms, as defined herein. Representative examples of haloalkyl include, but are not limited to, trifluoromethyl and fluoroethyl.

[0118] The term “hydroxy” is a term of art and as used herein refers to -OH.

[0119] The term “hydroxyalkyl”, as used herein, means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxy ethyl, 3 -hydroxypropyl, 2,3 -dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

[0120] The term “silyl”, as used herein, includes hydrocarbyl derivatives of the silyl (H3Si–) group (i.e., (hydrocarbyl)3Si–), wherein hydrocarbyl groups are univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can be combinations of differing groups which can be varied in order to provide a number of silyl groups, such as trimethyl silyl (TMS), tert-butyldiphenylsilyl (TBDPS), tertbutyldimethylsilyl (TBS / TBDMS), triisopropyl silyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

[0121] The term “silyloxy”, as used herein, means a silyl group, as defined herein, is appended to the parent molecule through an oxygen atom.

[0122] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such

[0123] -12- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0124] compounds, including cis- and trans-i somers, ( / ?)- and (5)-enantiomers, diastereoisomers, atropisomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0125] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention.

[0126] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0127] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, fragmentation, decomposition, cyclization, elimination, or other reaction.

[0128] The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0129] In certain embodiments, the optional substituents contemplated in this invention include, for example, halogen, oxo (=0), azide, alkyl, alkenyl, alkynyl, aryl, arylalkyl,

[0130] -13- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0131] heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, (cycloalkyl)alkyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, (heterocycloalkyl)alkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, amino (e.g., -NH2, -NH(alkyl), or -N(alkyl)2), aminoalkyl, nitro, sulfhydryl (-SH), imino, amido (e.g., -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -NHC(O)( alkyl), or -N(alkyl)C(O)(alkyl)), phosphoryl, phosphate (e.g., -OP(O)(O-alkyl)2), phosphonate (e.g., -P(O)(O-alkyl)2), phosphinate (e.g. -P(O)(alkyl)(O-alkyl)), phosphine (e.g., -P(aryl)2), carbonyl, carboxyl (-C(O)OH), carboxylalkyl (e.g., -alkylene-(COOH)), silyl, silyloxy, ether (e.g., -alkylene-O(alkyl)), thioether (e.g., -alkylene-S(alkyl)), alkylthio (-S-alkyl), sulfonyl (e.g., -S (0)2 (alkyl)), sulfoxide (e.g., -S(O)(alkyl)), sulfonamido (e.g., -S(O)2NH2, -S(O)2NH(alkyl), or -S(O)2N(alkyl)2), sulfmamido (e.g., S(O)NH2, -S(O)NH(alkyl), or -S(O)N(alkyl)2), Boc (-C(O)-O-C(CH3)3), ketone (e.g., -C(O)(alkyl)), aldehyde (-C(O)H), ester (e.g., -alkylene-C(O)O(alkyl) or -C(O)O(alkyl)), acyloxy (e.g., -OC(O)(alkyl)), haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, and cyano (-CN).

[0132] As used herein, the term “optionally substituted” or “substituted or unsubstituted” when it precedes a list of chemical moieties means that the list of chemical moieties that follow are each substituted or unsubstituted. For example, “substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” or “optionally substituted aryl, heteroaryl, and cycloalkyl” means substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted cycloalkyl.

[0133] The term “vicinal” describes the positional relationship between two substituents, moieties, or functional groups each of which is bonded to one of two adjacent carbon atoms that are bonded to each other (i.e., the two substituents, moieties, or functional groups are in a 1,2-relationship). The methyl groups in 3,4-dimethylheptane are vicinal.

[0134] The term “geminal” describes the positional relationship between two substituents, moieties, or functional groups bonded to the same carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,1 -relationship). The methyl groups in 3,3-dimethylheptane are geminal.

[0135] The term “hominal” describes the positional relationship between two substituents, moieties, or functional groups each of which is bonded to one of two carbon atoms that themselves are each bonded to a single carbon atom (i.e., the two substituents, moieties, or functional groups are in a 1,3-relationship). The methyl groups in 3, 5 -dimethylheptane are hominal.

[0136] -14- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0137] The phrase “protecting group”, as used herein, means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nded.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this invention.

[0138] For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0139] Other chemistry terms herein are used according to conventional usage in the art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated herein by reference). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0140] The term " GLP-1R" or " GLP-1 receptor" as used herein is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous, and / or orthologous GLP-IR molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0141] The term " GLP-1 -associated disease" as used herein is meant to include, without limitation, all those diseases, disorders, or conditions in which modulating glucagon-like peptide-1 (GLP-1) receptor signaling can alter the pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0142] The term " GLP-1 agonist" or " GLP-IR agonist" or “GLP-1RA” as used herein refers to an agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-IR agonists enhance glucose-dependent insulin secretion; suppress inappropriately elevated glucagon levels, both in fasting and postprandial states; and slow gastric emptying (Karla et al., Glucagon-like peptide-I receptor agonists in the treatment of type 2 diabetes: Past, present, and future, Indian J. Endocrinol. Metab. 2016 Mar- Apr; 20(2): 254-267). GLP-IR agonists have been shown to treat type 2 diabetes. Examples of GLP-IR agonists include, but are not limited to, albiglutiden (TANZEUM®), dulaglutide (LY2189265, TRULICITY®), efpeglenatide, exenatide (BYETTA®, BYDUREON®, Exendin-4), liraglutide (VICTOZA®, NN2211), lixisenatide (LYXUMIA®), semaglutide (OZEMPIC®), tirzepatide, Orforglipron,

[0143] -15- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0144] Danuglipron, Lotiglipron, Aleniglipron (GSBR-1290), ECC-5004, ZP2929, NNCOI 13-0987, BPI-3016, and TT401. See, also, for example, additional GLP-1 receptor agonists described in U. S. patent numbers 12,187,724; 11,814,381; 10,858,356; 10,370,426; 10,308,700;

[0145] 10,259,823; 10,208,019; 9,920,106; 9,839,664; 8,129,343; 8,536,122; 7,919,598; 6,414,126; 6,628,343; and RE45313; and international publication numbers WO 2025 / 006921; WO 2024 / 169952; WO 2024 / 125602; WO 2023 / 169456; WO 2023 / 016546; WO 2022 / 052958; WO 2022 / 048665; WO 2021 / 155841; WO 2022 / 017338; WO 2024 / 153070; WO 2025 / 002250; WO 2023 / 220109; WO 2023 / 220112; WO 2019 / 239319; WO 2019 / 239371; WO 2020 / 103815; WO 2020 / 207474; WO 2020 / 234726; WO 2020 / 044266; WO 2020 / 117987; WO 2020 / 263695; WO 2018 / 056453; and foreign publication numbers CN 116003403; CN 117069743; and CN 117447493.

[0146] The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula I. As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula I per molecule of tartaric acid.

[0147] The terms “carrier” and “pharmaceutically acceptable carrier” as used herein refer to a diluent, adjuvant, excipient, or vehicle with which a compound is administered or formulated for administration. Non-limiting examples of such pharmaceutically acceptable carriers include liquids, such as water, saline, and oils; and solids, such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, flavoring, and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in Remington ’s Pharmaceutical Sciences by E. W. Martin, herein incorporated by reference in its entirety.

[0148] The term “treat” as used herein means prevent, halt or slow the progression of, or eliminate a disease or condition in a subject. In certain embodiments “treat” means halt or slow the progression of, or eliminate a disease or condition in a subject. In certain

[0149] -16- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0150] embodiments, “treat” means reduce at least one objective manifestation of a disease or condition in a subject.

[0151] The term “effective amount” as used herein refers to an amount that is sufficient to bring about a desired biological effect.

[0152] The term “therapeutically effective amount” as used herein refers to an amount that is sufficient to bring about a desired therapeutic effect.

[0153] The term “inhibit” as used herein means decrease by an objectively measurable amount or extent. In various embodiments “inhibit” means decrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95 percent compared to relevant control. In certain embodiments “inhibit” means decrease 100 percent, i.e., halt or eliminate.

[0154] The term “activate” as used herein means increase by an objectively measurable amount or extent. In various embodiments “activate” means increase by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 percent compared to relevant control.

[0155] The term “induce” as used herein includes the promotion of a function, activity, or expression of a particular protein or enzyme. In certain embodiments, a compound of the disclosure induces GLP-1R activity, e.g., increases the activity of GLP-1R. Induction of GLP-1R activity may be measured according to techniques known to those skilled in the art. For example, induction of GLP-1R activity can be measured using a cellular GLP-1R agonist cAMP assay as described below in the Examples.

[0156] The term “modulate” or “modulation”, as used herein, refers to a regulation or an adjustment (e.g., increase or decrease) and can include, for example agonism, partial agonism, or antagonism.

[0157] The term “subject” as used herein refers to a mammal. In various embodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep, horse, cow, or non-human primate. In certain embodiments, a subject is a human.

[0158] As used herein, the symbol •nnn', when used in connection with a carbon-carbon double bond, indicates that the stereoisomeric configuration of the substituents with respect to the double bond is unknown, or is a mixture of the cis and trans isomers.

[0159] Compounds

[0160] In certain aspects, provided herein are compounds of formula (I):

[0161] -17- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0162]

[0163] or a pharmaceutically acceptable salts thereof; wherein,

[0164] A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0165] B is –(alkylene)O(alkylene)–, alkylene, haloalkylene, alkenylene, –O(alkylene)–, –(alkylene)O–, –O(alkylene)O–,–O(alkylene)O(alkylene)–, –(alkylene)O(alkylene)O–,–S(alkylene)–, –(alkylene)S–, –(alkylene)S(alkylene)–, –S(alkylene)S–, –S(alkylene)S(alkylene)–, –(alkylene)S(alkylene)S– –NH(alkylene)–, –(alkylene)NH–, –(alkylene)NH(alkylene)–, –NH(alkylene)NH– –NH(alkylene)NH(alkylene)–, –(alkylene)NH(alkylene)NH–, –N(alkyl)(alkylene)–, –(alkylene)N(alkyl)–, or is a bond;

[0166] C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0167] H H

[0168] \\ J \\ / /

[0169] Ring D

[0170]

[0171] is or;

[0172] Ring Z is heterocycloalkylene or heteroarylene;

[0173] R1is independently for each occurrence alkyl, alkoxy, or halo; or two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring;

[0174] R2is independently for each occurrence alkyl, alkoxy, or halo;

[0175] R3is haloalkyl, unsubstituted cycloalkyl, cycloalkyl substituted with alkyl, cycloalkyl substituted with haloalkyl, cycloalkyl substituted with halo, unsubstituted heteroaryl, heteroaryl substituted with alkyl, heteroaryl substituted with halo, unsubstituted heterocycloalkyl, heterocycloalkyl substituted with alkyl, heterocycloalkyl substituted with halo, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0176] -18- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0177] R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0178] R4is independently for each occurrence alkyl, alkoxy, or halo;

[0179] k is an integer selected from 0-2;

[0180] m is an integer selected from 0-6;

[0181] n is an integer selected from 0-4;

[0182] p is an integer selected from 0-4; and

[0183] q is an integer selected from 0-2.

[0184] In certain embodiments, the compound is represented by formula (I-a):

[0185]

[0186] or a pharmaceutically acceptable salt thereof; wherein,

[0187] A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0188] B is alkylene, haloalkylene, alkenylene, -O(alkylene)-, -(alkylene)O-, -(alkylene)O(alkylene)-,-O(alkylene)O-, -O(alkylene)O(alkylene)-, -(alkylene)O(alkylene)O-,-S(alkylene)-, -(alkylene)S-, -(alkylene)S(alkylene)-, -S(alkylene)S-,-S(alkylene)S(alkylene)-, -(alkylene)S(alkylene)S-, -NH(alkylene)-, -(alkylene)NH-, -(alkylene)NH(alkylene)-, -NH(alkylene)NH- -NH(alkylene)NH(alkylene)-, -(alkylene)NH(alkylene)NH-,-N(alkyl)(alkylene)-, -(alkylene)N(alkyl)-, or is a bond;

[0189] C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0190] Ring Z is heteroarylene or heterocycloalkylene;

[0191] R1is independently for each occurrence alkyl, alkoxy, or halo; or

[0192] -19- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0193] two occurrences of R1taken together with the atom(s) to which they are attached form an optionally substituted cycloalkyl ring;

[0194] R2is independently for each occurrence alkyl, alkoxy, or halo;

[0195] R3is haloalkyl, unsubstituted cycloalkyl, cycloalkyl substituted with alkyl, cycloalkyl substituted with haloalkyl cycloalkyl substituted with halo, unsubstituted heteroaryl, heteroaryl substituted with alkyl, heteroaryl substituted with halo, unsubstituted heterocycloalkyl, heterocycloalkyl substituted with alkyl, heterocycloalkyl substituted with halo, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0196] R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0197] R4is independently for each occurrence alkyl, alkoxy, or halo;

[0198] k is an integer selected from 0-2;

[0199] m is an integer selected from 0-6;

[0200] n is an integer selected from 0-4;

[0201] p is an integer selected from 0-4; and

[0202] q is an integer selected from 0-2.

[0203] In certain embodiments, wherein k is 1.

[0204] In certain embodiments, the compound is represented by formula (I-b):

[0205]

[0206] or a pharmaceutically acceptable salt thereof; wherein,

[0207] -20- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0208] RAis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl; andr is an integer selected from 0-4.

[0209] In certain embodiments, the compound is represented by formula (I-c):

[0210]

[0211] or a pharmaceutically acceptable salt thereof; wherein,

[0212] Rcis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl; ands is an integer selected from 0-4.

[0213] -21- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0214] In certain embodiments, the compound is represented by formula (I-d):

[0215]

[0216] or a pharmaceutically acceptable salt thereof.

[0217] In certain embodiments, the compound is represented by formula (I-e):

[0218]

[0219] or a pharmaceutically acceptable salt thereof.

[0220] -22- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0221] In certain embodiments, the compound is represented by formula (I-f):

[0222] (RA)r

[0223]

[0224] or a pharmaceutically acceptable salt thereof.

[0225] In certain embodiments, the compound is represented by formula (I-g):

[0226]

[0227] or a pharmaceutically acceptable salt thereof.

[0228] -23- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0229] In certain embodiments, the compound is represented by formula (I-h):

[0230]

[0231] (i-h);

[0232] or a pharmaceutically acceptable salt thereof; wherein,

[0233] RAis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl;R^C is independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl;r is an integer selected from 0-4; and

[0234] s is an integer selected from 0-4.

[0235] -24- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0236] In certain embodiments, A is optionally substituted phenylene, pyridinylene, pyridazinylene, pyrimidinylene, or pyrazinylene. In more particular embodiments, A is optionally substituted phenylene.

[0237] In certain embodiments, A is optionally substituted by one or more RA, wherein RAis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO2, -N3, aryl, or heteroaryl.

[0238] In certain embodiments, each RAis independently alkyl, haloalkyl, cycloalkyl, alkoxy, or halo.

[0239] In certain embodiments, RAis independently methyl, trifluoromethyl, cyclopropyl, methoxy, fluoro, or chloro. In more particular embodiments, each RAis independently methyl, fluoro, or chloro.

[0240] In certain embodiments, r is an integer selected from 1 or 2. In alternative embodiments, r is 0.

[0241]

[0242] wherein the asterisk (*) indicates the point of attachment to B.

[0243] -25- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0244] In more particular embodiments, -

[0245]

[0246] A-* is wherein the asterisk (*) indicates the point of attachment to B.

[0247] In certain embodiments, B is *-CH2CH2-, *-CH2CH2CH2-,*-CH2CH2CH2CH2-*-CH2CH2CH2CH2CH2- *-CF2CH2CH2CH2- *-CH(CH3)OCH2- *-OCH2-,*-CH2O-*-OCH2CH2- *-CH2OCH2- *-CH2CH2O- *-OCH2CH2CH2- *-CH2OCH2CH2-*-CH2CH2OCH2- *-CH2CH2CH2O- *-OCH2CH2O- *-OCH2CH2CH2CH2-*-CH2OCH2CH2CH2- *-CH2CH2OCH2CH2-,*-CH2CH2CH2OCH2-*-CH2CH2CH2CH2O- *-SCH2- *-CH2S- *-SCH2CH2- *-CH2SCH2- *-CH2CH2S-*-SCH2CH2CH2- *-CH2SCH2CH2- *-CH2CH2SCH2- *-CH2CH2CH2S- *-SCH2CH2S- *-SCH2CH2CH2CH2- *-CH2SCH2CH2CH2- *-CH2CH2SCH2CH2- *-CH2CH2CH2SCH2-*-CH2CH2CH2CH2S- *-CH=CH- *-CH=CHCH2- *-CH2CH=CH- *-CH=CHCH2CH2- *-CH2CH=CHCH2- *-CH2CH2CH=CH- *-CH=CHCH2CH2CH2-*-CH2CH=CHCH2CH2- *-CH2CH2CH=CHCH2- *-CH2CH2CH2CH=CH-*-N(CH3)CH2CH2- or *-CH2CH2N(CH3)-;

[0248] wherein the asterisk (*) indicates the point of attachment to A.

[0249] In more particular embodiments, B is *-CH2CH2-, *-CH2CH2CH2-*-CH2CH2CH2CH2-, *-CF2CH2CH2CH2-, *-CH=CHCH2-, *-CH2CH=CHCH2-*-CH2O-, *-OCH2-, *-CH2OCH2-,*-OCH2CH2-, *-OCH2CH2CH2-, *-CH2OCH2CH2-, *-CH2CH2OCH2-, *-CH2CH2CH2O-, *-OCH2CH2O-, *-CH(CH3)OCH2-*-N(CH3)CH2CH2-, *-SCH2CH2-, *-SCH2CH2CH2-;

[0250] wherein the asterisk (*) indicates the point of attachment to A.

[0251] In further embodiments, B is

[0252]

[0253] wherein the asterisk (*) indicates the point of attachment to A.

[0254] In some embodiments, B is *-CH2OCH2-;

[0255] wherein the asterisk (*) indicates the point of attachment to A.

[0256] -26- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0257] In certain embodiments, C is optionally substituted phenylene, pyridinylene, pyridazinylene, pyrimidinylene, pyrazinylene, indolylene, indazolylene, benzimidazolylene, or 2-hydroxybenzimidazolylene. In more particular embodiments, C is optionally substituted phenylene.

[0258] In certain embodiments, C is optionally substituted by one or more Rc, wherein Rcis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO2, -N3, aryl, or heteroaryl.

[0259] In more particular embodiments, each Rcis independently alkyl, alkoxy, halo, -C(O)NH(alkyl), -C(O)N(alkyl)(cycloalkyl), -S(O)2-alkyl, -S(O)2-cycloalkyl, -CN, or heterocycloalkyl.

[0260] In further embodiments, each Rcis independently methyl, methoxy, chloro, fluoro, - O

[0261] C

[0262]

[0263] (O)NHMe, -S(O)2Me, -S(O)2Et, -CN,. In some embodiments, Rcis fluoro.

[0264] In certain embodiments, s is an integer selected from 1 or 2.

[0265] In alternative embodiments, s is 0.

[0266] In certain embodiments, *-C- is

[0267]

[0268] -27- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0269]

[0270] wherein the asterisk (*) indicates the point of attachment to B.

[0271] In more particular embodiments, *

[0272]

[0273] -C- is

[0274] wherein the asterisk (*) indicates the point of attachment to B.

[0275] In certain embodiments, ring Z is heterocycloalkylene.

[0276] In more particular embodiments, ring Z is tetrahydropyranylene, morpholinylene, 8-oxa-3-azabicyclo[3.2.1]octanylene, 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinylene, 6,7-dihydro-5H-cyclopenta[b]pyridinylene, 2-oxa-6-azaspiro[3.3]heptanylene, or 1,4-oxazepanylene. In some embodiments, ring Z is morpholinylene.

[0277] In certain embodiments, ring Z is heteroarylene.

[0278] In more particular embodiments, ring Z is pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, imidazolylene, 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinylene, 6,7-dihydro-5H-cyclopenta[b]pyridinylene, lH-pyrrolo[2,3-b]pyridinylene, 1,2,3-triazolylene, or pyrazolylene. In some embodiments, ring Z is pyridinylene.

[0279] In certain embodiments, R3is -NH2, -N(Me)(Et), NMe2, -CHF2, -CF3, -CH2CF3, -

[0280] CF2CH3, -CF2CF3, -OCHF2, -OCF3, 1^1,

[0281]

[0282] In more particular embodiments, R

[0283]

[0284] 3is CF3, -CF2CH3, or

[0285] -28- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0286] In certain embodiments, R3ais alkyl or halo. In more particular embodiments, R3ais methyl or fluoro.

[0287] In certain embodiments, p is 1. In alternative embodiments, p is 0.

[0288]

[0289] -29- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0290] In further embodiments, Hz><R3‘)P. (R)p. In some embodiments,

[0291] R3

[0292]

[0293] In certain embodiments, R1is alkyl. In more particular embodiments, R1is methyl. In certain embodiments, two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring. In more particular embodiments, two geminal occurrences of R1taken together with the carbon atom to which they are attached form a spirocyclic cyclopropyl ring.

[0294] In certain embodiments, m is an integer selected from 1-3. In more particular embodiments, m is 1.

[0295] In certain embodiments, m is an integer selected from 3 and 4, wherein two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring, and the remaining occurrences of R1are each independently alkyl, alkoxy, or halo. In more particular embodiments, m is 3, two geminal occurrences of R1taken together with the carbon atom to which they are attached form a spirocyclic cyclopropyl ring, and the remaining occurrence of R1is methyl.

[0296] In certain embodiments, R2is alkyl. In more particular embodiments, R2is methyl. In certain embodiments, n is 1.

[0297] In certain embodiments, q is 0.

[0298] In certain embodiments, ring D is

[0299]

[0300] -30- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0301] In certain embodiments, the compound is selected from:

[0302]

[0303] -31- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0304]

[0305] -32- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0306]

[0307] -33- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0308]

[0309] or a pharmaceutically acceptable salt thereof.

[0310] -34- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0311] In certain embodiments, the compound is selected from:

[0312]

[0313] -35- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0314]

[0315] -36- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0316]

[0317] -37- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0318]

[0319] -38- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0320]

[0321] -39- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0322]

[0323] -40- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0324]

[0325] -41- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0326]

[0327] -42- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0328]

[0329] -43- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0330]

[0331] -44- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0332]

[0333] -45- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0334]

[0335] -46- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0336]

[0337] -47- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0338]

[0339] -48- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0340]

[0341] -49- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0342]

[0343] -50- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0344]

[0345] -51- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0346]

[0347] -52- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0348]

[0349] or a pharmaceutically acceptable salt thereof.

[0350] In certain aspects, provided herein is a compound selected from:

[0351]

[0352] -53- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0353]

[0354] -54- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0355]

[0356] -55- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0357]

[0358] -56- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0359]

[0360] or a pharmaceutically acceptable salt thereof.

[0361] In certain aspects, provided herein is a compound selected from:

[0362] -57- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0363]

[0364] -58- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0365]

[0366] -59- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0367]

[0368] -60- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0369]

[0370] -61- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0371]

[0372] -62- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0373]

[0374] -63- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0375]

[0376] -64- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0377]

[0378] -65- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0379]

[0380] -66- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0381]

[0382] -67- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0383]

[0384] -68- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0385]

[0386] -69- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0387]

[0388] -70- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0389]

[0390] -71- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0391]

[0392] -72- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0393]

[0394] -73- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0395]

[0396] or a pharmaceutically acceptable salt thereof.

[0397] In certain aspects, provided herein is a compound selected from:

[0398]

[0399] -74- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0400]

[0401] -75- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0402]

[0403] -76- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0404] F F

[0405] X:-°X) A xr X \\ / / x

[0406] O^JQT feoc

[0407] / X

[0408] xF F

[0409] ■x?p N- N II r D

[0410] NA \ N' V'NA

[0411] \\ / / Af[H

[0412] ' VNH

[0413] '0^>0

[0414] Nx 1 1 }

[0415] N NAA_Br

[0416] A™

[0417] bAo

[0418]

[0419] or a salt thereof.

[0420] -77- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0421] In certain aspects, the present invention provides a compound of formula (I-p):

[0422]

[0423] or a pharmaceutically acceptable salt thereof; wherein,

[0424] A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0425] B is alkylene, alkenylene, –O(alkylene)–, –(alkylene)O–, –(alkylene)O(alkylene)–, –O(alkylene)O–, –O(alkylene)O(alkylene)–, –(alkylene)O(alkylene)O– –S(alkylene)–, –(alkylene)S–, –(alkylene)S(alkylene)–, –S(alkylene)S– –S(alkylene)S(alkylene)–, –(alkylene)S(alkylene)S–, –NH(alkylene)–, –(alkylene)NH–, –(alkylene)NH(alkylene)–, –NH(alkylene)NH– –NH(alkylene)NH(alkylene)–, –(alkylene)NH(alkylene)NH–, or is a bond;

[0426] C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0427] Ring Z is heteroarylene or heterocycloalkylene;

[0428] R1is independently for each occurrence alkyl, alkoxy, or halo;

[0429] R2is independently for each occurrence alkyl, alkoxy, or halo;

[0430] R3is haloalkyl, unsubstituted cycloalkyl, cycloalkyl substituted with alkyl, cycloalkyl substituted with halo, unsubstituted heteroaryl, heteroaryl substituted with alkyl, heteroaryl substituted with halo, unsubstituted heterocycloalkyl, heterocycloalkyl substituted with alkyl, heterocycloalkyl substituted with halo, haloalkoxy, -NH2, - NH(alkyl), or -N(alkyl)2;

[0431] R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0432] R4is independently for each occurrence alkyl, alkoxy, or halo;

[0433] k is an integer selected from 0-2;

[0434] m is an integer selected from 0-6;

[0435] -78- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0436] n is an integer selected from 0-4;

[0437] p is an integer selected from 0-4; and

[0438] q is an integer selected from 0-2.

[0439] In certain aspects, the present invention provides a compound of Formula (I-o):

[0440]

[0441] or a pharmaceutically acceptable salt thereof; wherein,

[0442] A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0443] B is alkylene, alkenylene, –O(alkylene)–, –(alkylene)O–, –(alkylene)O(alkylene)–, –O(alkylene)O–, –O(alkylene)O(alkylene)–, –(alkylene)O(alkylene)O– –S(alkylene)–, –(alkylene)S–, –(alkylene)S(alkylene)–, –S(alkylene)S– –S(alkylene)S(alkylene)–, –(alkylene)S(alkylene)S–, –NH(alkylene)–, –(alkylene)NH–, –(alkylene)NH(alkylene)–, –NH(alkylene)NH– –NH(alkylene)NH(alkylene)–, –(alkylene)NH(alkylene)NH–, or is a bond;

[0444] C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0445] R1is independently for each occurrence alkyl, alkoxy, or halo;

[0446] R2is independently for each occurrence alkyl, alkoxy, or halo;

[0447] R3is independently for each occurrence alkyl, alkoxy, or halo;

[0448] or two geminal or vicinal occurrences of R3, taken together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring;

[0449] R4is independently for each occurrence alkyl, alkoxy, or halo;

[0450] k is an integer selected from 0-2;

[0451] m is an integer selected from 0-6;

[0452] n is an integer selected from 0-4;

[0453] p is an integer selected from 0-9; and

[0454] -79- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0455] q is an integer selected from 0-2.

[0456] In certain aspects, the present invention provides a compound of Formula (I-z):

[0457]

[0458] or pharmaceutically acceptable salts thereof; wherein,

[0459] A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0460] B is –(alkylene)O(alkylene)–, alkylene, haloalkylene, alkenylene, –O(alkylene)–, –(alkylene)O–, –O(alkylene)O–,–O(alkylene)O(alkylene)–, –(alkylene)O(alkylene)O–,–S(alkylene)–, –(alkylene)S–, –(alkylene)S(alkylene)–, –S(alkylene)S–, –S(alkylene)S(alkylene)–, –(alkylene)S(alkylene)S– –NH(alkylene)–, –(alkylene)NH–, –(alkylene)NH(alkylene)–, –NH(alkylene)NH– –NH(alkylene)NH(alkylene)–, –(alkylene)NH(alkylene)NH–, –N(alkyl)(alkylene)–, –(alkylene)N(alkyl)–, or is a bond;

[0461] C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;

[0462]

[0463] Ring Z is heterocycloalkylene or heteroarylene;

[0464] R1is independently for each occurrence alkyl, alkoxy, or halo; or two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring;

[0465] R2is independently for each occurrence alkyl, alkoxy, or halo;

[0466] R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;

[0467] R4is independently for each occurrence alkyl, alkoxy, or halo;

[0468] FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0469] k is an integer selected from 0-2;

[0470] m is an integer selected from 0-6;

[0471] n is an integer selected from 0-4;

[0472] p is an integer selected from 0-4; and

[0473] q is an integer selected from 0-2.

[0474] Pharmaceutical Compositions

[0475] The invention provides pharmaceutical compositions, each comprising one or more compounds of the invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a compound of the disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0476] In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the disclosure. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of a disease or condition that would be benefitted by activation of GLP-1R. For example, the at least one additional pharmaceutically active agent may be a GLP-1R agonist, as described herein.

[0477] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0478] Methods of Use

[0479] The present invention provides compounds, and pharmaceutically acceptable salts thereof, that are useful for treating or preventing a disease or condition whose treatment would benefit from GLP-1R activation.

[0480] In certain embodiments, the compounds described herein are useful for modulating the activity of the glucagon-like peptide-I (GLP-1) receptor. In certain embodiments, the compounds described herein are agonists of the glucagon-like peptide-1 (GLP-1) receptor. In certain embodiments, the compounds described herein activate, or induce activity of, the glucagon-like peptide-I (GLP-1) receptor.

[0481] -81- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0482] In certain aspects, the invention provides a method of inducing GLP-1R activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). In certain aspects, the invention provides a method of inducing GLP-1R activity in a subject in need thereof, comprising administering to the subject an amount of a compound of the disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same). In certain embodiments, the amount is an effective amount.

[0483] In certain aspects, the invention provides a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0484] The present invention also provides a method of treating a GLP-1 -associated disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In some aspects, the present invention provides a method of treating a GLP-1-associated disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject an amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the amount is a therapeutically effective amount.

[0485] In certain embodiments, the GLP-1 -associated disease, disorder, or condition is type I diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type I diabetes mellitus (Type lb), youth onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, obstructive sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, hyperosmolar hyperglycemic state, post-prandial lipemia, metabolic acidosis, diabetic ketoacidosis, ketosis, hyperinsulinemia, impaired glucose -82- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0486] metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, anginapectoris, diabetic nephropathy, impaired glucose tolerance, neuropathy, diabetic neuropathy, neuropathy of eight cranial nerve, neuropathic pain, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, primary and secondary osteoarthritis, psoriatic arthritis, rheumatoid arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder, major depressive disorder, cognitive dysfunction in major depressive disorder, persistent depressive disorder (dysthymia), skin and connective tissue disorders, foot ulcerations, foot ulcers, presure ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn' s disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, Huntington’s disease, impaired cognition, schizophrenia, Polycystic Ovary Syndrome (PCOS), peri- and post-menopausal symptom regulation, peri- and post-menopausal hormone regulation, gambling disorder, hypersexuality, adrenaline addiction, tobacco-use disorder, substance use disorder, metabolic dysfunction-associated steatotic liver disease (MASLD), spinal stenosis, degenerative disc disease, fractures, major and mild neurocognitive disorder, multiple sclerosis, Addison’s disease, celiac disease, Grave’s disease, Hashimoto’s thyroiditis, myasthenia gravis, pernicious anemia, Sjogren’s syndrome, systemic lupus erythematosus, cancer, cholecystitis, coronary artery disease, cardiac fibrosis, atrial fibrillation, arrythmia, renal fibrosis, asthma, restrictive lung disease, erectile dysfunction, infertility, glaucoma, macular edema, diabetic papillopathy, nyctalopia, sensorineural hearing loss, auditory neuropathy spectrum disorder, auditory processing disorder, malignant otitis externa, meniere’s disease, gastroparesis, gastroesophageal reflux disease, hepatic fibrosis, chronic and acute pancreatitis, infection-associated chronic condition (long COVID), cellulitis (bacterial and fungal), periodontal disease, HIV lipohypertrophy, necrobiosis lipoidica, acanthosis nigricans, diabetic dermopathy, scleroderma-type skin changes, scleroderma diabetocorum, bullosis diabeticorum, ichthyosiform changes of the shins, xerosis, acquired perforating dermatosis, eruptive xanthomas, acrochordons, diabetes-associated pruritis, Huntley’s papules, keratosis pilaris, pigmented purpuric dermatosis, palmar erythema, periungual telangi ectasias, rubeosis faciei, onychocryptosis, generalized granuloma annulare, vitiligo, hidradenitis supparativa, glucagonoma, all-cause mortality, sedentary lifestyle, body dysmorphic disorder, inferiority complex, or any combination thereof.

[0487] -83- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0488] In certain embodiments, the GLP-1 -associated disease, disorder, or condition is obesity.

[0489] In certain embodiments, the GLP-1 -associated disease, disorder, or condition is diabetes.

[0490] In certain embodiments, the GLP-1 -associated disease, disorder, or condition is cancer.

[0491] In certain embodiments, the cancer is endometrial cancer, breast cancer, colorectal cancer, prostate cancer, liver cancer, gallbladder cancer, kidney cancer, ovarian cancer, esophageal cancer, meningioma cancer, stomach cancer, or pancreatic cancer.

[0492] The compounds of the invention are useful in treating any disease or condition whose treatment would benefit from GLP-1R activation, meaning that in such disease or condition it would be desirable to increase GLP-1R activity. For example, it may be desirable to increase GLP-1R activity in the setting of inappropriate inactivation of GLP-1R.

[0493] In any of the foregoing, an additional pharmaceutically active agent other than a compound of the disclosure may also be administered to the subject.

[0494] Formulations, Routes of Administration, and Dosing

[0495] The compounds of the invention, and pharmaceutically acceptable salts thereof, either alone or as a component of a pharmaceutical composition, can be administered to a mammalian host, such as a human patient, in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intraperitoneal, intramuscular, topical, or subcutaneous routes. Additional routes of administration are also contemplated by the invention.

[0496] Thus, the present compounds or pharmaceutically acceptable salts thereof may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound, or a pharmaceutically acceptable salt thereof, may be combined with one or more pharmaceutically acceptable carriers and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. In some embodiments, such compositions and preparations contain at least 0.1% by weight of active compound, or a pharmaceutically acceptable salt thereof. The percentage of the active compound, or a pharmaceutically acceptable salt thereof, in such compositions and preparations may, of

[0497] -84- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0498] course, be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form. In some embodiments, the amount of active compound, or a pharmaceutically acceptable salt thereof, in such compositions is a therapeutically effective amount.

[0499] The tablets, troches, pills, capsules, and the like may also contain the following diluents and carriers: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, or a pharmaceutically acceptable salt thereof, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound, or a pharmaceutically acceptable salt thereof, may be incorporated into sustained-release preparations and devices.

[0500] The active compound, or a pharmaceutically acceptable salt thereof, may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound, or a pharmaceutically acceptable salt thereof, can be prepared in water or physiologically acceptable aqueous solution, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0501] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active compound, or a pharmaceutically acceptable salt thereof, which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under

[0502] -85- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0503] the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0504] Sterile injectable solutions are prepared by incorporating the active compound, or a pharmaceutically acceptable salt thereof, in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation can include vacuum drying and the freeze drying techniques, which yield a powder of the active compound, or a pharmaceutically acceptable salt thereof, plus any additional desired ingredient present in the previously sterile-filtered solutions.

[0505] For topical administration, the active compound, or a pharmaceutically acceptable salt thereof, may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a pharmaceutically acceptable carrier suitable for dermatologic use, which may be a solid or a liquid.

[0506] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, in which the active compound, or pharmaceutically acceptable salt thereof, can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

[0507] -86- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0508] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

[0509] Examples of useful dermatological compositions which can be used to deliver the compounds of the invention, or pharmaceutically acceptable salts thereof, to the skin are known in the art; for example, see Jacquet et al. (U. S. Pat. No. 4,608,392; incorporated herein by reference), Geria (U. S. Pat. No. 4,992,478; incorporated herein by reference), Smith et al. (U. S. Pat. No. 4,559,157; incorporated herein by reference), and Wortzman (U. S. Pat. No. 4,820,508; incorporated herein by reference).

[0510] Useful dosages of the active compound, or a pharmaceutically acceptable salt thereof, can be determined, at least initially, by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; for example, see U. S. Pat. No. 4,938,949 (incorporated herein by reference).

[0511] The amount of the active compound, or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

[0512] In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg / kg body weight of the recipient per day, e.g., from about 3 to about 90 mg / kg of body weight per day, from about 6 to about 75 mg per kilogram of body weight per day, from about of 10 to about 60 mg / kg of body weight per day, or from about 15 to about 50 mg / kg of body weight per day.

[0513] An active compound, or a pharmaceutically acceptable salt thereof, can be conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active compound, or a pharmaceutically acceptable salt thereof, per unit dosage form. In certain embodiments, the invention provides a composition comprising an active compound, or pharmaceutically acceptable salt thereof, formulated in such a unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses to be administered at appropriate intervals, for example, as two, three, four -87- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0514] or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

[0515] An active compound, or a pharmaceutically acceptable salt thereof, can also be administered in combination with other therapeutic agents, for example, other agents that are useful for treating or preventing a disease or condition whose treatment would benefit from GLP-1R activation.

[0516] Other delivery systems can include time-release, delayed release, or sustained release delivery systems such as are well-known in the art. Such systems can avoid repeated administrations of the active compound, or a pharmaceutically acceptable salt thereof, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. Use of a long-term sustained release implant may be desirable. Long-term release, as used herein, means that the delivery system or is implant constructed and arranged to deliver therapeutic levels of the active compound, or a pharmaceutically acceptable salt thereof, for at least 30 days, and preferably 60 days.

[0517] In certain embodiments, an active compound, or pharmaceutically acceptable salt thereof, is formulated for intraocular administration, for example direct injection or insertion within or in association with an intraocular medical device.

[0518] An active compound, or a pharmaceutically acceptable salt thereof, may be formulated for depositing into a medical device, which may include any of a variety of conventional grafts, stents, including stent grafts, catheters, balloons, baskets, or other device that can be deployed or permanently implanted within a body lumen. As a particular example, it would be desirable to have devices and methods which can deliver compounds of the invention, or pharmaceutically acceptable salts thereof, to the region of a body which has been treated by interventional technique.

[0519] In exemplary embodiments, an active compound, or a pharmaceutically acceptable salt thereof, may be deposited within a medical device, such as a stent, and delivered to the treatment site for treatment of a portion of the body.

[0520] Stents have been used as delivery vehicles for therapeutic agents (i.e., drugs).

[0521] Intravascular stents are generally permanently implanted in coronary or peripheral vessels. Stent designs include those of U. S. Pat. No. 4,733,655 (Palmaz), U. S. Pat. No. 4,800,882 (Gianturco), or U. S. Pat. No. 4,886,062 (Wiktor). Such designs include both metal and

[0522] -88- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0523] polymeric stents, as well as self-expanding and balloon-expandable stents. Stents may also be used to deliver a drug at the site of contact with the vasculature, as disclosed in U. S. Pat. No. 5,102,417 (Palmaz), U. S. Pat. No. 5,419,760 (Narciso, Jr.), U. S. Pat. No. 5,429,634 (Narciso, Jr.), and in International Patent Application Nos. WO 91 / 12779 (Medtronic, Inc.) and WO 90 / 13332 (Cedars-Sanai Medical Center), for example.

[0524] The term “deposited” means that the active compound, or a pharmaceutically acceptable salt thereof, is coated, adsorbed, placed, or otherwise incorporated into the device by methods known in the art. For example, the active compound, or a pharmaceutically acceptable salt thereof, may be embedded and released from within (“matrix type”) or surrounded by and released through (“reservoir type”) polymer materials that coat or span the medical device. In the latter example, the active compound, or a pharmaceutically acceptable salt thereof, may be entrapped within the polymer materials or coupled to the polymer materials using one or more the techniques for generating such materials known in the art. In other formulations, the active compound, or a pharmaceutically acceptable salt thereof, may be linked to the surface of the medical device without the need for a coating, for example by means of detachable bonds, and release with time or can be removed by active mechanical or chemical processes. In other formulations, the active compound, or a pharmaceutically acceptable salt thereof, may be in a permanently immobilized form that presents the active compound at the implantation site.

[0525] In certain embodiments, the active compound, or a pharmaceutically acceptable salt thereof, may be incorporated with polymer compositions during the formation of biocompatible coatings for medical devices, such as stents. The coatings produced from these components are typically homogeneous and are useful for coating a number of devices designed for implantation.

[0526] The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but frequently a bioabsorbable polymer is suitable for this embodiment because, unlike a biostable polymer, it will typically not be present long after implantation to cause any adverse, chronic local response. Bioabsorbable polymers that could be used include, but are not limited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA), poly(lactide-co-glycolide) (PLLA / PGA), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lactic acid), poly(D, L-lactic acid), poly(D, L-lactide) (PLA), poly (L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate) (PGA / PTMC), polyethylene oxide (PEO), polydioxanone (PDS),

[0527] -89- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0528] polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g., PEO / PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, cross linked or amphipathic block copolymers of hydrogels, and other suitable bioabsorbable poplymers known in the art. Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used, and other polymers could also be used if they can be dissolved and cured or polymerized on the medical device such as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-m ethyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; pyran copolymer; polyhydroxy-propyl-methacrylamide-phenol; polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysine substituted with palmitoyl residues; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0529] Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.

[0530] In certain embodiments of the invention, the compound of the disclosure, or pharmaceutically acceptable salt thereof, is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device.

[0531] Typically, polymers are applied to the surface of an implantable device by spin coating, dipping, or spraying. Additional methods known in the art can also be utilized for this purpose. Methods of spraying include traditional methods as well as microdeposition techniques with an inkjet type of dispenser. Additionally, a polymer can be deposited on an implantable device using photo-patterning to place the polymer on only specific portions of

[0532] -90- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0533] the device. This coating of the device provides a uniform layer around the device which allows for improved diffusion of various analytes through the device coating.

[0534] In certain embodiments of the invention, the compound of the disclosure, or pharmaceutically acceptable salt thereof, is formulated for release from the polymer coating into the environment in which the medical device is placed. Preferably, the active compound, or a pharmaceutically acceptable salt thereof, is released in a controlled manner over an extended time frame (e.g., months) using at least one of several well-known techniques involving polymer carriers or layers to control elution. Some of these techniques are described in U. S. Patent Application 2004 / 0243225A1, the entire disclosure of which is incorporated herein in its entirety.

[0535] Moreover, as described for example in U. S. Pat. No. 6,770,729, which is incorporated herein in its entirety, the reagents and reaction conditions of the polymer compositions can be manipulated so that the release of the active compound, or a pharmaceutically acceptable salt thereof, from the polymer coating can be controlled. For example, the diffusion coefficient of the one or more polymer coatings can be modulated to control the release of the active compound, or a pharmaceutically acceptable salt thereof, from the polymer coating. In a variation on this theme, the diffusion coefficient of the one or more polymer coatings can be controlled to modulate the ability of an analyte that is present in the environment in which the medical device is placed (e.g., an analyte that facilitates the breakdown or hydrolysis of some portion of the polymer) to access one or more components within the polymer composition (and for example, thereby modulate the release of the active compound, or a pharmaceutically acceptable salt thereof, from the polymer coating). Yet another embodiment of the invention includes a device having a plurality of polymer coatings, each having a plurality of diffusion coefficients. In such embodiments of the invention, the release of the active compound, or a pharmaceutically acceptable salt thereof, from the polymer coating can be modulated by the plurality of polymer coatings.

[0536] In yet another embodiment of the invention, the release of the active compound, or a pharmaceutically acceptable salt thereof, from the polymer coating is controlled by modulating one or more of the properties of the polymer composition, such as the presence of one or more endogenous or exogenous compounds, or alternatively, the pH of the polymer composition. For example, certain polymer compositions can be designed to release an active compound, or a pharmaceutically acceptable salt thereof, in response to a decrease in the pH of the polymer composition.

[0537] -91- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0538] Kits

[0539] Kits comprising a compound of the disclosure are also provided. In certain embodiments, a kit is provided comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one of packaging material, and instructions for administering the compound of the disclosure or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat or prevent a disease or condition that would benefit from GLP-1R activation. In certain embodiments, the mammal is a human. In a specific embodiment, the mammal is a human.

[0540] In another embodiment, a kit is provided comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one of at least one other therapeutic agent, packaging material, and instructions for administering the compound of the disclosure or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to a mammal to treat or prevent a disease or condition that would benefit from GLP-1R activation. In a specific embodiment, the mammal is a human.

[0541] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof.

[0542] -92- FoleyHoagUS13277851.4Attorney Docket No.: ABR-00125

[0543] EXAMPLES

[0544] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

[0545] Preparation 1 - Synthetic Scheme

[0546]

[0547] Attorney Docket No.: ABR-00125

[0548] Preparation 1 - Synthetic Procedure

[0549]

[0550] Step A: To a solution of 5-bromo-2-indolecarboxylic acid (20 g, 83.3 mmol) and N-methylaniline (9.82 g, 91.6 mmol) in DMF (0.2 L) at 0 °C were added EDCI (31.9 g, 167 mmol) and HOBT (22.5 g, 167 mmol). The mixture was warmed to ambient temperature and stirred for 16 hours. The mixture was then diluted with water (200 mL) and the precipitate was collected by vacuum filtration. The solid was washed with water (100 mL) then dried to give N-methyl-N-phenyl-5-bromo-2-indolecarboxamide (24 g, 65.6 mmol) as an off-white solid. m / z (ESI-pos) M+l = 329.0, 331.0.

[0551] Step B: To a solution of N-methyl-N-phenyl-5-bromo-2-indolecarboxamide (10 g, 27.3 mmol) in DMF (50 mL) at 0 °C was added sodium hydride (60%w / w, 1.97 g, 49.2 mmol). The mixture was stirred at 0 °C for 30 mins and then chloroacetonitrile (4.13 g, 54.7 mmol) was added dropwise at this temperature. The resulting mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched with water, extracted with EtOAc (2x). The combined EtOAc layers were washed with brine (2x), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give N-methyl-N-phenyl-5-bromo-l-(cyanomethyl)-2-indolecarboxamide (9 g, 22 mmol) as a yellow solid, m / z (ESI-pos) M+l = 368.0, 370.0 Step C: To a mixture of N-methyl-N-phenyl-5-bromo-l-(cyanomethyl)-2-indolecarboxamide (9 g, 24.4 mmol), (2-methyl-4-pyridyl)boranediol (4.02 g, 29.3 mmol) and K2CO3(6.76 g, 48.9 mmol) in 1,4-dioxane (180 mL) and water (36 mL) was added Pd(dppf)C12 dichloromethane complex (2 g, 2.44 mmol). The mixture was stirred at 80 °C for 2.5 h and then the reaction mixture was cooled to ambient temperature. The mixture was diluted with ethyl acetate and washed with water (2x). The aqueous layer was back extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography (0-50% EtOAc in PE) to give N-methyl-N-phenyl-l-(cyanomethyl)-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (5 g, 13.1 mmol) as a yellow solid, m / z (ESI-pos) M+l = 381.2Attorney Docket No.: ABR-00125

[0552] Step D: To a solution of N-methyl-N-phenyl-l-(cyanomethyl)-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (5 g, 13.1 mmol) in DMPU (250 mL) at was added (R)-4-methyl-l,3,2-dioxathiolane 2,2-dioxide (4.54 g, 32.9 mmol), followed by dropwise addition of KHMDS (1.0 M in THF, 52.6 mL, 52.6 mmol). The mixture was stirred at 0 °C for 2 hours and quenched with aqueous NH4CI. The mixture was extracted with EtOAc (2x). The combined EtOAc layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give N-methyl-N-phenyl-l-[(2S)-l-cyano-2-methylcyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (4.5 g, 10.7 mmol) as a yellow liquid, m / z (ESI-pos) M+l = 421.3

[0553] Step E: To a solution of N-methyl-N-phenyl-l-[(2S)-l-cyano-2-methylcyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (4 g, 9.51 mmol) in EtOH (77.7 mL) were added Hydroxylamine hydrochloride (3.31 g, 47.6 mmol) and K2CO3(7.23 g, 52.3 mmol). The mixture was stirred at 100 °C for 2 hours and then concentrated under reduced pressure. The residue was diluted with H2O and the precipitate was collected by vacuum filtration to give N-methyl-N-phenyl-l-[(2S)-l-(hydroxyamino)carboximidoyl-2-methylcyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (3 g, 6.61 mmol) as a white solid, m / z (ESI-pos) M+l = 454.2

[0554] Step F: To a solution ofN-methyl-N-phenyl-l-[(2S)-l-(hydroxyamino)carboximidoyl-2-methylcyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (3 g, 6.61 mmol) in DMSO (61.8 mL) was added CDI (2.15 g, 13.2 mmol) and DBU (2.52 g, 16.5 mmol). The mixture was stirred at 80 °C for 2 hours and then cooled to ambient temperature, diluted with ethyl acetate, and washed with water (2x). The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated to give the crude compound, which was purified by column chromatography (0-80% EA in PE) to give N-methyl-N-phenyl-l-[(2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (2.1 g, 4.38 mmol) as a yellow solid, m / z (ESI-pos) M+l = 480.3

[0555] Step G: To a solution of N-methyl-N-phenyl-l-[(2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxamide (2.1 g, 4.38 mmol) in n-propanol (63 mL) was added KOH (2.46 g, 43.8 mmol). The mixture was stirred at 130 °C for 16 h, then additional KOH (1.23 g, 21.9 mmol) was added and stirred at 130 °C for another 16 h. The reaction mixture was concentrated under reduced pressure. The residueAttorney Docket No.: ABR-00125

[0556] was diluted with H2O (5 mL) at 0°, then 6N aq. HC1 was added dropwise to the mixture until solid began to precipitate, then additional IN aq. HC1 was added dropwise until the pH was ~5-6. The precipitate was collected by vacuum filtration, to give l-[(2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-(2-methyl-4-pyridyl)-2-indolecarboxylic acid (1.04 g, 2.66 mmol) as a white solid, m / z (ESI-pos) M+l = 381.2,1H NMR (400 MHz, DMSO) 88.45 (d, J= 5.2 Hz, 1H), 8.00 (s, 1H), 7.66 (dd, J= 1.6, 8.8 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H) 6.81 (s, 1H), 2.52 (s, 3H), 1.71-1.63 (m,2H), 1.50-1.47 (m,lH) 1.11 (d, J=6.0 Hz, 3H).

[0557] Preparation 2 - Synthetic Scheme

[0558] Pd2dba3,RuPhos,

[0559] t-BuOK, NMP

[0560] KOH, 1 -Propanol, 130 °C

[0561]

[0562] Preparation 2 - Synthetic Procedure

[0563]

[0564] Step A: To a mixture of 5-bromo-N-methyl-l-(l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-lH-indole-2-carboxamide (500 mg, 1.11 mmol), 2,2-dimethylmorpholine (165 mg, 1.14 mmol) in N-Methyl-2-pyrrolidone (25 mL) were added t-BuONa (319 mg, 3.32 mmol), 2-Dicyclohexylphosphino-2',6'-di-i-propoxy-l,l'-biphenyAttorney Docket No.: ABR-00125

[0565] (103 mg, 0.221 mmol) and tris(dibenzylideneacetone)dipalladium (101 mg, 0.11 mmol) under N2 protection and then stirred at 100 °C for 0.5 h. The reaction mixture was cooled to ambient temperature, quenched with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to give a residue, which was purified by column chromatography (0-50% EtOAc in PE) to give 5-(2,2-dimethylmorpholino)-N-methyl-l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-lH-indole-2-carboxamide (500 mg, 0.84 mmol) as a yellow oil. m / z (ESI-pos) M+l = 502.3

[0566] Step B: To a solution of 5-(2,2-dimethylmorpholino)-N-methyl-l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-N-phenyl-lH-indole-2-carboxamide (220 mg, 439 pmol) in 1-propanol (5 mL) was added potassium hydroxide (426 mg, 4.39 mmol). The reaction mixture was stirred at 130 °C for 36 h. The reaction mixture was cooled to ambient temperature and concentrated to remove 1-propanol. The residue was suspended in water (30 mL) and extracted with EtOAc (10 mL, the organics were discarded). The aqueous layer was acidified to pH about 5 with IN aq. HC1 and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and the filtrate was concentrated to give crude 5-(2,2-dimethylmorpholino)-l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-lH-indole-2-carboxylic acid (70 mg, 153 pmol) as a yellow solid, m / z (ESI-pos) M+l = 411.2

[0567] Preparation 3 - Synthetic SchemeAttorney Docket No.: ABR-00125

[0568] GPhos Pd G6

[0569] NaOTMS, THF

[0570]

[0571] Preparation 3 - Synthetic Procedure

[0572]

[0573] Step A: To a mixture of 5-bromo-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (315 mg, 833 pmol), (R)-2-(difluoromethyl)morpholine hydrochloride (214 mg, 1.25 mmol), bromidopalladium(l+) 2-(trimethylsilyl)ethyl 1 -benzenid-4-carboxylate — (3 -tert-butoxy-2',6'-diisopropyl-6-methoxy-2-biphenylyl)dicyclohexylphosphine (1 / 1) (39.3 mg, 41.6 pmol), sodium trimethylsilanolate (467 mg, 4.16 mmol), was added tetrahydrofuran (2.78 mL). The mixture was sparged for 5 minutes with Ar and then heated to 70 °C for 16 hours. The reaction was cooled and diluted with EtOAc. The organics were washed twice with IM aq HC1, then brine. Organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase prep-HPLC purification eluting with 20-80% MeCN+0.1% FA in water+0.1% FA. Desired fractions were concentrated to afford 5-[(R)-2-(difluoromethyl)-4-morpholinyl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (302 mg, 695 pmol). m / z (ESI-pos) M+l = 435.3;1H NMR. (400 MHz, CHLOROFORM-D) 8 11.69 (s, 1H), 10.61 (s, 1H), 7.63 (d, J = 9.1 Hz, 1H), 7.24 -7.16 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 5.82 (td, J = 55.3, 4.3 Hz, 1H), 4.10 (d, J= 11.3 Hz, 1H), 4.02 - 3.83 (m, 2H), 3.49 (d, J = 11.5 Hz, 1H), 3.34 (d, J = 11.9 Hz, 1H), 2.90 (td, J = 11.6, 3.3 Hz, 1H), 2.85 - 2.75 (m, 1H), 1.90 - 1.74 (m, 2H), 1.54 - 1.46 (m, 1H), 1.26 (d, J = 5.9 Hz, 3H); 19F NMR (376 MHz, CHLOROFORM-D) 6 -127.79 (ddd, J = 295.9, 55.1, 9.2 Hz), -131.12 (ddd, J = 295.9, 55.4, 11.0 Hz).

[0574] Preparation 4 - Synthetic SchemeAttorney Docket No.: ABR-00125

[0575] OH

[0576]

[0577] Preparation 4 - Synthetic Procedure

[0578] OH

[0579]

[0580] Step A: To a mixture of 5-bromo-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (2 g, 5.29 mmol), (R)-2-(trifluoromethyl)morpholine hydrochloride (1.3 g, 6.87 mmol), bromidopalladium(l+) 2-(trimethylsilyl)ethyl l-benzenid-4-carboxylate — (3-tert-butoxy-2',6'-diisopropyl-6-methoxy-2-biphenylyl)dicyclohexylphosphine (1 / 1) (250 mg, 264 pmol), and sodium trimethylsilanolate (2.97 g, 26.4 mmol), was added tetrahydrofuran (17.6 mL). The mixture was sparged for 5 minutes then heated to 70 °C for 16 hours. The reaction was cooled and diluted with EtOAc. The organics were washed twice with IM aq HC1, then brine. Organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase prep-HPLC purification eluting with 20-75% MeCN+0.1% FA in water+0.1% FA. Desired fractions were concentrated to afford l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-[(R)-2-(trifluoromethyl)-4-morpholinyl]-2-indolecarboxylic acid (1.58 g, 3.49 mmol), m / z (ESI-pos) M+l = 453.3;1H NMR (400 MHz, CHLOROFORM-D) 5 11.91 (s, 1H), 10.66 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 4.20 -4.08 (m, 2H), 3.90 (td, J = 11.4, 2.6 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.39 - 3.31 (m, 1H), 2.98 - 2.81 (m, 2H), 1.90 - 1.74 (m, 2H), 1.58 - 1.46 (m, 1H), 1.26 (d, J = 6.0 Hz, 3H).

[0581] Preparation 5 - Synthetic SchemeAttorney Docket No.: ABR-00125

[0582] Pd2dba3, RuPhos,

[0583] NaOtBu, NMP

[0584]

[0585] Preparation 5 - Synthetic Procedure

[0586]

[0587] Step A: A 50 mL round bottom flask was charged with (S)-4-chloro-2-cyclopropyl-45-morpholine (833 mg, 5.16 mmol), Pd2dba3 (182 mg, 198 pmol), dicyclohexyl(2',6'-diisopropoxy-2-biphenylyl)phosphine (185 mg, 397 pmol), NaOtBu (1.91 g, 19.8 mmol) and N-methyl-2-pyrrolidone (13.2 mL). The mixture was sparged for 5 minutes with Ar, then 5-bromo-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (1.5 g, 3.97 mmol) was added and the mixture was heated to 100 °C where it stirred for 1 hour. The mixture was cooled to ambient temperature and diluted with water and extracted with EtOAc (3x). The EtOAc layer was discarded. The aqueous phase was then treated with IM HC1 (14 mL) until pH= ~1, and the mixture was extracted with EtOAc (4x). The combined organics were dried over Na₂SO₄, filtered through Celite, and concentrated. The product was purified by Prep HPLC (Isco ACCQ Prep, Gemini column NX-C18, 250 x 50 mm, 120 ml / min, 35-minute separation, 10 to 60% ELO / ACN with 0.1% Formic acid buffer), to give 5-[(S)-2-cyclopropyl-4-morpholinyl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (1.39 g, 3.28 mmol), m / z (ESI-pos) M+l = 425.3,1H NMR (400 MHz, CHLOROFORM-D) 8 10.64 (s, 1H), 7.60 (d, J = 9.1 Hz, 1H), 7.22 - 7.01 (m, 3H), 4.07 -4.00 (m, 1H), 3.77 (td, J = 11.4, 2.5 Hz, 1H), 3.50 (d, J = 11.5 Hz, 1H), 3.32 (d, J = 11.7 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.83 (td, J = 11.6, 3.2 Hz, 1H), 2.69 (dd, J = 11.7, 10.1 Hz, 1H), 1.88 - 1.73 (m, 2H), 1.57 - 1.45 (m, 1H), 1.28 - 1.22 (m, 4H), 0.95 (dtd, J = 13.4, 8.6, 5.0 Hz, 1H), 0.66 - 0.50 (m, 2H), 0.45 (dq, J = 9.1, 4.7 Hz, 1H), 0.29 (dq, J = 9.6, 4.8 Hz, 1H).Attorney Docket No.: ABR-00125

[0588] Preparation 6 - Synthetic Scheme

[0589] CbzCI SFC Separation

[0590] NaHCO3, THF

[0591]

[0592] Preparation 6 - Synthetic Procedure

[0593]

[0594] Step A: A solution of 2-(l,l-difluoroethyl)morpholine hydrogen chloride (5.0 g, 26.7 mmol) in tetrahydrofuran (53.3 mL) and water (17.8 mL) was treated with sodium hydrogencarbonate (8.96 g, 107 mmol) followed by phenylmethyl chloroformate (4.13 mL, 29.3 mmol). The mixture was then stirred at ambient temperature overnight. The mixture was then diluted with water and extracted with EtOAc (3x). The combined organic layers were then washed with brine (2x), dried over Na2SO4, filtered and concentrated. The crude product was then purified via column chromatography (0-15 % EtOAc / heptane) to afford benzyl 2-(l,l-difluoroethyl)-4-morpholinecarboxylate (6.72 g, 23.6 mmol) as a thick, colorless oil. m / z (ESI-pos) M+l = 286.2,1H NMR (400 MHz, CHLOROFORM-D) 87.39 -7.29 (m, 5H), 5.19 - 5.12 (m, 2H), 4.31 - 3.82 (m, 4H), 3.65 - 3.43 (m, 2H), 3.00 (br s, 1H), 1.62 (t, J = 19.3 Hz, 3H).

[0595] Step B: Benzyl 2-(l,l-difluoroethyl)-4-morpholinecarboxylate (5.95 g) was then separated by SFC using a Berger MG-II Preparative SFC with a Regis® Whelk-Ol (R, R)Attorney Docket No.: ABR-00125

[0596] (250 x 20 mm) column @ 35 °C. The mobile phase CO2 modifier was 5% [1:1] methanol: ethanol (neat) w / 8 mL / min post-BPR make-up flow ethanol with a flow rate of 60 mL / min.

[0597] Peak 1: benzyl (S)-2-(l,l-difluoroethyl)-4-morpholinecarboxylate (2.40 g, stereochemistry arbitrarily assigned), [OC]D23+7.9° (c 1.8, MeOH).

[0598] Peak 2: benzyl (R)-2-(l,l-difluoroethyl)-4-morpholinecarboxylate (2.50 g, stereochemistry arbitrarily assigned), [OC]D23-7.9° (c 2.7, MeOH).

[0599] Step C: A solution of benzyl (R)-2-(l,l-difluoroethyl)-4-morpholinecarboxylate (SFC separation Peak 2, 2.45 g, 8.59 mmol) in ethyl acetate (28.6 mL) was treated with Pd / C (5%w / w, 274 mg, 129 pmol). The mixture was then purged of air by placing the system under vacuum and then introducing hydrogen gas (3x). The vial was sealed and the mixture was stirred under a H2 atmosphere (balloon pressure) for 4 hours. The hydrogen atmosphere was removed and the mixture was briefly purged with N2. The mixture was then filtered through celite and the filtrate was treated with hydrogen chloride (2.15 mL, 4.0M in dioxane, 8.59 mmol) and heptane (25 mL). The mixture was concentrated in vacuo. The crude product was then dissolved in CH2CI2 and MTBE and the mixture was concentrated in vacuo to a thick oil that was placed under vacuum overnight to form a tan solid. The solid was then sonicated in MTBE and the solid was isolated by vacuum filtration. The solid was then washed with heptane and dried in vacuo to provide (R)-2-(l,l-difluoroethyl)morpholine hydrogen chloride (1.52 g, 8.1 mmol) as an off-white solid, m / z (ESI-pos) M+l = 152.1,1H NMR (400 MHz, CHLOROFORM-D) δ 10.23 (s, 2H), 4.27 - 3.95 (m, 3H), 3.63 - 3.45 (m, 1H), 3.36 (d, J = 12.9 Hz, 1H), 3.18 - 2.94 (m, 2H), 1.65 (t, J = 19.2 Hz, 3H), [a]D23+7.7° (c 1.15, MeOH).

[0600] Step D: A mixture of (R)-2-(l,l-difluoroethyl)morpholine hydrogen chloride (957 mg, 5.16 mmol), Pd2dba3 (182 mg, 198 pmol), dicyclohexyl(2',6'-diisopropoxy-2-biphenylyl)phosphine (185 mg, 397 pmol), NaOtBu (1.91 g, 19.8 mmol) and N-methyl-2-pyrrolidone (13.2 mL) was sparged for 5 minutes with Ar. Then 5-bromo-l-[(lS,2S)-2-methyl- 1 -(5 -oxo-4, 5 -dihydro- 1,2,4-oxadiazol-3 -yl)cyclopropyl]-2-indolecarboxylic acid (1.5 g, 3.97 mmol) was added and the mixture was heated to 100 °C under an Ar atmosphere where it stirred for 2 hours. The mixture was cooled to ambient temperature and diluted with water and EtOAc and the mixture was filtered through celite. The layers were separated and the aqueous phase was extracted with EtOAc (2 x). The EtOAc layers were discarded. The aqueous phase was then treated with IM HC1 (15 mL) until pH= ~1, and the mixture wasAttorney Docket No.: ABR-00125

[0601] extracted with EtOAc (4x). The combined organics were dried over Na2SO4, filtered through Celite, and the filtrate was concentrated. The product purified by Prep HPLC (Isco ACCQ Prep, Gemini column NX-C18, 250 x 50 mm, 120 ml / min, 35-minute separation, 10 to 60% H2O / ACN with 0.1% Formic acid buffer) to give 5-[(R)-2-(l,l-difluoroethyl)-4-morpholinyl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (1.46 g, 3.26 mmol), m / z (ESI-pos) M+l = 449.3,1H NMR (400 MHz, CHLOROFORM-D) δ 10.66 (s, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.21 - 7.08 (m, 3H), 4.15 - 4.06 (m, 1H), 3.91 - 3.77 (m, 2H), 3.56 (d, J = 11.6 Hz, 1H), 3.34 (d, J = 11.9 Hz, 1H), 2.86 (td, J= 11.8, 3.3 Hz, 1H), 2.75 (t, J = 11.1 Hz, 1H), 1.89 - 1.76 (m, 2H), 1.68 (t, J = 19.3 Hz, 3H), 1.56 - 1.43 (m, 1H), 1.26 - 1.23 (m, 3H).

[0602] Preparation 7 - Synthetic Scheme

[0603]

[0604] Preparation 7 - Synthetic Procedure

[0605]

[0606] Step A: A solution of (S)-3 -aminobutyronitrile — hydrogen chloride (1 / 1) (17 g, 141 mmol) and methyl 1 -formylcyclopropanecarboxylate (19.9 g, 155 mmol) in DCM (300 mL) was stirred for 30 minutes, then NaCNBHs (11 g, 183 mmol) was added and stirred overnight at room temperature. The solution was then filtered through celite and partitioned between sat. aq. NH4CI and DCM. The organics were dried with sodium sulfate, filtered, concentrated, and taken forward as the crude material, m / z (ESI-pos) [M + 1] = 197.2 Step B: A solution of crude methyl l-{[(S)-2-cyano-l-methylethylamino]methyl} cyclopropanecarboxylate (20 g, 102 mmol) and BOC2O (28.9 g, 132 mmol) in DCM (300 mL) was stirred overnight at room temperature. The solution was then concentrated and purified by silica gel chromatography (5-95% EtOAc / heptanes usingAttorney Docket No.: ABR-00125

[0607] ELSD to monitor peaks), and the product was concentrated to give methyl l-({tert-butyl[(S)-2-cyano-l-methylethyl](oxycarbonylamino)}methyl)cyclopropanecarboxylate (9 g, 30.4 mmol), m / z (ESI-pos) [M + 1 - CH3] = 283.2

[0608] Step C: To a solution of methyl 1 -({tert-butyl [(S)-2-cyano-l-methylethyl](oxycarbonylamino)}methyl)cyclopropanecarboxylate (8.3 g, 28 mmol) in THF (120 mL) at 0 °C was added KOtBu (3.46 g, 30.8 mmol) and stirred for 2 hours at room temperature. The solution was then quenched with aq. sat. NH4CI and partitioned between DCM and water. The organics were dried with sodium sulfate, filtered, and concentrated to give tert-butyl (6S)-7-cyano-6-methyl-8-oxo-5-aza-5-spiro[2.5]octanecarboxylate (7.4 g, 28 mmol), m / z (ESI-pos) [M + 1 - tBu] = 209.1

[0609] Preparation 8 - Synthetic Scheme

[0610]

[0611] Preparation 8 - Synthetic Procedure

[0612] F F

[0613]

[0614] Step A: To a solution of 4-bromo-3-fluoro-2-pyridinecarbaldehyde (153 mg, 750 pmol) in 4 mL of DCM in a vial was slowly added DAST (495 pL, 3.75 mmol) and stirred for 30 minutes at room temperature. The solution was then carefully quenched with sat. NaHCO3and partitioned between water and DCM. The organics were concentrated and purified by silica gel chromatography (0-20% EtOAc / heptanes), and the product was concentrated to give 4-bromo-2-(difluoromethyl)-3-fluoropyridine (50 mg, 221 pmol).1H NMR (400 MHz, chloroform-D) δ 8.28 (d, J= 5.1 Hz, 1H), 7.67 (tt, J= 5.0, 0.9 Hz, 1H), 6.77 (t, J = 53.5 Hz, 1H).

[0615] Preparation 9 - Synthetic SchemeAttorney Docket No.: ABR-00125

[0616] DMI, Water,

[0617] NaOC(CH3)3

[0618]

[0619] Preparation 9 - Synthetic Procedure

[0620] Step A: To a mixture of N-methyl-N-phenyl-5-bromo-l-[(2S)-l-cyano-2-methylcyclopropyl]-2-indolecarboxamide (290 mg, 710 pmol), (R)-3-(trifluoromethyl)morpholine hydrogen chloride (272 mg, 1.42 mmol) in Toluene (4 mL) were added dicaesium carbonate (1.16 g, 3.55 mmol), RuPhos (66.3 mg, 142 pmol) and tBuBrettPhos Pd G3 (60.8 mg, 71 pmol) under N2 protection and then stirred at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered over celite. The filtrate was concentrated to give a residue, which was purified by column chromatography (0-50% EtOAc in PE) to give N-methyl-N-phenyl-l-[(2S)-l-cyano-2-methylcyclopropyl]-5-[(R)-3-(trifluoromethyl)-4-morpholinyl]-2-indolecarboxamide (98 mg, 203 pmol) as a yellow foam. m / z (ESI-pos) M+l = 483.3

[0621] Step B: To a solution of N-methyl-N-phenyl-l-[(2S)-l-cyano-2-methylcyclopropyl]-5-[(R)-3-(trifluoromethyl)-4-morpholinyl]-2-indolecarboxamide (50 mg, 92.3 pmol) in 1,3-Dimethyl-2-imidazolidinone (1.79 mL, 51.7 mmol) and water (2.08 pL, 115 pmol) was added Sodium tert-butoxide (26.6 mg, 277 pmol). The reaction mixture was stirred at 85°C for 24 h. The pH value of the mixture was adjusted to around 3 by adding 6M HC1. The mixture was extracted with 3:1 IPA / chloroform in Water, collected organic layer and dried over sodium sulfate, concentrated, the crude residue was directly loaded (with some MeCN, MeOH, and H2O) onto the reverse phase column and purified by Prep HPLC (Isco ACCQ Prep, Gemini column NX-C18, 250 x 21 mm, 20 ml / min, 45 minute separation, 20 to 80%Attorney Docket No.: ABR-00125

[0622] H20 / ACN with 0.1% Formic acid buffer), fractions were collected and lyophilized to give. 1-[(2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-[(R)-3-(trifluoromethyl)-4-morpholinyl]-2-indolecarboxylic acid (10 mg, 22.1 pmol) m / z (ESI-pos) M+l = 453.2.

[0623] Preparation 10 - Synthetic Scheme

[0624] HO

[0625] nBuLi, BF3. QEt2

[0626] PhMe

[0627]

[0628] Preparation 10 - Synthetic Procedure

[0629] Step A: To a 40 mL vial was added 5-bromo-6-iodo-l-methyl-lH-indazole (633 mg, 1.88 mmol) and toluene (18.8 mL) under nitrogen. After cooling the mixture to -78° C, 2.5M / / BuLi in Hexane (751 pL, 1.88 mmol) was added dropwise to the solution and the resulting mixture was stirred for 1 hour. 2.5M oxirane in THF (1.13 mL, 2.82 mmol) was added, the resulting mixture was stirred at -78° C for 5 minutes, and then ethoxyethane — trifluoroborane (1 / 1) (348 pL, 2.82 mmol) was added to the mixture. The resulting mixture was stirred at -78° C for 20 minutes and the reaction was quenched with saturated aqueous sodium bicarbonate and transferred to a separatory funnel. The mixture was extracted twice with EtOAc. Organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified over silica eluting with 20-75% EtOAc / Heptane to afford 2-(5-bromo-l-methyl-lH-indazol-6-yl)ethanol (222 mg, 870 pmol). m / z (ESI-pos) M+l = 255.0 / 257.0

[0630] Preparation 11 - Synthetic Scheme

[0631] Na2CO3, Dioxane / H20

[0632]

[0633] Preparation 11 - Synthetic Procedure

[0634] Step A: A solution of 5-bromo-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (0.2 g, 529 pmol) Pd(dppf)Ch (21.6 mg,Attorney Docket No.: ABR-00125

[0635] 26.4 pmol), [2-(trifluoromethyl)-4-pyridyl]boranediol (151 mg, 793 pmol) and disodium carbonate (280 mg, 2.64 mmol) in 1,4-dioxane (5.29 mL) and water (1.76 mL) was heated to 80 °C for 2 hours. The solution was partitioned between EtOAc and IN aqueous HC1, the organic layer was collected and dried with Na₂SO₄, filtered and concentrated. The crude residue was purified by reverse-phase chromatography eluting with 10-75% MeCN / water with 0.1% formic acid. Desired fractions were lyophilized to afford l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-[2-(trifluoromethyl)-4-pyridyl]-2-indolecarboxylic acid (110 mg, 248 pmol). m / z (ESI-pos) M+l = 445.2

[0636] Preparation 12 - Synthetic Scheme

[0637] Pd(PPh3)4

[0638] Na2CO3

[0639]

[0640] dioxane / H20

[0641] Preparation 12 - Synthetic Procedure

[0642]

[0643] Step A: To a mixture of 2-bromo-4-fluoro-l -iodobenzene (343 mg, 1.14 mmol), disodium carbonate (242 mg, 2.28 mmol), water (1.14 mL), 1,4-dioxane (5.7 mL) was added palladium — triphenylphosphine (1 / 4) (132 mg, 114 pmol) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (641 pL, 3.42 mmol) at room temperature. The mixture was sparged with N2 for 10 minutes and stirred at 80 °C overnight. Additional palladium — triphenylphosphine (1 / 4) (132 mg, 114 pmol) and 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (641 pL, 3.42 mmol) were added and the mixture was sparged with N2 for 10 minutes. The reaction was stirred at 80 °C for 5 hours. Additional palladium — triphenylphosphine (1 / 4) (66 mg, 57 pmol) and disodium carbonate (121 mg, 1.14 mmol) were added and the mixture was sparged with N2 for 10 minutes. The reaction was stirred at 80 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 0-20% EtOAc / heptane) to afford l-allyl-2-bromo-4-Attorney Docket No.: ABR-00125

[0644] fluorobenzene (156 mg, 726 μmol).1H NMR (400 MHz, CHLOROFORM-D) δ 7.30 (dd, J = 8.3, 2.7 Hz, 1H), 7.19 (dd, J= 8.6, 6.0 Hz, 1H), 6.98 (td, J= 8.3, 2.7 Hz, 1H), 5.94 (ddt, J = 16.7, 10.1, 6.5 Hz, 1H), 5.17 - 4.99 (m, 2H), 3.47 (d, J= 6.4 Hz, 2H).

[0645] Preparation 13 - Synthetic Scheme

[0646] Pd(PPh3)4

[0647] Na2CO3

[0648]

[0649] dioxane / H20

[0650] Preparation 13 - Synthetic Procedure

[0651]

[0652] Step A: To a mixture of l-bromo-4-fluoro-2-iodobenzene (324 mg, 1.08 mmol), disodium carbonate (228 mg, 2.15 mmol), water (1.08 mL), 1,4-dioxane (5.38 mL) was added palladium — triphenylphosphine (1 / 4) (124 mg, 108 pmol) and 2-allyl-4, 4,5,5-tetramethyl-l,3,2-dioxaborolane (606 pL, 3.23 mmol) at room temperature. The mixture was sparged with N2 for 10 minutes and stirred at 80 °C overnight. Additional 2-allyl-4, 4,5,5-tetramethyl-l,3,2-dioxaborolane (606 pL, 3.23 mmol) and palladium — triphenylphosphine (1 / 4) (124 mg, 108 pmol) were added and the mixture was sparged with N2 for 10 minutes. The mixture was stirred at 80 °C for 4 hours. Additional 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (303 pL, 162 mmol), palladium — triphenylphosphine (1 / 4) (62 mg, 54 pmol), and disodium carbonate (114 mg, 1.08 mmol) were added, and the mixture was sparged with N2 for 10 minutes. The reaction was stirred at 80 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica, 0-20% EtOAc / heptane) to afford 2-allyl- 1 -bromo-4-fluorobenzene (113 mg, 525 pmol).1H NMR (400 MHz, CHLOROFORM- / / ) δ 7.49 (dd, J= 8.8, 5.4 Hz, 1H), 6.97 (dd, J= 9.4, 3.1 Hz, 1H), 6.82 (td, J= 8.3, 3.1 Hz, 1H), 5.94 (ddt, J= 16.8, 10.1, 6.6 Hz, 1H), 5.21 - 5.07 (m, 2H), 3.48 (dt, J= 6.6, 1.6 Hz, 2H).Attorney Docket No.: ABR-00125

[0653] Preparation 14 - Synthetic Scheme

[0654] CuI magnesium 2-propanide chloride

[0655]

[0656] THF Preparation 14 - Synthetic Procedure

[0657] F

[0658]

[0659] Step A: 2M magnesium 2-propanide chloride (0.65 mL, 1.3 mmol) was added to a solution of l-bromo-3-fluoro-2-iodobenzene (0.3 g, 997 pmol) in THF (1 mL) at -20 °C. The solution was stirred for 15 minutes, and copper iodide (47.5 mg, 249 pmol) was added. The solution was stirred for 10 minutes and allowed to warm to 0 °C. 3 -bromopropene (172 pL, 1.99 mmol) was added and the reaction was stirred at 0 °C for 30 minutes. The reaction was quenched with sat. aq. NH4CI, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica, 0-10% EtOAc / heptane) to afford 2-allyl- 1 -bromo-3-fluorobenzene (117 mg, 544 pmol).1H NMR (400 MHz, CHLOROFORM-D) δ 7.36 (dt, J= 7.8, 1.2 Hz, 1H), 7.12 - 6.97 (m, 2H), 5.93 (ddt, J= 16.6, 10.3, 6.1 Hz, 1H), 5.12 - 5.05 (m, 2H), 3.58 (dq, J= 5.9, 1.8 Hz, 2H).

[0660] Example 1 - Synthesis of Compound 1

[0661] Synthetic SchemeAttorney Docket No.: ABR-00125

[0662]

[0663] Attorney Docket No.: ABR-00125

[0664] Procedure for Synthesis of Compound 1

[0665]

[0666] (Compound 1)

[0667] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4El-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-L2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyl}carbonyl)-8-methyl-2,3,7,lL14- pentaazahexacyclor22, 3, LI11,14.02,10.04,9.015,201nonacosa-l(28),3, 9,12,15, 17,19,22,24,26- decaen-29-one

[0668] Step A: To a mixture of (3-bromophenyl)hydrazine hydrogen chloride (2.0 g, 9.0 mmol) in ethanol (25 mL) was added DIEA (3.48 g, 27.03 mmol) at 25 °C and stirred for 5 minutes, then tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (3.2 g, 13.5 mmol) was added to the mixture. The resulting mixture was stirred at 80 °C for 3 hr. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (40 mL) and washed with water (50 mL x 3). The aqueous layer was extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine solution (40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-bromophenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.0 g, 4.03 mmol) as a yellow solid. m / z (ESI-pos) M+l = 407.1, 409.1.

[0669] Step B: To a mixture of tert-butyl (S)-3-amino-2-(3-bromophenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.22 g, 3.0 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.31 g, 15.0 mmol) and Na2CO3(636 mg, 6.0 mmol) in DMF / H2O (15 mL / 3 mL) was added Pd(PPh3)4(346 mg, 0.3 mmol) at 25 °C under a N2 atmosphere. The resulting mixture was stirred at 80 °C for 16 hr. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL) and washed with water (50 mL x 3). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combinedAttorney Docket No.: ABR-00125

[0670] organic layers were washed with brine solution (50 mLx 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-50% EtOAc in PE) to give tert-butyl (S)-3-amino-4-methyl-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (845 mg, 1.90 mmol) as a yellow oil. m / z (ESI-pos) M+l = 355.2

[0671] Step C: To a solution of tert-butyl (S)-3-amino-4-methyl-2-(3-vinylphenyl)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (845 mg, 2.38 mmol), N-ethyldiisopropylamine (921 mg, 7.14 mmol) in Tetrahydrofuran (15 mL) was added benzyl chloroformate (742 mg, 4.76 mmol). The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated to give the crude tert-butyl (S)-4-methyl-3-((phenoxycarbonyl)amino)-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.02 g crude) as a yellow oil, which was used directly in the next step, m / z (ESI-pos) M+l = 475.1

[0672] Step D: Crude tert-butyl (S)-4-methyl-3 -((phenoxy carbonyl)amino)-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.02 g, 2.15 mmol) was dissolved in pyridine (15 mL), to which 2, 2-dimethoxy ethylamine (226 mg, 2.15 mmol) was added. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated to give the crude tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo [4,3-c]pyridine-5-carboxylate (1.16 g crude) as a yellow oil, which was directly used for next step, m / z (ESI-pos) M+l = 486.3

[0673] Step E: To a solution of crude tert-butyl (S)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.16 g, 2.39 mmol) in tetrahydrofuran (20 mL) was treated with methanesulfonic acid (1.14 g, 11.95 mmol). The mixture was stirred at 60 °C for 2 hr. Aqueous K3PO4 was added to adjusted pH to about 9, and then tert-butoxy carbonyl -tert-butyl carbonate (781 mg, 3.58 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL, washed with water (30 mL x 2) and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine solution (50 mL) and dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl (S)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.06 mmol) as a yellow solid. M / z (ESI-pos) M+l = 422.2

[0674] Step F: To a solution of tert-butyl (S)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-Attorney Docket No.: ABR-00125

[0675] yl)-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (500 mg, 1.18 mmol) and l-allyl-2 -bromobenzene (301 mg, 1.53 mmol) in N-methyl-2-pyrrolidone (10 mL) were added (1R,2R)-1,2-bis(methylamino)cyclohexane (84 mg, 0.59 mmol), CuI (224 mg, 1.18 μmol) and K2CO3(488 mg, 3.54 mmol). The reaction mixture was heated at 130 °C for 3 hr under the N2. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (30 mL x 3) and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl (S)-3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (360 mg) as a yellow solid, m / z (ESI-pos) M+l = 538.3

[0676] Step G: To a solution of tert-butyl (S)-3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2-(3-vinylphenyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (350 mg, 0.65 mmol) in DCE (350 mL) was added Hoveyda-Grubbs II (350 mg, 0.56 mmol) at 25 °C under N2 protection. The reaction mixture was heated at 80 °C for 3 hr under the N2. The reaction mixture was cooled to ambient temperature and quenched with water (300 mL) and the aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the crude compound. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-8-methyl-29-oxo-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaene-7-carboxylate (248 mg) as a yellow solid, m / z (ESI-pos) M+l = 510.2

[0677] Step H: tert-butyl (S)-8-methyl-29-oxo-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaene-7-carboxylate (80 mg, 0.15 mmol) was dissolved in HCl / l,4-di oxane (4M, 4mL) and stirred at 25°C for Ih. The reaction mixture was directly concentrated under reduced pressure to give (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaen-29-one hydrogen chloride (100 mg, 0.24 mmol) as a yellow solid, m / z (ESI-pos) M+l = 410.1

[0678] Step I: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (65 mg, 0.157 mmol), in dimethylformamide (3 mL) was added DIEA (60 mg, 0.471 mmol) andAttorney Docket No.: ABR-00125

[0679] HATU (89 mg, 0.235 mmol), the mixture stirred at rt for 10 min, then (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaen-29-one hydrogen chloride (100 mg crude, 0.157 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL x 2). The aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude compound and purified by column chromatography (0-10% MeOH in DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]- 1 -[(1 S,2S)-2-m ethyl- 1 -(5 -oxo-4, 5 -dihydro- 1,2,4-oxadiazol-3 -yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaen-29-one (90 mg) as a yellow solid.

[0680] Step J: (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaen-29-one (90 mg, 0.11 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK OJ_3, 3* 150mm, 3um; Mobile Phase: CO2 / MeOH(0.1%DEA)=45 / 55 at 2 mL / min; Temp: 37 °C; Wavelength: 254 nm) to afford the crude Isomer 1 (30 mg, purity: 90%) and Isomer 2 (30 mg, purity: 90%), which was further purified by pre-HPLC [Waters MS-triggered Prep-LC with SQD2 detector, Xbridge 5u C18 150 x l9 mm, eluted with 60-100 % ACN in H2O(0.1%FA)] to give pure Isomer 1(11.6 mg) and Isomer 2 (10.1 mg) as white solids (The absolute configuration was unknown, the configuration of two isomers were assigned arbitrarily).

[0681] Isomer 1: m / z (ESI-pos) M+l = 803.3;1H NMR (400 MHz, DMSO) 8 11.63 (s, 1H) 7.63-7.57 (m, 2H), 7.51-7.45 (m, 3H), 7.39-7.33 (m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 6.72-6.65 (m, 2H), 6.57(d, J = 11.2 Hz, 1H), 5.96-5.90 (m, 1H), 5.64 (s, 1H), 4.43 (s, 1H), 3.73-3.71 (m, 2H), 3.57 (s, 1H), 3.26 (d, J = 8.0 Hz, 3H), 3.00-2.88 (m, 3H), 1.77-1.68 (m, 4H), 1.63-1.50 (m, 5H), 1.27 (s, 3H), 1.24-1.19 (m, 6H).

[0682] Isomer 2: m / z (ESI-pos) M+l = 803.3;1H NMR (400 MHz, DMSO) 6 11.56(s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.56-7.36 (m, 7H), 7.23 (d, J = 8.4Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.96 (s, 1H), 6.86 (s, 1H), 6.75- 6.72 (m, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 11.2 Hz, 1H), 5.99-Attorney Docket No.: ABR-00125

[0683] 5.92 (m, 1H), 5.65 (s, 1H), 4.41 (s, 1H), 3.73-3.70 (m, 2H), 3.60-3.52 (m, 1H), 3.29-3.25 (m, 3H), 2.95-2.86 (m, 3H), 1.80-1.68 (m, 4H), 1.61-1.49 (m, 5H), 1.27 (s, 3H), 1.22-1.12 (m, 6H). (The absolute configuration was unknown, the configuration was assigned arbitrarily) Example 2 - Synthesis of Compound 2

[0684] Synthetic Scheme

[0685]

[0686] Attorney Docket No.: ABR-00125

[0687] Procedure for Synthesis of Compound 2

[0688]

[0689] (Compound 2)

[0690] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4El-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyllcarbonyl)-8-methyl-2,3,7,l 1,14-pentaazahexacyclor22.3. l.1 ",l4.02,l(l.04,9.0l5,2(>]nonacosa-l (28),3,9, l 2,15, 17, 19,24,26-nonaen- 29-one

[0691] Step A: To a solution of tert-butyl (S)-8-methyl-29-oxo-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaene-7-carboxylate (70 mg, 0.13 mmol, from Example 1, step G) in methanol (8 mL) was added Pd / C (35 mg, 50% w / w) at 25 °C. The mixture was evacuated and backfilled with H2 (repeat three times). The mixture was stirred at 25 °C under H2 balloon for 16 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the tertbutyl (S)-8-methyl-29-oxo-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (70 mg) as a yellow solid, m / z (ESI-pos) M+l = 512.2

[0692] Step B: tert-butyl (S)-8-methyl-29-oxo-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (70 mg, 0.14 mmol) was dissolved in HCl / l,4-di oxane (4M, 4mL) and stirred at 25 °C for Ih. The reaction mixture was directly concentrated under reduced pressure to give crude (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (80 mg, 0.19 mmol) as a yellow solid, m / z (ESI-pos) M+l = 412.2 Step C: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (80Attorney Docket No.: ABR-00125

[0693] mg, 0.194 mmol) in DMF (3 mL) was added DIPEA (75 mg, 0.582 mmol) and HATU (110 mg, 0.291 mmol), the mixture stirred at ambient temperature for 10 min, then (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (80 mg crude, 0.19 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (2x). The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude compound and purified by column chromatography (0-10% MeOH in DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one (60 mg) as a yellow solid, m / z (ESI-pos) M+l = 805.3

[0694] Step D: (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one (60 mg, 0.07 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK IA 4.6*250mm, 5um; Mobile Phase: CO2 / EtOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm) to afford the Isomer 1 (30 mg) and Isomer 2 (30 mg), which was further purified by pre-HPLC [Instrument: Waters MS-triggered Prep-LC with SQD2 detector; Column: Xbridge 5u C18 150 x 19 mm; Gradient: eluted with 60-100 % ACN in H2O(0.1%FA)] to give Isomer 1(10.5 mg) and Isomer 2 (12.2 mg) as white solids.

[0695] Isomer 1: m / z (ESI-pos) M+l = 805.3;1H NMR (400 MHz, DMSO) 8 11.59 (s, 1H), 7.50 (s, 1H), 7.43-7.38 (m, 6H), 7.35-7.27 (m, 1H), 7.24-7.19 (m, 2H), 7.15 (s, 1H), 6.88 (s, 1H), 6.60-6.55 (m, 2H), 5.60 (s, 1H), 4.43 (s, 1H), 3.72-3.70 (m, 2H), 3.62-3.55 (m, 1H), 3.02-2.99 (m, 2H), 2.88-2.83 (m, 2H), 2.75-2.68(m, 1H), 2.37-2.29 (m, 1H), 2.15-2.08 (m, 1H), 1.91-1.86(m, 2H), 1.70-1.67 (m, 3H), 1.61-1.49 (m, 6H), 1.31-1.24 (m, 4H), 1.18 (s, 6H).

[0696] Isomer 2: m / z (ESI-pos) M+l = 805.3;1H NMR (400 MHz, DMSO) 6 11.63 (s, 1H), 7.51 (s, 1H), 7.47-7.39 (m, 5H), 7.36-7.28 (m, 2H), 7.25-7.20 (m, 2H), 7.13 (s, 1H), 6.84 (s, 1H), 6.62 (s, 2H), 5.61 (s, 1H), 4.44 (s, 1H), 3.73 (d, J = 7.6 Hz, 2H), 3.63-3.52 (m, 1H), 2.91- 2.73 (m, 5H), 2.37-2.31 (m, 1H), 2.12-2.07 (m, 1H), 1.91-1.85 (m, 3H), 1.72-1.69 (m, 3H), 1.65-1.50 (m, 6H), 1.27 (s, 3H), 1.19 (s, 6H). (The absolute configurationwas unknown, the configuration was assigned arbitrarily)Attorney Docket No.: ABR-00125

[0697] Example 3 - Synthesis of Compound 3

[0698] Synthetic Scheme

[0699] OH

[0700]

[0701] The absolute configuration was unknown,

[0702] the configuration of two atropisomers were assigned arbitrarily

[0703] Procedure for Synthesis of Compound 3

[0704]

[0705] (Compound 3)

[0706] (S)-8-methyl-7-(f l-r(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)cyclopropyl]-5-(tetrahydro-4H-pyran-4-yl)-2-indolyllcarbonyl)-2,3,7,ll,14-pentaazahexacyclor22.3.1.111,14.02,10,04,9.015,201nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen- 29-oneAttorney Docket No.: ABR-00125

[0707] Step A: To a solution of l-((lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl)-5-(tetrahydro-2H-pyran-4-yl)-lH-indole-2-carboxylic acid (466 mg, 1.22 mmol) in dimethylformamide (8 mL) was added DIEA (1.57 g, 12.2 mmol) and HATU (693 mg, 1.82 mmol) at 25 °C, the mixture stirred for 10 min, then (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (500 mg crude, 1.22 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3x). The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude compound and purified by pre-HPLC [Instrument: GILSON Prep LC with UV detector; Column: XBridge Prep C18 19*150mm 5um; Gradient: eluted with 70-95 % ACN in H2O(0.1%FA) in 10 min; Flow rate: 15ml / min] to give (S)-8-methyl-7-({l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro- I,2,4-oxadiazol-3-yl)cyclopropyl]-5-(tetrahydro-4H-pyran-4-yl)-2-indolyl}carbonyl)-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one (225 mg) as a yellow solid

[0708] Step B: (S)-8-methyl-7-({l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-5-(tetrahydro-4H-pyran-4-yl)-2-indolyl}carbonyl)-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one (225 mg, 0.11 mmol) was dissolved in MeOH (140 mL) and separated by chiral supercritical fluid chromatography [separation condition: Daicel CHIRALPAK IA 4.6*250mm, 5um; Mobile Phase: CO2 / MeOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm] to afford Isomer 1 (84.0 mg) and Isomer 2 (104.5 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily). Isomer 1: m / z (ESI-pos) M+l = 777.3;1H NMR (400 MHz, DMSO) δ 11.52 (s, 1H), 7.50 (s, 1H), 7.43-7.39 (m, 6H), 7.35-7.31 (m, 1H), 7.25-7.21 (m, 2H), 7.14 (s, 1H), 6.88 (s, 1H), 6.60-6.55 (m, 2H), 5.66-5.57 (m, 1H), 4.52-4.35 (m, 1H), 3.97-3.94 (m, 2H), 3.66-3.56 (m, 1H), 3.50-3.43 (m, 2H), 2.89-2.81 (m, 3H), 2.72-2.65 (m, 1H), 2.35-2.31 (m, 1H), 2.16-2.08 (m, 1H), 1.93-1.86 (m, 2H), 1.75-1.71 (m, 6H), 1.59-1.48 (m, 4H), 1.30-1.11 (m, 4H). Isomer 2: m / z (ESI-pos) M+l = 777.3;1H NMR (400 MHz, DMSO) 6 11.59 (s, 1H), 7.52 (s, 1H), 7.42-7.39 (m, 5H), 7.38-7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.21-7.19 (m, 1H), 7.13 (s, 1H), 6.90-6.81 (m, 1H), 6.70-6.55 (m, 2H), 5.71-5.57 (m, 1H), 4.56-4.30 (m,Attorney Docket No.: ABR-00125

[0709] 1H), 3.97-3.95 (m, 2H), 3.50-3.44 (m, 3H), 2.86-2.75 (m, 4H), 2.35-2.31 (m, 1H), 2.13-2.06 (m, 1H), 1.91-1.71 (m, 10H), 1.59-1.48 (m, 2H), 1.28-1.13 (m, 4H).

[0710] Example 4 - Synthesis of Compound 4

[0711] Synthetic Scheme

[0712] 1) 6M HCI Fe, NH4Cl NaNO2, H2O NaH, DMF EtOH 1) SnCl2·HCl

[0713]

[0714] Attorney Docket No.: ABR-00125

[0715] Procedure for Synthesis of Compound 4

[0716]

[0717] (Compound 4)

[0718] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyncarbonyl)-8-methyl-22-oxa-2,3,7,l 1,14-pentaazahexacyclor22, 3, l.l11,14.02,10.04,9.015,201nonacosa- 1(28),3,9, 12, 15,17, 19,24,26-nonaen- 29-one

[0719] Step A: To the solution of (2-bromophenyl)methanol (3 g, 16 mmol) in DMF (60 mL, 775 mmol) was added sodium hydride (770 mg, 32.1 mmol) at 0 °C under N2. The reaction stirred at 0 °C for 30 min. Then 1 -(brom omethyl)-3 -nitrobenzene (4.16 g, 19.2 mmol) was added to the mixture. The reaction was allowed to warm to ambient temperature where it stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4CI (20 mL), diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and the aqueous layer was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (0-10% EtOAc in PE) to give 1-bromo-2-(((3-nitrobenzyl)oxy)methyl)benzene (4.7 g, 14.6 mmol) as a yellow oil.

[0720] 1H NMR (400 MHz, DMSO) 88.24 (s, 1H), 8.17 (dd, J= 1.6 Hz, 8.0 Hz, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.56 (dd, J= 1.2 Hz, 7.2 Hz, 1H),7.43 (td, J= 0.8 Hz, 1H), 7.28 (td, J =1.6 Hz, 1H), 4.76 (s, 2H), 4.63 (s, 2H).

[0721] Step B: To a solution of l-bromo-2-(((3-nitrobenzyl)oxy)methyl)benzene (4.7 g, 14.6 mmol) in the ethanol (80 mL) and water (10 mL) was added iron (4.07 g, 72.9 mmol) and ammonium chloride (3.9 g, 72.9 mmol). The reaction was stirred at 80 °C for 2h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (20 mL x 2).Attorney Docket No.: ABR-00125

[0722] The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-6% MeOH in DCM) to give 3-(((2-bromobenzyl)oxy)methyl)aniline (3.7 g, 12.7 mmol) as a colorless oil. m / z (ESI-pos) M+l = 292.0

[0723] Step C: To a solution of 3-(((2-bromobenzyl)oxy)methyl)aniline (3.7 g, 12.7 mmol) in 6M HC1 at 0 °C was added a solution of sodium nitrite (874 mg, 12.7 mmol) in water (103 mL, 5.71 mol) dropwise at 0 °C. The mixture was then stirred at 0 °C for Ih. A solution of SnCl₂ (4.8 g, 25.3 mmol) in HC1 (30 mL) was added dropwise to the reaction mixture and then the mixture was allowed to warm to ambient temperature and stirred for 2h. The pH was adjusted to ~14 with 4N aqueous NaOH. The mixture was diluted with ethyl acetate (40 mL), washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give (3-(((2-bromobenzyl)oxy)methyl)phenyl)hydrazine (3 g, 9.77 mmol) as a yellow oil. m / z (ESI-pos) M+l = 307.0 / 309.0

[0724] Step D: To a solution of (3-(((2-bromobenzyl)oxy)methyl)phenyl)hydrazine (1 g, 3.26 mmol) in Ethanol (30 mL) was added tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (776 mg, 3.26 mmol). The resulting mixture was stirred at 80 °C for 8 hr. The reaction mixture was concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (0-6% MeOH in DCM) to give tert-butyl (S)-3-amino-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.1 g, 2.09 mmol) as a yellow oil. m / z (ESI-pos) M+l = 527.0 / 529.0

[0725] Step E: To a solution of tert-butyl (S)-3-amino-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.1 g, 2.09 mmol) and N-ethyldiisopropylamine (809 mg, 6.26 mmol) in tetrahydrofuran (30 mL) was added benzyl chloroformate (653 mg, 4.17 mmol). The reaction was stirred at 25 °C for 2 hr. The reaction mixture was concentrated to give crude tert-butyl (S)-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.1 g, 1.85 mmol) as a yellow oil, which was used directly for the next step without any further purification, m / z (ESI-pos) M+l = 647.0 / 649.1Attorney Docket No.: ABR-00125

[0726] Step F: Crude tert-butyl (S)-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.1 g, 1.85 mmol) was dissolved in pyridine (50 mL), to which 2,2-dimethoxyethylamine (2 g, 19 mmol) was added. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (0-5% MeOH in DCM) to give tert-butyl (S)-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 2.28 mmol) as a yellow oil. m / z (ESI-pos)M+l = 658.2

[0727] Step G: To a solution of tert-butyl (S)-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 1.98 mmol) in tetrahydrofuran (26 mL) was added methanesulfonic acid (190 mg, 1.98 mmol). The mixture was stirred at 60 °C for 2 hr. Aqueous K3PO4 was added to adjust the pH to about 9, and then tert-butyl -tert-butyl (oxy carbonyloxy )formylate (432 mg, 1.98 mmol) was added and the resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with ethyl acetate (50 mL) washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with IN aqueous HC1 (20 mL), brine (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-80% EA in PE) to give product tert-butyl (4S)-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (970 mg, 1.63 mmol) as a yellow solid, m / z (ESI-pos) M+1 = 594.1

[0728] Step H: A mixture of tert-butyl (4S)-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (570 mg, 959 pmol), Cui (30.5 mg, 479 pmol), (1R,2R)-1,2-bis(methylamino)cyclohexane (205 mg, 1.44 mmol) and dipotassium carbonate (398 mg, 2.88 mmol) in N-methyl-2-pyrrolidone (14 mL) was stirred at 130 °C for 4h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with aq. LiCl solution (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The obtained residue was purified by column chromatography (0-80% EtOAc in PE) to give tert-butyl (S)-8-methyl-29-oxo-22-oxa-2,3,7, 11,14-Attorney Docket No.: ABR-00125

[0729] pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (0.1 g, 195 pmol), which was separated by SFC [Column: Daicel CHIRALCEL ID, 250mm 30 mm ID., 10μmMobile phase: CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]= 50 / 50] to provide isomer 1 (40 mg) and isomer 2 (60 mg) (The absolute configuration was unknown, and assigned arbitrarily), m / z (ESI-pos) M+l = 514.1

[0730] Step I: Isomer 1 from the SFC separation (40 mg, 77.9 pmol) was dissolved in HCl / 1,4-di oxane (4M, ImL) and stirred at 25 °C for Ih. The reaction mixture was directly concentrated to give the crude product (S)-8-methyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (40 mg, 77.4 pmol) as a yellow solid, which was used directly in the next step, m / z (ESI-pos) M+l = 414.2

[0731] Step J: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (39.8 mg, 96.7 pmol) in DMF (4 mL) was added DIPEA (37.5 mg, 290 pmol) and HATU (55.2 mg, 145 pmol), the mixture stirred at ambient temperature for 10 min, then (S)-8-methyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (40 mg, 96.7 pmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (15 mL), washed with water (10 mL x 2). The aqueous layer was extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The obtained residue was purified by prep-HPLC [Instrument: Waters MS-triggered Prep-LC with SQD2 detector; Column: Xbridge 5u C18 150 x 19 mm; Gradient: 75-100 % ACN in H2O(0.1%FA) in 9.5 min; Flow rate: 20mL / min] to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one Isomer 1 (14.5 mg) as a white solid, m / z (ESI-pos) M+l = 807.3;1H NMR (400 MHz, DMSO) 8 11.66 (br, IH), 7.59-7.50 (m, 7H), 7.42 (d, J = 8.4 Hz, IH), 7.30-7,24 (m, 2H), 7.17 (s, IH), 6.90 (s, IH), 6.73 (d, J = 2.0 Hz, IH), 6.58 (d, J = 2.8 Hz, IH), 5.76-5.56 (m, IH), 4.65(dd, JI = 14.4Hz, J2 = 46.8Hz, 2H), 4.51-4.35 (m, IH), 4.18 (dd, Jl= 9.2Hz, J2 = 22.4 Hz, 2H), 3.77 - 3.67 (m, 2H), 3.67-3.54(m, IH), 3.05 - 2.87(m,Attorney Docket No.: ABR-00125

[0732] 3H), 1.84 - 1.51 (m, 10H), 1.29 (s, 3H), 1.13 (s, 6H). (The absolute configuration was unknown, the configuration was assigned arbitrarily)

[0733] Step K: Steps I and J were repeated using Isomer 2 (60 mg, 117 pmol) in place of Isomer 1 to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one Isomer 2 (30.7 mg) as a white solid, m / z (ESI-pos) M+l = 807.3; ¹H NMR (400 MHz, DMSO) δ 11.66 (br, 1H), 7.59-7.50 (m, 7H), 7.42 (d, J = 8.4 Hz, 1H), 7.30-7,24 (m, 2H), 7.17 (s, 1H), 6.90 (s, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 5.76-5.56 (m, 1H), 4.65(dd, JI = 14.4Hz, J2 = 46.8Hz, 2H), 4.51-4.35 (m, 1H), 4.18 (dd, Jl= 9.2Hz, J2 = 22.4 Hz, 2H), 3.77 - 3.67 (m, 2H), 3.67-3.54(m, 1H), 3.05 - 2.87(m, 3H), 1.84 - 1.51 (m, 10H), 1.29 (s, 3H), 1.13 (s, 6H). (The absolute configuration was unknown, the configuration was assigned arbitrarily)Attorney Docket No.: ABR-00125

[0734] Example 5 - Synthesis of Compound 5

[0735] Synthetic Scheme

[0736]

[0737] Attorney Docket No.: ABR-00125

[0738] Procedure for Synthesis of Compound 5

[0739]

[0740] (Compound 5)

[0741] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4El-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-L2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyl}carbonyl)-8-methyl-2,3,7,lL14- pentaazahexacyclor23, 3, LI11,14.02,10.04,9.015,201triaconta-l(29),3, 9,12,15, 17,19,22,25,27- decaen-30-one

[0742] Step A: To a mixture of tert-butyl (S)-3-amino-2-(3-bromophenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 3.68 mmol, from Example 1 step A), 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (805 mg, 4.79 mmol) and CsF (1.68 g, 11.0 mmol) in THF (20 mL) was added Pd(PPh3)4 (213 mg, 0.184 mmol) at 25 °C under N2 protection. The resulting mixture was stirred at 80 °C for 16 hr and then cooled down to room temperature^ diluted with ethyl acetate (50 mL), washed with water (50 mL x 3). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated to give the crude compound. The crude compound was purified by column chromatography (0-50% EtOAc in PE) to give tert-butyl (S)-2-(3-allylphenyl)-3-amino-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1100 mg, 2.69 mmol) as a yellow oil. m / z (ESI-pos) M+l = 369.2

[0743] Step B: To a solution of tert-butyl (S)-2-(3-allylphenyl)-3-amino-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1100 mg, 2.98 mmol), DIPEA (1156 mg, 8.94 mmol) in Tetrahydrofuran (15 mL) was added benzyl chloroformate (929 mg, 5.96 mmol). The reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was directly concentrated under reduced pressure to give the crude tert-butyl (S)-2-(3-allylphenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-Attorney Docket No.: ABR-00125

[0744] carboxylate (1.3 g crude) as a yellow oil, which was used directly in the next step without any further purification, m / z (ESI-pos) M+l = 489.2

[0745] Step C: Crude tert-butyl (S)-2-(3-allylphenyl)-4-methyl-3 -((phenoxy carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 2.66 mmol) was dissolved in pyridine (15 mL) and then 2, 2-dimethoxy ethylamine (279 mg, 2.66 mmol) was added. The mixture was stirred at 25 °C for 3 hr and directly concentrated under reduced pressure to give the crude residue (1.5 g) as a yellow oil, which was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl (S)-2-(3-allylphenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.2 g, 2.40 mmol) as a yellow solid, m / z (ESI-pos) M+l = 500.2

[0746] Step D: To a solution of tert-butyl (S)-2-(3-allylphenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.2 g, 2.40 mmol) in THF (20 mL) was added methanesulfonic acid (1.15 g, 12.02 mmol). The mixture was stirred at 60 °C for 2 hr and cooled to ambient temperature. Aqueous K3PO4 was added to the reaction mixture to adjust pH to ~9, tert-butoxycarbonyl -tert-butyl carbonate (784 mg, 3.60 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with ethyl acetate (40 mL), washed with water (30 mL x 2) and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. Filtered and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl (S)-2-(3-allylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (1.0 g, 2.29 mmol) as a yellow solid, m / z (ESI-pos) M+l = 436.2 Step E: To a solution of tert-butyl (S)-2-(3-allylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1000 mg, 2.29 mmol) and l-allyl-2-bromobenzene (583 mg, 2.97 mmol) in NMP (10 mL) were added (1R,2R)-1,2-bis(methylamino)cyclohexane (325 mg, 2.29 mmol), Cui (436 mg, 2.29 mmol) and K2CO3(948 mg, 6.87 mmol). The reaction mixture was heated at 130 °C for 3 hr under N2. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (30 mL x 3) and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-80% EtOAc in PE) to give tert-butyl (S)-2-(3-allylphenyl)-3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-Attorney Docket No.: ABR-00125

[0747] imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (507 mg) as a yellow solid, m / z (ESI-pos) M+l = 552.2

[0748] Step F: To a solution of tert-butyl (S)-2-(3-allylphenyl)-3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (507 mg, 0.92 mmol) in DCE (507 mL) was added Hoveyda-Grubbs II (507 mg, 0.81 mmol) at 25 °C under N2 atmosphere. The reaction mixture was then heated at 80 °C for an additional 3 hr under N2. The reaction mixture was then concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-8-methyl-30-oxo-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaene-7-carboxylate (400 mg, 83% yield) as a yellow solid, m / z (ESI-pos) M+l = 524.2 Step G: tert-butyl (S)-8-methyl-30-oxo-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaene-7-carboxylate (190 mg, 0.36 mmol) was dissolved in HCl / l,4-di oxane (4M, 4mL) and stirred at 25 °C for Ih. The reaction mixture was concentrated under reduced pressure to give (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaen-30-one hydrogen chloride (190 mg crude, 0.42 mmol) as a yellow solid, m / z (ESI-pos) M+l = 424.2

[0749] Step H: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (110 mg, 0.26 mmol) in DMF (3 mL) were added DIEA (335 mg, 2.6 mmol) and HATU (152 mg, 0.40 mmol), the mixture stirred at ambient temperature for 10 min, then (S)-8-methyl- 2.3.7.11.14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaen-30-one hydrogen chloride (113 mg crude, 0.26 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight and then diluted with ethyl acetate (30 mL) and washed with water (30 mL x 2). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-10% MeOH in DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl- 2.3.7.11.14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaen-30-one (120 mg) as a yellow solid, m / z (ESI-pos) M+l = 817.3Attorney Docket No.: ABR-00125

[0750] Step I: (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaen-30-one (120 mg, 0.14 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK IA 4.6*250mm, 5um; Mobile Phase: C02 / MeOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm) to afford the Isomer 1 (20 mg) and Isomer 2 (50 mg), which were further purified by prep-HPLC [Waters MS-triggered Pre LC with QDA detector, Welch 21.2*250mm lOum C18, eluted with 60-100 % ACN in H2O(0.1%NH3)] to give pure Isomer 1 (11.86 mg) and Isomer 2 (33.37 mg) as white solids The absolute configuration was unknown, the configuration was assigned arbitrarily).

[0751] Isomer 1: m / z (ESI-pos) M+l = 817.3;1H NMR (400 MHz, DMSO) 8 11.62 (s, 1H), 7.54-7.50 (m, 2H), 7.40-7.32 (m, 6H), 7.25-7.15 (m, 3H), 6.97-6.85 (m, 4H), 6.54 (d, J = 3.2 Hz, 1H), 5.61-5.46 (m, 2H), 5.33-5.23 (m, 1H), 4.41 (s, 1H), 3.73-3.68 (m, 2H), 3.59-3.51 (m, 1H), 3.42-3.38 (m, 1H), 3.28-3.24 (m, 2H), 2.88-2.82 (m, 1H), 1.71-1.63 (m, 4H), 1.57-1.47 (m, 4H), 1.32-1.24 (m, 6H), 1.18 (s, 6H).

[0752] Isomer 2: m / z (ESI-pos) M+l = 817.3;1H NMR (400 MHz, DMSO) 6 11.57 (s, 1H), 7.55-7.50 (m, 2H), 7.39-7.30 (m, 7H), 7.25-7.21 (m, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 6.85-6.56 (m, 3H), 5.54-5.47 (m, 2H), 5.34-5.27 (m, 1H), 4.42 (s, 1H), 3.76-3.71 (m, 2H), 3.66-3.59 (m, 1H), 3.45-3.33 (m, 2H), 3.29-3.24 (m, 2H), 2.99-2.88 (m, 2H), 1.73-1.67 (m, 4H), 1.62-1.49 (m, 5H), 1.27 (s, 3H), 1.18 (s, 6H).

[0753] Example 6 - Synthesis of Compound 6

[0754] Synthetic SchemeAttorney Docket No.: ABR-00125

[0755]

[0756] (Compound 6)

[0757] 3-((lS,2S)-l-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((2-S)-2--methyl-3--oxo- 2-,2-,2-,2-,3-,3--hexahydro-2-H,3-H-2(2,3)-pyrazolor4,3-c1pyridina-3(l,3)-imidazola- (1, 3 ),4 1,2)-dibenzenacyclooctaphane-2--carbonyl)- IH-indol- 1 -yl)-2-methylcyclopropyl)- l,2,4-oxadiazol-5(4H)-oneAttorney Docket No.: ABR-00125

[0758] Step A: To a solution of tert-butyl (S)-8-methyl-30-oxo-2,3,7,ll,14-pentaazahexacyclo[23.3. Ll11,14.02,1004,9.015,20]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaene-7-carboxylate (210 mg, 0.40 mmol) in methanol (10 mL) was added Pd / C (105 mg) at 25 °C followed by the introduction of a H2 atmosphere. The mixture was stirred at 25 °C for 16 hr. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure to give tert-butyl (S)-8-methyl-30-oxo-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (150 mg, 0.28 mmol) as a yellow solid, m / z (ESI-pos) M+l = 526.3 Step B: tert-butyl (S)-8-methyl-30-oxo-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (140 mg, 0.26 mmol) was dissolved in HCl / l,4-di oxane (4M, 4mL) and stirred at 25 °C for Ih. The reaction mixture was directly concentrated under reduced pressure to give crude (S)-8-methyl-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one hydrogen chloride (150 mg, 0.32 mmol) as a yellow solid, m / z (ESI-pos) M+l = 426.2 Step C: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (87 mg, 0.21 mmol) in DMF (3 mL) was added DIEA (114 mg, 0.88 mmol) and HATU (114 mg, 0.88 mmol), the mixture stirred at ambient temperature for 10 min, then (S)-8-methyl- 2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta- 1(29), 3, 9, 12, 15, 17,19,25,27-nonaen-30-one hydrogen chloride (75 mg crude, 0.17 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL x 2). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound and purified by column chromatography (0-10% MeOH in DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl- 2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one (100 mg) as a yellow solid, m / z (ESI-pos) M+l = 819.4

[0759] Step D: (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl- 2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-Attorney Docket No.: ABR-00125

[0760] 1(29), 3, 9, 12, 15, 17,19,25,27-nonaen-30-one (100 mg, 0.12 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK IA 4.6*250mm, 5um; Mobile Phase: CO2 / EtOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm) to afford crude Isomer 1 ( 20 mg) and Isomer 2 (30 mg), which was further purified by prep-HPLC [Waters MS-triggered Prep-LC with SQD2 detector, Xbridge 5u C18 150 x 19 mm, eluted with 60-100 % ACN in H2O(0.1%FA)] to give Isomer 1(10.23 mg) and Isomer 2 (18.88 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily). Isomer 1: m / z (ESI-pos) M+l = 819.4;1H NMR (400 MHz, DMSO) 8 11.56 (s, 1H), 7.53-7.48 (m, 1H), 7.44-7.38 (m, 3H), 7.36-7.33 (m, 2H), 7.30-7.18 (m, 4H), 7.00-6.96 (m, 1H), 6.85- 6.69 (m, 3H), 5.60 (s, 1H), 4.40 (s, 1H), 3.76-3.71 (m, 2H), 3.59-3.52 (m, 1H), 2.92-2.85 (m, 1H), 2.75-2.62 (m, 3H), 1.84-1.76 (m, 2H), 1.71-1.68 (m, 4H), 1.62-1.46 (m, 7H), 1.32-1.24 (m, 7H), 1.19 (s, 6H).

[0761] Isomer 2: m / z (ESI-pos) M+l = 819.4;1H NMR (400 MHz, DMSO) 6 11.41 (s, 1H), 7.55-7.50 (m, 1H), 7.47-7.40 (m, 3H), 7.38-7.35 (m, 2H), 7.29-7.20 (m, 4H), 7.02-6.98 (m, 1H), 6.90- 6.70 (m, 3H), 5.61 (s,lH), 4.40 (s, 1H), 3.74-3.72 (m, 2H), 3.62-3.47 (m, 1H), 2.95-2.85 (m, 1H), 2.75-2.63 (m, 3H), 1.85-1.77 (m, 2H), 1.73-1.70 (m, 4H), 1.67-1.41 (m, 7H), 1.32-1.26 (m, 7H), 1.20 (s, 6H)Attorney Docket No.: ABR-00125

[0762] Example 7 - Synthesis of Compound 7

[0763] Synthetic Scheme

[0764] SFC

[0765]

[0766] Attorney Docket No.: ABR-00125

[0767] Procedure for Synthesis of Compound 7

[0768]

[0769] (Compound 7)

[0770] (S)-7-(I5-l(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl1-l-l(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-L2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyHcarbonyl)-8-methyl-21-oxa-2,3,7,l 1,14- pentaazahexacyclor23.3. Ll11,14.02,10.04,9.015,201triaconta-l(29),3,9,12,15,17,19,25,27-nonaen- 30-one

[0771] Step A: To a solution of 3-(3-aminophenyl)propionic acid (3 g, 18.2 mmol) in THF (30 mL) was added Borane-methyl sulfide complex (21.8 mL, 21.8 mmol) at 0 °C. After addition, the mixture was allowed to warm to ambient temperature and stirred for 12 h. The reaction solution was quenched carefully by H2O (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-50% EtOAc in PE) to give 3 -(3 -aminophenyl)- 1 -propanol (2 g, 11.9 mmol, 73% yield) as colorless oil. m / z (ESI-pos) M+l = 152.2

[0772] Step B: A solution of 3 -(3 -aminophenyl)- 1 -propanol (2 g, 11.9 mmol) in conc. HCl (4.5 mL) and H2O (4.5 mL) at 0 °C was added NaNO2 (904 mg, 13.1 mmol) in H2O (6 mL) dropwise. After the mixture was stirred at 0 °C for 1 hour, SnCl₂ (4.97 g, 26.2 mmol) in cone. HC1 (4.5 mL) and H2O (4.5 mL) was added. The mixture was stirred at ambient temperature for another 1 hour. The reaction mixture was quenched with aqueous NaOH (10 N, 12 mL) to adjust pH to ~8-9 and the mixture was extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-100% EtOAc in PE), to give 3-(3-hydrazineylphenyl)propan-l-ol (1.3 g, 7.04 mmol, 59% yield) as a yellow solid, m / z (ESI-pos) M+l = 167.1Attorney Docket No.: ABR-00125

[0773] Step C: To a solution of 3-(3-hydrazineylphenyl)propan-l-ol (1.25 g, 6.77 mmol) in EtOH (20 mL) was added tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (1.94 g, 8.12 mmol) and the mixture was stirred at 80 °C for 16 hours. The mixture was concentrated and the crude was purified by column chromatography (0-100 EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-(3-hydroxypropyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 3.36 mmol, 45% yield) as a yellow solid, m / z (ESI-pos) M+l = 387.2;1H NMR (400MHz, CDC13) 87.40 - 7.32 (m, 3H), 7.18 (d, J = 7.2Hz, 1H), 5.21-5.03 (m, 1H), 4.41-4.24 (m, 1H), 3.72 (s, 1H), 3.65 (t, J = 6.4Hz, 2H), 3.12 (s, 1H), 2.78- 2.74 (m, 2H), 2.69 (s, 2H), 1.93-1.86 (m, 2H), 1.50 (s, 9H), 1.35 (d, J = 6.8Hz, 3H).

[0774] Step D: To a solution of tert-butyl (S)-3-amino-2-(3-(3-hydroxypropyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 3.03 mmol) in CH2CI2 (26 mL) was added tert-butyl(chloro)bis(phenyl)silane (832 mg, 3.03 mmol) and imidazole (412 mg, 6.05 mmol). The mixture was stirred at 20 °C for 16 hours and then quenched with water (15 mL), extracted with CH2CI2 (2 x 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 2.28 mmol, 75% yield) as a light yellow solid. m / z (ESI-pos) M+l = 625.2;1HNMR(400MHz, MeOD) 67.66-7.63 (m, 4H), 7.43 - 7.28 (m, 9H), 7.18 (d, J = 7.6Hz, 1H), 5.15 (q, J = 6.4Hz, 1H), 4.27 (s, 1H), 3.68 (t, J = 6.4Hz, 2H), 3.14 (s, 1H), 2.80 (t, J = 7.2Hz, 2H), 2.61-2.57 (m, 2H), 1.93 - 1.85 (m, 2H), 1.50 (s, 9H), 1.35 (d, J = 6.4Hz, 3H), 1.04 (s, 9H)

[0775] Step E: To a solution of tert-butyl (S)-3-amino-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (1.5 g, 2.28 mmol) in tetrahydrofuran (15 mL) at 0 °C was added N-ethyldiisopropylamine (884 mg, 6.84 mmol) and benzyl chloroformate (714 mg, 4.56 mmol) and the mixture solution was stirred at 20 °C for 2 hours. Then the mixture was concentrated to provide crude tert-butyl (S)-2-(3-(3-((tert-butyldiphenyl silyl)oxy)propyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1900 mg, 2.04 mmol) as a light yellow solid, which was used directly in the next step without further purification.. m / z (ESI-pos) M+l = 745.3

[0776] Step F: To a solution of tert-butyl (S)-2-(3-(3-((tert-butyldiphenyl silyl)oxy)propyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.9 g, 2.04 mmol) in pyridine (20 mL) was added 2,2-Attorney Docket No.: ABR-00125

[0777] dimethoxyethylamine (644 mg, 6.12 mmol) and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to provide the crude product, which was purified by column chromatography (0-50% EtOAc in PE) to give tert-butyl (S)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 1.63 mmol, 72% yield over 2 steps) as a white solid, m / z (ESI-pos) M+l = 756.3

[0778] Step G: To a solution of tert-butyl (S)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 1.63 mmol) in THF (20 mL) was added methanesulfonic acid (173 mg, 1.8 mmol). The mixture was stirred at 60 °C for 2 hr. Aqueous K3PO4 was added to adjust the pH to ~9, and then BOC2O (71.1 mg, 0.33 mmol) was added, and the resulting mixture was stirred at 25 °C for 2 hrs. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL x 2) and the aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (1000 mg, 1.3 mmol) as a yellow solid, m / z (ESI-pos) M+l = 692.3;1HNMR(400MHz, DMSO) 8 10.33 (s, 1H), 7.62 - 7.60 (m, 4H), 7.48 - 7.40 (m, 6H), 7.31 (t, J = 8.0Hz, 1H), 7.21 (s, 1H), 7.15 - 7.13 (m, 2H), 6.51 (t, J = 2.4Hz, 1H), 6.48 (s, 1H), 5.07 (s, 1H), 4.20 (s, 1H), 3.64 (t, J = 6.0Hz, 2H), 3.11 (s, 1H), 2.74 - 2.63 (m, 4H), 1.83 - 1.76 (m, 2H), 1.43 (s, 9H), 1.13 (d, J = 6.4 Hz, 3H), 1.01 (s, 9H).

[0779] Step H: To a solution of o-bromophenol (2 g, 11.6 mmol) in DCM (20 mL) at 0 °C was added DIPEA (3.14 g, 24.3 mmol) and bromomethoxymethane (1.73 g, 13.9 mmol). The mixture was allowed to warm to ambient temperature and stirred for 4 hours. Water (50 mL) was added and the mixture was extracted with DCM (2 x 100 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (0-10% EtOAc in PE) to give l-bromo-2-(methoxymethoxy)benzene (2.2 g, 9.63 mmol) as a colorless oil^HNMR (400MHz, CDCI3) 67.55-7.53 (m, 1H), 7.27-7.22 (m, 1H), 7.16-7.14 (mlH), 6.91-6.87 (m, 1H), 5.25 (s, 2H), 3.52 (s, 3H).

[0780] Step I: To a solution of (S)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-Attorney Docket No.: ABR-00125

[0781] c]pyridine-5 -carboxylate (0.9 g, 1.17 mmol) in NMP (34.1 mL) was added l-bromo-2-(methoxymethoxy)benzene (508 mg, 2.34 mmol), Cuprous iodide (111 mg, 585 pmol), trans-(lR,2R)N, N'-Dimethyl-cyclohexane-l,2-diamine (167 mg, 1.17 mmol) and K2CO3(485 mg, 3.51 mmol). The resulting mixture was stirred under N2 at 130 °C for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with water (80 mL), extracted with EtOAc (200 mL). The combined organics were washed with aqueous LiCl (3x50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give tert-butyl (4S)-2-(3 -(3 -((tert-butyl diphenyl silyl)oxy)propyl)phenyl)-3 -(3 -(2-(methoxymethoxy)phenyl)-2-oxo-2, 3-dihydro-lH-imidazol-l-yl)-4-methyl-2, 4,6, 7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (820 mg, 891 pmol) as a white solid, m / z (ESI-pos) M+l = 828.3

[0782] Step J: To a solution of tert-butyl (4S)-2-(3-(3-((tert-butyldiphenylsilyl)oxy)propyl)phenyl)-3-(3-(2-(methoxymethoxy)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.8 g, 869 pmol) in THF (30 mL) at 0 °C was added TBAF (1.0 M in THF, 1.3 mL, 1.3 mmol) and the mixture was allowed to warm to ambient temperature and stirred for 2 hours. Water (20 mL) was added and the mixture was extracted with EtOAc (3x20 mL). The organics were dried over anhydrous Na₂SO₄, filtered and concentrated to provide the crude product, which was purified by column chromatography (0-100% EtOAc in PE) to tert-butyl (4 S)-2-(3 -(3 -hy droxypropyl)phenyl)-3 -(3 -(2-(methoxymethoxy)phenyl)-2-oxo-2, 3 -dihydro-lH-imidazol-l-yl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (520 mg, 794 pmol) as a white solid, m / z (ESI-pos) M+l = 590.2

[0783] Step K: A solution of tert-butyl (4S)-2-(3-(3-hydroxypropyl)phenyl)-3-(3-(2-(methoxymethoxy)phenyl)-2-oxo-2, 3-dihydro-lH-imidazol-l-yl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (520 mg, 794 pmol) in HCl / l,4-di oxane (4M, 10 mL) was stirred at 25 °C for 1 hour. Then directly concentrated under vacuum. The residue was diluted with DCM (15 mL) and aqueous K₃PO₄ was added to adjusted pH to ~9, then BOC2O (207.7 mg, 0.95 mmol) was added. The resulting mixture was stirred at 25 °C for 2 hrs. Water (10 mL) was added and the mixture was extracted with EtOAc (3x100 mL), The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give tertbutyl (4 S )- 3 -(3 -(2-hy droxyphenyl)-2-oxo-2, 3 -dihydro- 1 H-imidazol- 1 -y 1 ) -2 -(3 -(3 -hydroxypropyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (330 mg, 544 pmol) as a white solid, m / z (ESI-pos) M+l = 546.3; 'HAttorney Docket No.: ABR-00125

[0784] NMR(400MHz, DMSO) 6 9.96 (s, 1H), 7.38-7.33 (m, 1H), 7.23 - 7.20 (m, 5H), 6.99 (d, J = 7.2Hz, 1H), 6.89 - 6.85 (m, 2H), 6.78 (s, 1H), 5.14 (s, 1H), 4.49 (s, 1H), 4.22 (s, 1H), 3.39 (s, 2H), 3.14 (s, 1H), 2.76-2.61 (m, 4H), 1.71 - 1.67 (m, 2H), 1.44 (s, 9H), 1.21 (d, J = 6.0Hz, 3H).

[0785] Step L: To a solution of tert-butyl tert-butyl (4S)-3-(3-(2-hydroxyphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-(3-hydroxypropyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (290 mg, 478 pmol) in THF (29 mL) at 0 °C was added PPhs (314 mg, 1.2 mmol) and DIAD (242 mg, 1.2 mmol) under N2 atmosphere. The mixture was stirred at 60 °C under N2 for 2 hours. The reaction was cooled to ambient temperature and quenched with water (100 mL), extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-45% EtOAc in PE) to give tert-butyl (S)-8-methyl-30-oxo-21-oxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (185 mg, 316 pmol) as a white solid, m / z (ESI-pos)M+l = 528.2

[0786] Step M: A solution of tert-butyl (S)-8-methyl-30-oxo-21-oxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (0.1 g, 171 pmol) in HCl / l,4-di oxane (4M, 2 mL) was stirred at ambient temperature for 1 hour. The mixture was concentrated to give (S)-8-methyl-21-oxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-1(29), 3, 9, 12, 15, 17,19,25,27-nonaen-30-one hydrogen chloride (80 mg, 168 pmol) as a white solid, m / z (ESI-pos) M+l = 428.1

[0787] Step N: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (69.3 mg, 168 pmol) in DMF (1 mL) was added DIEA (87.1 mg, 674 pmol) and HATU (96.1 mg, 253 pmol). The mixture was stirred at ambient temperature for 30 mins, and then (S)-8-methyl-21-oxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one hydrogen chloride (80 mg, 168 pmol)inDMF (0.5 mL) was added. The resulting mixture was stirred for 16 hours. Water (50 mL) was added and the reaction mixture was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-5% MeOH in DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-21-oxa-2,3,7,l 1,14-Attorney Docket No.: ABR-00125

[0788] pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one (110 mg, 114 pmol) as a white solid, m / z (ESI-pos) M+l = 821.3

[0789] Step O: (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-21-oxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1° 04,9.015,2O]triaconta- 1(29), 3,9,12,15,17,19,25,27 -nonaen-30-one (110 mg, 114 pmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK IA-H, 250mm x 30 mm I. D., 10pm; Mobile Phase: CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]= 50 / 50 at 120 g / min; Temp: 35 °C; Wavelength: 214 nm) to afford the crude Isomer 1 (30 mg) and Isomer 2 (60 mg), which were further purified by prep-HPLC [Waters MS-triggered Prep-LC with SQD2 detector, Xbridge 5uC18 150x l9 mm, eluted with 80-100 % ACN inH2O(0.1%FA)] to give pure Isomer 1(18.5 mg) and Isomer 2 (34.6 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0790] Isomer 1: m / z (ESI-pos) M+l = 821.3;1H NMR (400 MHz, DMSO) 8 11.59 (s, 1H), 7.50 -7.45 (m, 2H), 7.42-7.38 (m, 4H), 7.24-7.22 (m, 1H), 7.20-7.17 (m, 2H), 7.11 (s, 1H), 7.08 -7.05 (m, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 6.59 (d, J = 2.4Hz, 1H), 5.59 (s, 1H), 4.42 (s, 1H), 3.91-3.87 (m, 2H), 3.73 - 3.70 (m, 2H), 3.59 (s, 1H), 3.02-2.98 (m, 2H), 2.89 - 2.80 (m, 2H), 2.75 - 2.68 (m, 1H), 2.15 - 2.11 (m, 1H), 2.04 - 1.98 (m, 2H), 1.70-1.67 (m, 3H), 1.62 - 1.55 (m, 2H), 1.53 (d, J = 4.0Hz, 3H), 1.27-1.25 (m, 6H), 1.19 (s, 4H).

[0791] Isomer 2: m / z (ESI-pos) M+l = 821.3;1H NMR (400 MHz, DMSO) 6 11.66 (s, 1H), 7.51 (s, 1H), 7.47-7.45 (m, 1H), 7.42-7.39 (m3H), 7.37 - 7.34 (m, 1H), 7.24 (d, J = 8.8Hz, 1H), 7.18 (d, J = 5.6 Hz, 3H), 7.08 (t, J = 7.6Hz, 1H), 6.84 (s, 1H), 6.68-6.59 (m, 2H), 5.60 (s, 1H), 4.42 (s, 1H), 3.94-3.89 (m, 1H), 3.83 - 3.78 (m, 1H), 3.73 - 3.71 (m, 2H), 3.58 (s, 1H), 3.03 - 2.99 (m, 2H), 2.90 - 2.79 (m, 2H), 2.76 - 2.70 (m, 1H), 2.17 - 1.98 (m, 3H), 1.74 - 1.68 (m, 3H), 1.65 - 1.56 (m, 2H), 1.51 (d, J= 13.2Hz, 3H), 1.28 - 1.25 (m, 4H), 1.19 (s, 6H).

[0792] Example 8 - Synthesis of Compound 8

[0793] Synthetic SchemeAttorney Docket No.: ABR-00125 TBDPSCI

[0794] □Imidazole' DCM HO-— °TBDPSDIAD, PPh3, THF

[0795]

[0796] Procedure for Synthesis of Compound 8Attorney Docket No.: ABR-00125

[0797]

[0798] (Compound 8)

[0799] (S)-7-({ 5 -l(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl1- 1-1(1 S,2S)-2-methyl- 1 -(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyHcarbonyl)-8-methyl-21,24-dioxa- 2,3,7, 1 l,14-pentaazahexacyclol23.3,1,111,14.02,10. 04,9.015,20]triaconta- 1(29),3, 9,12,15, 17,19,25, 27-nonaen-30-one

[0800] Step A: A solution of 3-aminophenol (5 g, 45.8 mmol) in cone. HC1 (50 mL) at 0 °C was treated with NaNC>2 (3.48 g, 50.4 mmol) in H2O (25 mL) dropwise. After the mixture was stirred for 25 mins, SnCl2(19.1 g, 101 mmol) in cone. HC1 (25 mL) was added dropwise and the mixture was stirred for 1 hour. The reaction was quenched with aqueous NaOH (ION, 90 mL) to adjust pH to about 9. Then the mixture was extracted with EtOAc (3 x 500 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give 3-hydrazineylphenol (2.8 g, 20.3 mmol) as a yellow solid, m / z (ESI-pos) M+l = 125.2;1H NMR(400MHz, DMSO) 88.90 (s, 1H), 6.84 (t, J = 7.6Hz, 1H), 6.51 (s, 1H), 6.23 (t, J = 2.0Hz, 1H), 6.19-6.17 (m, 1H), 6.01-5.98 (m, 1H), 3.91 (s, 2H).

[0801] Step B: To a solution of 3-hydrazinophenol (1.4 g, 10.1 mmol) in EtOH (30 mL) was added tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (2.42 g, 10.1 mmol). The mixture was stirred at 80 °C for 16 hours and then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-hydroxyphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.6 g, 6.79 mmol) as a yellow solid, m / z (ESI-pos) M+l = 345.1

[0802] Step C: To a solution of tert-butyl (S)-3-amino-2-(3-hydroxyphenyl)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1 g, 2.61 mmol) in CH2CI2 (20 mL) atAttorney Docket No.: ABR-00125

[0803] 0 °C was added imidazole (356 mg, 5.23 mmol) and tert-butyl(chloro)bis(phenyl)silane (790 mg, 2.87 mmol). The mixture was allowed to stir at ambient temperature for 2 hours. The reaction was quenched with H2O (50 mL), extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 2.32 mmol) as a yellow solid. / ?? z (ESI-pos) M+l = 583.3

[0804] Step D: To a solution To a solution of tert-butyl (S)-3-amino-2-{m-[tert-butylbis(phenyl)siloxy]phenyl}-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (1.5 g, 2.32 mmol) in THF (20 mL) at 0 °C were added DIEA (898 mg, 6.95 mmol) and benzyl chloroformate (725 mg, 4.63 mmol). The mixture was allowed to stir at ambient temperature for 2 hours and then concentrated under vacuum to provide crude tert-butyl (S)-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.7g) as a light yellow solid, which was directly used in next step without further purification, m / z (ESI-pos) M+1 = 703.3

[0805] Step E: To a solution of tert-butyl (S)-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.7 g, 2.3 mmol) in pyridine (20.8 mL) was added 2, 2-dimethoxy ethylamine (727 mg, 6.91 mmol) and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to provide the crude product, which was purified by column chromatography (0-50% EtOAc in PE) to give tert-butyl (S)-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.6 g, 2.02 mmol) as a white solid, m / z (ESI-pos) M+l = 714.3

[0806] Step F: To a solution of tert-butyl (S)-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-3-(3-(2, 2-dimethoxy ethyl)ureido)-4-methyl-2, 4, 6, 7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.6 g, 2.02 mmol) in THF (30 mL) was added methanesulfonic acid (194 mg, 2.02 mmol) and the mixture was stirred at 60 °C for 1 hour. The reaction was quenched by the addition of H2O (50 mL) and the mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give tertbutyl (4S)-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.2 g, 1.66 mmol) as a white solid, m / z (ESI-pos) M+l = 650.3Attorney Docket No.: ABR-00125

[0807] Step G: To a solution of ethylene glycol (2 g, 32.2 mmol) in CH2CI2 (20 mL) was added tert-butyl(chloro)bis(phenyl)silane (8.86 g, 32.2 mmol) and imidazole (4.39 g, 64.4 mmol). The mixture was stirred at ambient temperature for 16 hours. The reaction was quenched with water (50 mL), extracted with CH2CI2 (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give 2-[tert-butylbis(phenyl)siloxy]ethanol (4 g, 12 mmol) as colorless oil. m / z (ESI-pos) M+1 = 323.1;1H NMR(400MHz, CDC13) 8 7.68 - 7.66 (m, 4H), 7.46 - 7.37 (m, 6H), 3.78-3.75 (m, 2H), 3.69-3.67 (m, 2H), 2.15-2.11 (m, 1H), 1.08-1.07 (m, 9H).

[0808] Step H: To a solution of 2-[tert-butylbis(phenyl)siloxy]ethanol (2 g, 5.99 mmol) in THF (20 mL) was added o-bromophenol (1.04 g, 5.99 mmol) and triphenylphosphine (3.14 g, 12 mmol) at 0 °C under N2 atmosphere. Then isopropyl(oxycarbonylamino) 2-propanecarbamate (2.42 g,12 mmol) was added dropwise. The resulting mixture was allowed to warm to ambient temperature and stir for 2 hours. The reaction was quenched with water (50 mL), extracted with CH2CI2 (2 x 100 mL). The combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give (2-(2-bromophenoxy)ethoxy)(tert-butyl)diphenylsilane (1.2 g, 2.37 mmol) as colorless oil.1H NMR (400MHz, CDCI3) 6 7.74-7.72 (m, 4H), 7.55-7.53 (m, 1H), 7.43-7.36 (m, 6H), 7.24 - 7.20 (m, 1H), 6.89 - 6.80 (m, 2H), 4.16 (t, J = 5.2Hz, 2H), 4.03 (t, J = 5.2Hz, 2H), 1.07-1.05 (m, 9H).

[0809] Step I: To a solution of tert-butyl (4S)-2-(3-((tert-butyldiphenylsilyl)oxy)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (1.1 g, 1.52 mmol) in NMP (20 mL) was added (2-(2-bromophenoxy)ethoxy)(tert-butyl)diphenylsilane (1.04 g, 2.29 mmol), copper iodide (145 mg, 762 pmol), (lS,2S)-l,2-bis(methylamino)cyclohexane (217 mg, 1.52 mmol) and K2CO3(632 mg, 4.57 mmol). The mixture was stirred at 130 °C for 3 hours. The reaction was cooled to ambient temperature and quenched with water (100 mL), extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with aqueous LiCl (2 x 50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (4S)-3-(3-(2-(2-hydroxyethoxy)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-hydroxyphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.5 g, 822 pmol) as a white solid, m / z (ESI-pos) M+l = 548.3Attorney Docket No.: ABR-00125

[0810] Step J: To a solution of tert-butyl (4S)-3-(3-(2-(2-hydroxyethoxy)phenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-hydroxyphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.5 g, 822 pmol) in THF (28 mL) was added triphenylphosphine (539 mg, 2.05 mmol) and isopropyl(oxycarbonylamino) 2-propanecarbamate (415 mg, 2.05 mmol) dropwise at 0 °C under N2 atmosphere. The mixture was warmed 60 °C where it stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (0-75% EtOAc in PE) to give tert-butyl (S)-8-methyl-30-oxo-21,24-dioxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (0.7 g, 661 pmol) as a white solid, m / z (ESI-pos) M+l = 530.2 Step K: To a solution of tert-butyl (S)-8-methyl-30-oxo-21,24-dioxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (0.3 g, 283 pmol) in CH2CI2 (4 mL) under N2 atmosphere at 0 °C and was added trifluoroacetic acid (2 mL) and the mixture was stirred for 1 hour. The mixture was concentrated to give crude (S)-8-methyl-21,24-dioxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one trifluoroacetic acid (260 mg, 285 pmol) as a white solid, m / z (ESI-pos) M+l = 430.2 Step L: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (0.1 g, 243 pmol) in DMF (2.5 mL) was added DIEA (126 mg, 972 pmol) and HATU (139 mg, 365 pmol). The mixture was stirred at 20 °C for 30 mins, and then (S)-8-methyl-21,24-dioxa- 2.3.7.11.14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta- 1(29), 3, 9, 12, 15, 17,19,25,27-nonaen-30-one trifluoroacetic acid (244 mg, 267 pmol) was added. The resulting mixture was stirred at 20 °C for 16 hours. The reaction was quenched with water (50 mL), extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (2 x 50 mL), dried over Na₂SO₄, filtered and concentrated to provide the crude product. The crude product was purified by column chromatography (0-5% MeOH in CH2CI2) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3 -yl)cyclopropyl]-2-indolyl } carbonyl)-8-methyl-21,24-dioxa- 2.3.7.11.14-pentaazahexacyclo[23.3.1.111,14.02,1°.04,9.015,2O]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one (0.3 g, 182 pmol) as a white solid, m / z (ESI-pos) M+l = 823.3

[0811] StepM: (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-21,24-Attorney Docket No.: ABR-00125

[0812] dioxa-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta- 1(29), 3,9,12,15,17,19,25,27 -nonaen-3 O-one (0.3 g, 182 pmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALCEL IH, 250mm X30 mm ID., 10pm; Mobile Phase: CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]= 50 / 50 at 80 g / min; Temp: 35 °C; Wavelength: 214 nm) to afford the crude Isomer 1 (60 mg) and Isomer 2 (50 mg), which was further purified by prep-HPLC [Waters MS-triggered Prep-LC with SQD2 detector, Xbridge 5u C18 150 x l9 mm, eluted with 70-100 % ACN in H2O(0.1%FA)] to give pure Isomer 1(31.35 mg) and Isomer 2 (25.28 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0813] Isomer 1: m / z (ESI-pos) M+l = 823.3;1H NMR (400 MHz, DMSO) 8 11.62 (s, IH), 7.51 (s, IH), 7.44 - 7.34 (m, 4H), 7.24 (d, J = 8.4Hz, 2H), 7.18 - 7.14 (m, 2H), 7.05 (t, J = 7.2Hz, IH), 6.93-6.91 (m, IH), 6.84 (s, IH), 6.57-6.48 (m, 2H), 5.58 (s, IH), 4.56-4.50 (m, IH), 4.39-4.31 (m, 3H), 4.21 (t, J = 9.2Hz, IH), 3.73-3.71 (m, 2H), 3.59 (s, IH), 3.03-2.99 (m, 2H), 2.90 -2.87 (m, IH), 1.74 - 1.68 (m, 4H), 1.65 - 1.56 (m, 2H), 1.51 (d, J = 12.8Hz, 3H), 1.28-1.25 (m, 4H), 1.19 (s, 6H).

[0814] Isomer 2: m / z (ESI-pos) M+l = 823.3;1H NMR (400 MHz, DMSO) 6 11.58 (s, IH), 7.49 (s, IH), 7.45 - 7.36 (m, 4H), 7.23 - 7.12 (m, 4H), 7.05 (t, J = 7.2Hz, IH), 6.96-6.93 (m, IH), 6.87 (s, IH), 6.56 (s, IH), 6.42 (d, J = 2.8Hz, IH), 5.59 (s, IH), 4.53 - 4.47 (m, IH), 4.39 - 4.32 (m, 3H), 4.23-4.18 (m, IH), 3.72 - 3.70 (m, 2H), 3.57 (s, IH), 3.02-2.97 (m, 2H), 2.89 - 2.85 (m, IH), 1.71-1.67 (m, 4H), 1.61 - 1.55 (m, 2H), 1.50 (d, J = 12.0Hz, 3H), 1.27-1.25 (m, 4H), 1.18 (s, 6H).

[0815] Example 9 - Synthesis of Compound 9

[0816] Synthetic SchemeAttorney Docket No.: ABR-00125

[0817] Pd(PPh3)4, Na2CO3DMF / H20 Boc Boc

[0818]

[0819] Isomer 1 Isomer 2Attorney Docket No.: ABR-00125

[0820] Procedure for Synthesis of Compound 9

[0821]

[0822] (Compound 9)

[0823] 8-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl1-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-L2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyl}carbonyl)-2,3,8,12,15- pentaazahexacyclor23,3, LI12,15.02,11.04,lo.016,211triaconta-l(29),3, 10,13, 16,18, 20,23, 25,27- decaen-30-one

[0824] Step A: To a solution of tert-butyl 3-cyano-4-oxoazepane-1-carboxylate (2.8 g, 11.76 mmol) in Ethanol (110 mL) was added (3-bromophenyl)hydrazine (2.41 g, 12.94 mmol) at 25 °C. The resulting mixture was warmed to 80 °C where it stirred for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with water (50 mL x 3). The aqueous layer was extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl 3-amino-2-(3-bromophenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (4.0 g, 8.47 mmol) as a yellow solid, m / z (ESI-pos) M+l = 407.1 / 409.1

[0825] Step B: To a mixture of tert-butyl 3-amino-2-(3-bromophenyl)-2,6,7,8-tetrahydro pyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.8 g, 4.43 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.41 g, 22.16 mmol) and Na2CO3(939 mg, 8.86 mmol) in DMF / H2O (30 mL / 6 mL) was added Pd(PPh3)4(511 mg, 0.443 mmol) at 25 °C under N2 protection. The resulting mixture was stirred at 80 °C for 16 hr under N2 and then cooled down to room temperature, and diluted with ethyl acetate (50 mL) and the organic phase was washed with water (50 mL x 3). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by columnAttorney Docket No.: ABR-00125

[0826] chromatography (0-60% EtOAc in PE) to give tert-butyl 3-amino-2-(3-vinylphenyl)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.5 g, 2.92 mmol) as a yellow oil. m / z (ESI-pos)M+l = 355.2

[0827] Step C: To a solution of tert-butyl 3-amino-2-(3-vinylphenyl)-2, 6,7,8-tetrahydropyrazolo [4,3-c]azepine-5(4H)-carboxylate (1.5 g, 4.23 mmol), NaHCO3(1.06 g, 12.69 mmol) in Tetrahydrofuran (15 mL) was added benzyl chloroformate (1.31 g, 8.46 mmol) at 0 °C. The reaction mixture was warmed to 30 °C where it stirred for 2 hr. The reaction mixture was directly concentrated to give crude tert-butyl 3 -((phenoxy carbonyl)amino)-2-(3-vinylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.6 g crude) as a yellow oil, which was used directly for next step without any further purification, m / z (ESI-pos) M+l = 475.1

[0828] Step D: Crude tert-butyl 3 -((phenoxy carbonyl)amino)-2-(3-vinylphenyl)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.6 g, 4.23 mmol) was dissolved in pyridine (15 mL), to which 2,2-dimethoxyethylamine (888 mg, 8.46 mmol) was added. The mixture was stirred at 25 °C for 3 hr and then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (0 - 60% EtOAc in PE) to give tert-butyl (S)-4-methyl-3-(2-oxo-2, 3 -dihydro- lH-imidazol-l-yl)-2-(3-vinylphenyl)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.4 g, 2.59 mmol) as a yellow solid, m / z (ESI-pos)M+l = 486.3

[0829] Step E: To a solution of tert-butyl 3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-vinylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.4 g, 2.88 mmol) in THF (20 mL) was added methanesulfonic acid (277 mg, 2.88 mmol). The mixture was stirred at 60 °C for 2 hr. Aqueous K3PO4 was then added to the reaction mixture to adjust pH to ~9, and then BOC2O (627 mg, 2.88 mmol) was added, and the resulting mixture was stirred at 25 °C for 16 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (30 mL x 3) and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl 3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-vinylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.1 g, 2.35 mmol) as a yellow solid, m / z (ESI-pos) M+l = 422.2

[0830] Step F: To a solution of tert-butyl 3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-vinylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1100 mg, 2.61 mmol) and l-allyl-2 -bromobenzene (668 mg, 3.39 mmol) in NMP (10 mL) were addedAttorney Docket No.: ABR-00125

[0831] (1R,2R)-1,2-bis(methylamino)cyclohexane (185 mg, 1.30 mmol), Cui (497 mg, 2.61 mmol) and K2CO3(1.08 g, 7.83 mmol). The reaction mixture was heated at 130 °C for 3 hr under N2. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (30 mL x 3) and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl 3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-vinylphenyl)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (675 mg) as a yellow solid, m / z (ESI-pos) M+l = 538.3

[0832] Step G: To a solution of tert-butyl 3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-vinylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (370 mg, 0.65 mmol) in DCE (350 mL) was added Hoveyda-Grubbs II (370 mg, 0.59 mmol) at 25 °C under N2 protection. The reaction mixture was heated to 80 °C where it stirred for 3 hr under N2. The reaction mixture was cooled to ambient temperature and quenched with water (300 mL) and the aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl 30-oxo-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,23,25,27-decaene-8-carboxylate (220 mg) as a yellow solid, m / z (ESI-pos) M+l = 510.3

[0833] Step H: tert-butyl 30-oxo-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,23,25,27-decaene-8-carboxylate (150 mg, 0.294 mmol) was dissolved in HCl / l,4-di oxane (4M, 6 mL) and stirred at 25 °C for Ih. The reaction mixture was directly concentrated under reduced pressure to give crude 2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,23,25,27-decaen-30-one hydrogen chloride (170 mg, 0.29 mmol) as a yellow solid, m / z (ESI-pos) M+l = 410.2

[0834] Step I: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (121 mg, 0.294 mmol) in DMF (5 mL) was added DIEA (114 mg, 0.882 mmol) and HATU (168 mg, 0.441 mmol) at 25 °C. The mixture stirred at ambient temperature for 10 min, then 2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-Attorney Docket No.: ABR-00125

[0835] l(29),3,10,13,16,18,20,23,25,27-decaen-30-one hydrogen chloride (150 mg crude, 0.294 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL x 2). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound and purified by prep-HPLC [Waters MS-triggered Prep-LC with QDA detector, WELCH Xtimate C18 21.2*250mm 10um, eluted with 60-100 % ACN in H2O(0.1%FA)] to give 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,23,25,27-decaen-30-one (90 mg) as a yellow solid, m / z (ESI-pos) M+l = 803.3

[0836] Step J: 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,23,25,27-decaen-30-one (90 mg, 0.11 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK OD_3, 3* 150mm, 3um; Mobile Phase: CO2 / MeOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm) to afford Isomer 1 (40.3 mg) and Isomer 2 (25.1 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0837] Isomer 1: m / z (ESI-pos) M+l = 803.3;1H NMR (400 MHz, DMSO) 89.04 (s, 1H), 7.62-7.55 (m, 2H), 7.48-7.28 (m, 6H), 7.15 (d, J= 8.4 Hz, 1H), 7.10 (d, J= 7.6 Hz, 1H), 6.80 (s, 1H), 6.61-6.53 (m, 4H), 5.90-5.84 (m, 1H), 4.77 (s, 1H), 4.06-3.89 (m, 2H), 3.73-3.68 (m, 2H), 3.27-3.14 (m, 4H), 2.89-2.84 (m, 2H), 2.02-1.93 (m, 2H), 1.74-1.67 (m, 3H), 1.58-1.48 (m, 4H), 1.26 (s, 3H), 1.15-1.08 (m, 6H).

[0838] Isomer 2: m / z (ESI-pos) M+l = 803.3;1H NMR (400 MHz, DMSO) 6 11.35 (s, 1H), 7.62-7.58 (m, 2H), 7.50-7.32 (m, 6H), 7.21 (d, J= 8.4 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.79 (s, 2H), 6.63-6.42 (m, 3H), 5.90-5.84 (m, 1H), 5.06-4.65 (m, 2H), 3.71 (d, J = 8.0 Hz, 2H), 3.32-3.15 (m, 2H), 2.18-1.99 (m, 3H), 1.65-1.43 (m, 8H), 1.30-1.22 (m, 6H), 1.14 (s, 6H).

[0839] Example 10 - Synthesis of Compound 10Attorney Docket No.: ABR-00125

[0840]

[0841] Procedure for Synthesis of Compound 10

[0842]

[0843] (Compound 10)

[0844] 8-((5-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl1-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyl}carbonyl)-2,3,8,12,15- pentaazahexacyclor23,3.1.112,15, 02,11.04,lo.016,211triaconta-l(29),3, 10,13, 16,18, 20,25, 27- nonaen-30-oneAttorney Docket No.: ABR-00125

[0845] Step A: To a solution of tert-butyl 30-oxo-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,23,25,27-decaene-8-carboxylate (210 mg, 0.41 mmol) in methanol (10 mL) was added Pd / C (105 mg, 50% w / w) at 25 °C. The mixture was evacuated and backfilled with H2 and then stirred under H2 atmosphere at 25 °C for 16 hr. The reaction mixture was filtered through a pad of Celite and the filtrate was evaporated under reduced pressure to give tert-butyl 30-oxo-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaene-8-carboxylate (120 mg, 0.199 mmol) as a yellow solid, m / z (ESI-pos) M+l = 512.2 Step B: tert-butyl 30-oxo-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaene-8-carboxylate (120 mg, 0.23 mmol) was dissolved in HCl / l,4-di oxane (4M, 6 mL) and stirred at 25 °C for Ih. The reaction mixture was concentrated under reduced pressure to give crude 2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one hydrogen chloride (130 mg, 0.23 mmol) as a yellow solid, m / z (ESI-pos) M+l = 412.3

[0846] Step C: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (94 mg, 0.23 mmol) in DMF (5 mL) was added DIEA (89 mg, 0.69 mmol) and HATU (131 mg, 0.345 mmol) at 25 °C, the mixture stirred for 10 min, then 2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one hydrogen chloride (130 mg crude, 0.23 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL x 2). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound which was purified by prep-HPLC [Instrument: Waters MS-triggered Prep-LC with QDA detector; Column: WELCH Xtimate Cl 8 21.2*250mm lOum; Gradient: 69-79 % ACN in H2O(0.1%FA) in lOmin; Flow rate: 30 mL / min] to give 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one (60 mg) as a yellow solid, m / z (ESI-pos) M+l = 805.3

[0847] Step D: 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4, 5-dihydro-l, 2, 4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2, 3,8,12,15-Attorney Docket No.: ABR-00125

[0848] pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-3 O-one (60 mg, 0.07 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography [separation condition: Daicel CHIRALPAK 0X 3, 3* 150mm, 3um; Mobile Phase: CO2 / MeOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm] to afford Isomer 1 (24.82 mg) and Isomer 2 (19.15 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0849] Isomer 1: m / z (ESI-pos) M+l = 805.3;1H NMR (400 MHz, DMSO) 8 11.34 (s, 1H), 7.44-7.26 (m, 8H), 7.18-7.15 (m, 2H), 6.92 (s, 1H), 6.70 (s, 1H), 6.51-6.19 (m, 2H), 4.96-4.68 (m, 2H), 3.74-3.68 (m, 2H), 2.86-2.65 (m, 4H), 2.41-2.31 (m, 1H), 2.06-1.97 (m, 4H), 1.85-1.79 (m, 3H), 1.64-1.43 (m, 6H), 1.24 (s, 3H), 1.17-1.12 (m, 8H).

[0850] Isomer 2: m / z (ESI-pos) M+l = 805.3;1H NMR (400 MHz, DMSO) 6 11.21 (s, 1H), 7.44-7.32 (m, 7H), 7.18-7.14 (m, 3H), 6.90 (s, 1H), 6.74-6.40 (m, 3H), 4.84-4.67 (m, 1H), 3.78-3.68 (m, 2H), 2.99-2.91 (m, 1H), 2.73-2.66 (m, 3H), 2.36-2.26 (m, 1H), 2.04-1.97 (m, 3H), 1.76-1.48(m, 10H), 1.26-1.24 (m, 6H), 1.16 (s, 3H), 1.07-0.94 (m, 3H).

[0851] Example 11 - Synthesis of Compound 11

[0852] Synthetic SchemeAttorney Docket No.: ABR-00125

[0853]

[0854] Procedure for Synthesis of Compound 11

[0855]

[0856] (Compound 11)

[0857] 8-(f5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-23-oxa-2,3,8,12,15- pentaazahexacyclor23,3.1.112,15, 02,11.04,lo.016,211triaconta-l(29),3, 10,13, 16,18, 20,25, 27- nonaen-30-oneAttorney Docket No.: ABR-00125

[0858] Step A: To a solution of (3-(((2-bromobenzyl)oxy)methyl)phenyl)hydrazine (0.7 g, 2.28 mmol, / Y> / 77 Example 3, step C) in EtOH (14 mL) was added tert-butyl 3-cyano-4-oxo-l-azepanecarb oxy late (543 mg, 2.28 mmol), and the reaction was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (0-40% EtOAc in PE) to give tert-butyl 3-amino-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (950 mg, 1.8 mmolj as a yellow oil. m / z (ESI-pos) M+l = 527.1 / 529.1

[0859] Step B: To a solution of tert-butyl 3-amino-2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (950 mg, 1.8 mmol) and DIPEA (698 mg, 5.4 mmol) in THF (38 mL) was added benzyl chloroformate (564 mg, 3.6 mmol), and the reaction was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give crude tert-butyl 2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-((phenoxycarbonyl)amino)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.7 g, 1.58 mmol) as a yellow oil, which was used directly in the next step without further purification, m / z (ESI-pos) M+l = 647.2 / 649.2

[0860] Step C: Crude tert-butyl 2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-((phenoxycarbonyl)amino)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.7 g, 2.63 mmol) was dissolved in pyridine (34 mL), to which 2, 2-dimethoxy ethylamine (828 mg, 7.88 mmol) was added. The mixture was stirred at 25°C for 3 hr. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (0-65% EtOAc in PE) to give tert-butyl 2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-(3-(2, 2-dimethoxy ethyl)ureido)-2, 6, 7, 8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.7 g, 1.06 mmol) as a yellow oil. m / z (ESI-pos) M+l = 658.1 / 660.1

[0861] Step D: To a solution of tert-butyl 2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-(3-(2, 2-dimethoxy ethyl)ureido)-2, 6, 7, 8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.7 g, 1.06 mmol) in THF (14 mL) was added methanesulfonic acid (102 mg, 1.06 mmol). The mixture was stirred at 60 °C for 1 hr. Aqueous K3PO4 was added to adjust the pH to ~9, and BOC2O (232 mg, 1.06 mmol) was added and the resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with IN aq. HC1 (20 mL), then brine (20 mL) and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The crude residueAttorney Docket No.: ABR-00125

[0862] was purified by column chromatography (0-80% EtOAc in PE) to give product tert-butyl 2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.5 g, 841 pmol) as a yellow solid, m / z (ESI-pos) M+l = 594.2 / 596.2

[0863] Step E: To a solution of tert-butyl 2-(3-(((2-bromobenzyl)oxy)methyl)phenyl)-3-(2-oxo-2, 3-dihydro-lH-imidazol-l-yl)-2, 6,7, 8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (0.3 g, 505 pmol) in NMP (15 mL) was added (1R,2R)-1,2-bis(methylamino)cyclohexane (108 mg, 757 pmol), copper iodide (48.1 mg, 252 pmol) and K2CO3(209 mg, 1.51 mmol). The reaction mixture was heated at 130 °C for 3 hr under N2. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with aqueous LiCl solution (20 mL) and dried over anhydrous Na2SO4. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0-40% EtOAc in PE) to give tert-butyl 30-oxo-23-oxa-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaene-8-carboxylate (0.2 g, 389 pmol) as a yellow oil. m / z (ESI-pos) M+l = 514.2 Step F: tert-butyl 30-oxo-23-oxa-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaene-8-carboxylate (0.2 g, 389 pmol) was dissolved in HCl / l,4-di oxane (4M, ImL) and stirred at 25°C for Ih. The reaction mixture was concentrated to give 23-oxa-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one hydrogen chloride (0.2 g, 387 pmol) as a yellow solid, which was used directly in the next step, m / z (ESI-pos) M+l = 414.1

[0864] Step G: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (199 mg, 484 pmol) in DMF (20 mL) was added HATU (221 mg, 580 pmol) and DIPEA (188 mg, 1.45 mmol). The mixture was stirred at ambient temperature for lOmin, then 23-oxa-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one hydrogen chloride (0.2 g, 484 pmol) was added to the mixture. The mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL x 2) and the aqueous layer was extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purifiedAttorney Docket No.: ABR-00125

[0865] by column chromatography (0-80% EtOAc in PE) to give 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl } carbonyl)-23 -oxa-2,3, 8, 12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one (160 mg, 0.198 mmol) as a white solid, m / z (ESI-pos) M+l = 807.3

[0866] Step H: 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-23-oxa-2,3,8,12,15-pentaazahexacyclo[23.3.1.112,15.02,11.04,1°.016,21]triaconta-l(29),3,10,13,16,18,20,25,27-nonaen-30-one (160 mg, 0.2 mmol) was

[0867] dissolved in MeOH (200 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALCEL OJ, 250mm * 30 mm I. D., 10pm; CO2 / MeOH[0.2%NH3(7M Solution in MeOH)]= 45 / 55 at 70 g / min; Temp: 35 °C; Wavelength: 214 nm) to afford Isomer 1 (50 mg, purity:90%) and Isomer 2 (60 mg, purity:90%), which was further purified by prep-HPLC [Instrument: Waters MS-triggered Prep-LC with SQD2 detector; Column: Xbridge 5u C18 150 x l9 mm; Gradient: eluted with 72-100 % ACN in H2O(0.1%FA) in 9.5 min; Flow rate: 20 mL / min] to give Isomer 1(17.56 mg, 35 % yield) and Isomer 2 (12.7 mg, 21.6% yield) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily). Isomer 1: m / z (ESI-pos) M+l = 807.3;1H NMR (400 MHz, DMSO) 8 11.60 (s, 1H), 7.59 -7.37 (m, 6H), 7.25 (dd, J= 7.6 Hz, 4H), 6.91 (s, 1H), 6.79 (s, 1H), 6.55 (s, 2H), 4.73-4.50 (m, 3H), 4.18 (s,lH), 4.00 (d, J= 9.6 Hz, 2H), 3.68 (s, 3H), 3.05 (s, 1H), 3.02 - 2.90 (m, 2H), 2.02 (d, J= 10.8 Hz, 2H), 1.69-1.54 (m,7H), 1.21 (d, J= 41.6 Hz, 8H), 0.93 (d, =56.0 Hz, 2H). Isomer 2: m / z (ESI-pos) M+l = 807.3;1H NMR (400 MHz, DMSO) 6 11.55 (s, 1H), 7.60-7.41 (m, 6H), 7.33 (d, J= 8.0 Hz, 1H), 7.21 (dd, J= 7.6 Hz, 3H), 6.92 (s, 1H), 6.74 (s, 1H), 6.50 (d, J = 92.0Hz, 2H), 4.97-4.70 (m, 3H), 4.50 (d, J = 13.6 Hz, 1H), 4.27 (s, 1H), 3.99 (d, J = 8.8 Hz, 1H), 3.69 (d, J= 6.0 Hz, 3H), 3.03 - 2.89 (m, 3H), 2.10-1.98 (m, 2H),1.85 - 1.34 (m, 7H), 1.30 - 0.99 (m, 10H).Attorney Docket No.: ABR-00125

[0868] Example 12 - Synthetis of Compound 12

[0869] Synthetic Scheme

[0870]

[0871] Procedure for Synthesis of Compound 12

[0872]

[0873] Attorney Docket No.: ABR-00125

[0874] (Compound 12)

[0875] 8-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl1-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-L2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyl}carbonyl)-2,3,8,12,15- pentaazahexacyclor24, 3, LI12,15.02,11.04,lo.016,211hentriaconta-l(30),3, 10,13, 16,18, 20,23, 26,28- decaen-31-one

[0876] Step A: To a mixture of tert-butyl 3-amino-2-(3-bromophenyl)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (2.2 g, 5.4 mmol, from Example 8, Step A), 2-allyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.36 g, 8.1 mmol) and CsF (2.46 g, 16.2 mmol) in THF (50 mL) was added Pd(PPh3)4 (312 mg, 0.27 mmol) at 25 °C under N2 protection. The resulting mixture was warmed to 80 °C where it stirred for 16 hr. The reaction mixture was cooled down to room temperature^ diluted with ethyl acetate (50 mL), and washed with water (50 mL x 3). The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. Then the crude compound was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl 3-amino-2-(3-vinylphenyl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (2.2 g, 4.72 mmol) as a yellow oil. m / z (ESI-pos) M+l = 369.3

[0877] Step B: To a solution of tert-butyl 3-amino-2-(3-vinylphenyl)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (2.0 g, 5.43 mmol), DIEA (2.1 g, 16.3 mmol)jn Tetrahydrofuran (15 mL) was added benzyl chloroformate (1.7 g, 10.9 mmol) at 0 °C. The reaction mixture was then allowed to warm to 30 °C where it stirred for 2 hr. The reaction mixture was concentrated to give crude tert-butyl 2-(3-allylphenyl)-3-((phenoxycarbonyl)amino)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (2.1 g crude) as a yellow oil, which was used directly without any further purification, m / z (ESI-pos) M+l = 489.3

[0878] Step C: Crude tert-butyl 2-(3-allylphenyl)-3 -((phenoxy carbonyl)amino)-2, 6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (2.1 g crude, 5.43 mmol) was dissolved in pyridine (50 mL), to which 2,2-dimethoxyethylamine (1.8 g, 17.1mmol) was added. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl 2-(3-allylphenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.5 g, 3.00 mmol) as a yellow solid, m / z (ESI-pos) M+l = 500.3 Step D: To a solution of tert-butyl 2-(3-allylphenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.5 g, 3.00 mmol) in THF (60Attorney Docket No.: ABR-00125

[0879] mL) was added methanesulfonic acid (346 mg, 3.6 mmol) at ambient temperature. The mixture was stirred at 60 °C for 2 hr. The mixture weas cooled to ambient temperature and then aqueous K₃PO₄ was added to adjust pH to ~9, and then BOC2O (654 mg, 3.00 mmol) was added. The resulting mixture was stirred at 25 °C for 16 hr and then diluted with ethyl acetate (50 mL), washed with water (30 mL x 3) and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl 2-(3-allylphenyl)-3-(2-oxo-2, 3-dihydro-lH-imidazol-l-yl)-2, 6,7, 8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (1.0 g, 2.07 mmol) as a yellow solid, m / z (ESI-pos) M+l = 436.2

[0880] Step E: To a solution of tert-butyl 2-(3-allylphenyl)-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (650 mg, 1.49 mmol).and 1 -allyl-2 -bromobenzene (382 mg, 1.94 mmol) in N-methyl-2-pyrrolidone (10 mL) were added (1R,2R)-1,2-bis(methylamino)cyclohexane (212 mg, 1.49 mmol), Cui (47 mg, 0.746 mmol) and K2CO3(618 mg, 4.48 mmol). The reaction mixture was heated at 130 °C for 3 hr under the N2. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL), washed with water (30 mL x 3) and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl 2-(3-allylphenyl)-3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (670 mg) as a yellow solid. m / z (ESI-pos) M+l = 552.3

[0881] Step F: To a solution of tert-butyl 2-(3-allylphenyl)-3-(3-(2-allylphenyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(4H)-carboxylate (670 mg, 1.21 mmol) in DCE (670 mL) was added Hoveyda-Grubbs II (670 mg, 1.07 mmol) at 25 °C under N2 atmosphere. The reaction mixture was heated at 80 °C for 3 hr. The reaction mixture was cooled to ambient temperature and quenched with water (300 mL) and the aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (350 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-100% EA in PE) to give tert-butyl 31-oxo-2,3,8,12,15-pentaazahexacyclo[24.3.1.l12,15.02,11.04,1° 016,21]hentriaconta-l(30),3, 10,13,16,18,20,23,26,28-decaene-8-carboxylate (510 mg) as a yellow solid, m / z (ESI-pos) M+l = 524.3Attorney Docket No.: ABR-00125

[0882] Step G: tert-butyl 31-oxo-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,23,26,28-decaene-8-carboxylate (160 mg, 0.306 mmol) was dissolved in HCl / l,4-di oxane (4M, 6 mL) and stirred at 25 °C for Ih. The reaction mixture was concentrated under reduced pressure to give 2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,23,26,28-decaen-31-one hydrogen chloride (180 mg crude, 0.306 mmol) as a yellow solid, which was used directly to next step, m / z (ESI-pos) M+l = 424.2 Step H: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (125 mg, 0.306 mmol) in DMF (5 mL) was added DIEA (394 mg, 3.06 mmol) and HATU (174 mg, 0.459 mmol) at 25 °C, the mixture was stirred at ambient temperature for 10 min, then 2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,23,26,28-decaen-31-one hydrogen chloride (180 mg crude, 0.306 mmol) was added to the mixture. The mixture was stirred overnight and then diluted with ethyl acetate (30 mL) and washed with water (30 mL x 2). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound which was purified by prep-HPLC [Waters MS-triggered Prep-LC with QDA detector, WELCH Xtimate C18 21.2*250mm lOum, eluted with 60-100 % ACN in H2O(0.1%FA)] to give 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta- 1(30), 3,10,13,16,18,20,23,26, 28-decaen-31-one (60 mg) as ayellow solid, m / z (ESI-pos) M+l = 817.3

[0883] Step I: 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[24.3.1.l12,15.02,11.04,1° 016,21]hentriaconta-l(30),3, 10,13,16,18,20,23,26,28-decaen-31-one (60 mg, 0.07 mmol) was dissolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography [separation condition: Daicel CHIRALPAK OZ_3, 3*150mm, 3um; Mobile Phase: CO2 / MeOH(0.1%DEA)=45 / 55 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm] to afford Isomer 1 (34.55 mg) and Isomer 2 (16.15 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).Attorney Docket No.: ABR-00125

[0884] Isomer 1: m / z (ESI-pos) M+l = 817.3;1HNMR (400 MHz, DMSO) 6 10.60 (s, 1H), 7.58-7.46 (m, 2H), 7.35-7.14 (m, 8H), 7.07-7.01 (m, 2H), 6.87-6.74 (m, 2H), 6.61- 6.42(m, 2H), 5.45-5.32 (m, 1H), 5.28-5.16 (m, 1H), 4.91-4.56 (m, 2H), 4.11-3.87 (m, 2H), 3.71-3.59 (m, 2H), 3.34-3.14 (m, 3H), 2.96-2.87 (m, 3H), 2.02-1.89 (m, 2H), 1.63-1.49 (m, 5H), 1.30-1.22 (m, 6H), 1.18-1.12 (m, 6H).

[0885] Isomer 2: m / z (ESI-pos) M+l = 817.3;1HNMR (400 MHz, DMSO) 6 11.48 (s, 1H), 7.48-7.27 (m, 9H), 7.06 (d, J= 7.6 Hz, 1H), 6.91-6.61 (m, 4H), 5.54-5.37 (m, 1H), 5.22-5.17 (m, 1H), 4.71-4.43 (m, 2H), 3.72-3.61 (m, 4H), 3.27-3.19 (m, 3H), 3.00-2.91 (m, 3H), 2.08-1.99 (m, 2H), 1.65-1.40 (m, 8H), 1.22 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H).

[0886] Example 13 - Synthesis of Compound 13

[0887] Synthetic Scheme

[0888]

[0889] Procedure for Synthesis of Compound 13Attorney Docket No.: ABR-00125

[0890]

[0891] (Compound 13)

[0892] 8-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl1-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-L2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyl}carbonyl)-2,3,8,12,15- pentaazahexacyclor24, 3, LI12,15.02,11.04,lo.016,211hentriaconta-l(30),3, 10,13, 16,18, 20,26,28- nonaen-31-one

[0893] Step A: To a solution of tert-butyl 31-oxo-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,23,26,28-decaene-8-carboxylate (210 mg, 0.40 mmol) in MeOH (10 mL) was added Pd / C (105 mg, 50% w / w) at 25 °C. The mixture was evacuated and backfilled with H2, then stirred at 25 °C, under H2 atmosphere for 16 hr. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure to give tert-butyl 31-oxo-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,26,28-nonaene-8-carboxylate (200 mg, 0.36 mmol) as a yellow solid, m / z (ESI-pos) M+l = 526.2 Step B: tert-butyl 31-oxo-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,26,28-nonaene-8-carboxylate (200 mg, 0.38 mmol) was dissolved in HCl / l,4-di oxane (4M, 6 mL) and stirred at 25 °C for Ih. The reaction mixture was concentrated under reduced pressure to give 2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,26,28-nonaen-31-one hydrogen chloride (220 mg crude, 0.38 mmol) as a yellow solid, m / z (ESI-pos) M+l = 426.3

[0894] Step C: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (156 mg, 0.38 mmol) in DMF (5 mL) was added DIE A (490 mg, 3.8 mmol) and HATU (216 mg, 0.56 mmol) at 25 °C, the mixture was stirred at ambient temperature for 10 min, then 2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-Attorney Docket No.: ABR-00125

[0895] l(30),3,10,13,16,18,20,26,28-nonaen-31-one hydrogen chloride (220 mg crude, 0.38 mmol) was added to the mixture. The mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water (30 mL x 2). The aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound which was purified by prep-HPLC [Waters MS-triggered Prep-LC with QDA detector, WELCH Xtimate Cl 8 21.2*250mm lOum, eluted with 60-100 % ACN in H2O(0.1%FA)] to give 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,26,28-nonaen-31-one (100 mg) as a yellow solid, m / z (ESI-pos) M+l = 819.4

[0896] Step D: 8-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-2,3,8,12,15-pentaazahexacyclo[24.3.1.112,15.02,11.04,1°.016,21]hentriaconta-l(30),3,10,13,16,18,20,26,28-nonaen-31 -one (100 mg, 0.12 mmol) was di ssolved in MeOH (150 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK 0X 3, 3*150mm, 3um; Mobile Phase: CO2 / MeOH(0.1%DEA)=50 / 50 at 1.5 mL / min; Temp: 37 °C; Wavelength: 254 nm) to afford the Isomer 1 (26.7 mg) and Isomer 2 (27.4 mg) as white solids The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0897] Isomer 1: m / z (ESI-pos) M+l = 819.4;1H NMR (400 MHz, DMSO) 8 11.29 (s, 1H), 7.43-7.12 (m, 10H), 6.98-6.65 (m, 4H), 4.86-4.66 (m, 2H), 4.04-3.67 (m, 4H), 2.91-2.65 (m, 1H), 2.73-2.65(m, 1H), 2.04-1.98(m, 2H), 1.69-1.47 (m, 9H), 1.30-1.23 (m, 8H), 1.17-1.08 (m, 6H), 1.04-0.93 (m, 2H).

[0898] Isomer 2: m / z (ESI-pos) M+l = 819.3;1H NMR (400 MHz, DMSO) 610.04 (s, 1H), 7.43-7.15 (m, 10H), 6.83-6.61 (m, 4H), 4.97-4.77 (m, 2H), 4.02-3.70 (m, 4H), 2.93-2.88 (m, 1H), 2.72-2.68 (m, 1H), 2.06-2.00 (m, 2H), 1.71-1.49 (m, 9H), 1.32-1.25 (m, 8H), 1.18-1.15 (m, 6H), 1.09-1.06 (m, 2H).

[0899] Example 14 - Synthesis of Compound 14Attorney Docket No.: ABR-00125

[0900]

[0901] (Compound 14)

[0902] 8-({5-[(S)-2.2-dimethyltetrahydro-4H-pyran-4-yl1-l-[(lS.2S)-2-methyl-l-(5-oxo-4.5-dihydro-1.2.4- oxadiazol-3 -yDcyclopropyl] -2-indolyl } carbonyl)-22-oxa-2,3, 8, 12,15-pentaazahexacyclo[24.3.1.112.15.02.11.04.10.016.211hentriaconta-l(30).3.10.13.16.18,20.26.28-nonaen-31-

[0903]

[0904] one

[0905] Compound 14 was synthesized following the procedure of Example 7, with tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate being replaced with tert-butyl 3-cyano-4-oxo- 1 -azepanecarboxylate.

[0906] Isomer 1: m / z (ESI-pos) M+l = 821.3;1H NMR (400MHz, DMSO) 6 11.59 (s, 1H), 7.47 -7.30 (m, 6H), 7.25-7.20 (m, 1H), 7.15-7.10 (m, 2H), 6.99 - 6.47 (m, 5H), 5.15-4.46 (m, 3H), 3.85 - 3.69 (m, 5H), 3.01 - 2.93 (m, 2H), 2.77 - 2.68 (m, 2H), 2.04-2.01 (m, 4H), 1.68 - 1.49 (m, 7H), 1.26-1.23 (m, 4H), 1.15-0.99 (m, 6H).

[0907] Isomer 2: m / z (ESI-pos) M+l = 821.3;1H NMR (400MHZ, DMSO) 6 11.60 (s, 1H), 7.47 - 7.30 (m, 5H), 7.25 - 7.13 (m, 4H), 6.98-6.88 (m, 2H), 6.77-6.47 (m, 3H), 4.81 - 4.26 (m, 3H), 3.88-3.69 (m, 5H), 3.02 - 2.95 (m, 2H), 2.79 - 2.71 (m, 2H), 2.05-2.01 (m, 4H), 1.69-1.49 (m, 7H), 1.27-1.23 (m, 4H), 1.15-1.00 (m, 6H).

[0908] Example 15 - Synthesis of Compound 15

[0909] Synthetic SchemeAttorney Docket No.: ABR-00125

[0910] THF, -78 °C

[0911] (1 R,2R)-N, N'-Dimethyl-1,2- cydohexanediamine Cui, K2CO3, NMP

[0912]

[0913] The absolute configuration was unknown, the configuration

[0914] of two atropisomers were assigned arbitrarily

[0915] Procedure for Synthesis of Compound 15Attorney Docket No.: ABR-00125

[0916]

[0917] (Compound 15)

[0918] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyllcarbonyl)-8,18-dimethyl- 2,3,7,11,14,19-hexaazahexacyclor22,3,1.111,14, O2,10,04,9,015,2O]nonacosa- 1 (28), 3,9, 12, 15, 17, 19,24,26-nonaen-29-one

[0919] Step A: To a solution of 2,3-dibromo-6-methylpyridine (4.6 g, 18.3 mmol) in tetrahydrofuran (50 mL) was added allylmagnesium bromide (2.8 g, 19.2 mmol, 1.0 mol / L in diethyl ether) at -78 °C N2 protection. The resulting mixture was allowed to warm to rt and stirred at ambient temperature for 16 hr. The reaction was quenched with water and diluted with ethyl acetate, washed with water (3x). The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution (3x), dried over anhydrous Na2SO4, filtered and concentrated to give the crude compound. The crude compound was purified by column chromatography (0-50% EtOAc in PE) to give 2-allyl-3-bromo-6-methylpyridine (3.3 g, 14 mmol, 76% yield) as a brown oil. 1H NMR (400 MHz, DMSO) 8 7.88 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.03-5.94 (m, 1H), 5.10-5.04 (m, 2H), 3.63-3.60 (m, 2H), 2.42 (s, 3H).

[0920] Step B: To a solution of tert-butyl (S)-2-(3-allylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1100 mg, 2.52 mmol) (See Example 4) and l-allyl-2 -bromobenzene (533 mg, 2.52 mmol) in N-methyl-2-pyrrolidone (10 mL) were added (lR,2R)-l,2-bis(methylamino) cyclohexane (429 mg, 3.02 mmol), Cui (480 mg, 2.52 mmol) and K2CO3(1043 mg, 7.56 mmol). The reaction mixture was heated at 130 °C for 3 hr under a N2 atmosphere. The reaction mixture was cooled to ambient temperature and was diluted with ethyl acetate, washed with water (3x) and the aqueous layer was back extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution (3x), dried over anhydrous Na2SO4and evaporated under reducedAttorney Docket No.: ABR-00125

[0921] pressure to give the crude compound. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-3-(3-(2-allyl-6-methylpyridin-3-yl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2-(3-allylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (660 mg, 41% yield) as a yellow solid, m / z (ESI-pos) M+l = 567.3

[0922] Step C: To a solution of tert-butyl (S)-3-(3-(2-allyl-6-methylpyridin-3-yl)-2-oxo-2,3-dihydro -lH-imidazol-l-yl)-2-(3-allylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (500 mg, 0.88 mmol) in DCE (500 mL) was added Hoveyda-Grubbs II (500 mg, 0.8 mmol) and acetic acid (1.2 g, 6.34 mmol) at 25 °C under N2. The reaction mixture was heated at 80 °C for 2 hr. The reaction mixture was cooled to ambient temperature and quenched with water and the aqueous layer was extracted with dichloromethane (3x). The combined organic layers were washed with brine, dried over anhydrous Na2SO4and concentrated. The crude compound was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-8,18-dimethyl-29-oxo-2,3,7,ll,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaene-7-carboxylate (160 mg) as a yellow solid, m / z (ESI-pos) M+l = 525.2

[0923] Step D: To a solution of tert-butyl (S)-8,18-dimethyl-29-oxo-2,3,7,ll,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,22,24,26-decaene-7-carboxylate (130 mg, 0.41 mmol) in tetrahydrofuran (10 mL) was added Pd / C (65 mg, 50% w / w) at 25 °C. The mixture was then stirred under a H2 atmosphere at 25 °C for 16 hr. The reaction mixture was filtered and the filtrate was concentrated to give crude tert-butyl (S)-8, 18-dimethyl-29-oxo-2,3,7, 11,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (130 mg) as a yellow solid. m / z (ESI-pos) M+l = 527.2.

[0924] Step E: tert-butyl (S)-8,18-dimethyl-29-oxo-2,3,7,ll,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (130 mg, 0.15 mmol) was dissolved in HCl / l,4-di oxane (4M, 6 mL) and stirred at 25°C for Ih. The reaction mixture was directly concentrated under reduced pressure to give (S)-8,18-dimethyl-2,3,7,ll,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (120 mg, 0.25 mmol) as a yellow solid, m / z (ESI-pos) M+l = 427.1.

[0925] Step F: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (116 mg, 0.28 mmol) in dimethylformamide (6 mL) was added DIEA (364 mg, 2.81 mmol) andAttorney Docket No.: ABR-00125

[0926] HATU (160 mg, 042 mmol), the mixture stirred at ambient temperature for 10 min, then (S)-8,18-dimethyl-2,3,7,ll,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (120 mg crude, 0.28 mmol) was added to the mixture. The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3x). The aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated to give the crude compound which was purified by pre-HPLC [Waters MS-triggered Prep-LC with QDA detector, WELCH Xtimate C18 21.2*250mm lOum, eluted with 60-100 % ACN in H2O(0.1%FA)] to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8,18-dimethyl-2,3,7,ll,14,19-hexaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one (40 mg) as a yellow solid. The material was then was dissolved in Hex / EtOH (130 mL) and separated by chiral supercritical fluid chromatography (Column: Daicel CHIRALCEL IB N-5, 250mm X 30 mm I. D., 10 m; Mobile Phase: Hex / EtOH[0.2%NH3(7M Solution in MeOH)]= 50 / 50 at 30 mL / min; Temp: 35 ° C; Wavelength: 214 nm) to afford the Isomer 1 (19.58 mg) and Isomer 2 (11.32 mg) as white solids (The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0927] Isomer 1: m / z (ESI-pos) M+l = 820.3. 1H NMR (400 MHz, DMSO) 8 11.30 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.43-7.39 (m, 3H), 7.23-7.15 (m, 4H), 6.85-6.78 (m, 1H), 6.67-6.55 (m, 2H), 5.69-5.52 (m, 1H), 4.51-4.28 (m, 1H), 3.73-3.71 (m, 2H), 3.60-3.48 (m, 1H), 2.91-2.75 (m, 4H), 2.38-2.21 (m, 2H), 2.02-1.94 (m, 2H), 1.71-1.49 (m, 9H), 1.36-1.16 (m, 14H).

[0928] Isomer 2: m / z (ESI-pos) M+l = 820.3. 1H NMR (400 MHz, DMSO) 67.75 (d, J = 6.4 Hz, 1H), 7.46-7.38 (m, 4H), 7.24-7.15 (m, 4H), 6.81-6.75 (m, 1H), 6.62-6.57 (m, 2H), 5.66-5.57 (m, 1H), 4.43-4.28 (m, 1H), 3.76-3.70 (m, 2H), 3.58-3.50 (m, 1H), 2.94-2.71 (m, 4H), 2.34-2.25 (m, 2H), 2.05-1.90 (m, 2H), 1.70- 1.52 (m, 9H), 1.36-1.15 (m, 14H).Attorney Docket No.: ABR-00125

[0929] Example 16 - Synthesis of Compound 16

[0930] Synthetic Scheme

[0931]

[0932] Procedure for Synthesis of Compound 16

[0933]

[0934] (Compound 16)Attorney Docket No.: ABR-00125

[0935] (S)-7-(15-r(R)-2,2-dimethyltetrahydro-4H-pyran-4-yl1-l-r(2S)-2-methyl-l-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl1-2-indolyllcarbonyl)-26-fluoro-8,17-dimethyl- 2,3, 7,11, 14,16-hexaazahexacyclor23, 3,1,111,14.02,10. 04,9.015,20]triaconta- 1(29),3, 9,12,15, 17,19,25, 27-nonaen-30-one

[0936] Step A: A solution of tert-butyl (S)-2-(3-allyl-4-fluorophenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (120 mg, 265 pmol), 2-bromo-3-chloro-6-methylpyridine (81.9 mg, 397 pmol) (Obtained from following a similar procedure to that shown for Compound 1), Cui (25.2 mg, 132 pmol), (lS,2S)-l,2-bis(methylamino)cyclohexane (33.9 mg, 238 pmol), and K2CO3(HO mg, 794 pmol) in 0.6 mL of NMP was placed under vacuumed and then backfilled with nitrogen and heated to 130 °C for 9 hours. The solution was then taken up in EtOAc and washed with water (3x). The organics were concentrated and purified by silica gel chromatography (1-10% MeOH / DCM), the product was concentrated to give tert-butyl (S)-2-(3-allyl-4-fluorophenyl)-3-[3-(3-chloro-6-methyl-2-pyridyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (135 mg) as an oil. m / z (ESI-pos) M+l = 579.3

[0937] Step B: A solution of tert-butyl (S)-2-(3-allyl-4-fluorophenyl)-3-[3-(3-chloro-6-methyl-2-pyridyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (135 mg, 233 pmol), allyltris(butyl)stannane (216 pL, 699 pmol), CataXCium A Pd G3 (34 mg, 46.6 pmol), and CsF (106 mg, 699 pmol) in 1.2 mL of dioxane was vacuum / backfilled with nitrogen and heated to 90 °C overnight. The solution was then diluted with filtered through celite, concentrated, and purified by silica gel chromatography chromatography (1-10% MeOH / DCM). This provided tert-butyl (S)-2-(3-allyl-4-fluorophenyl)-3-[3-(3-allyl-6-methyl-2-pyridyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (91 mg) as an oil. m / z (ESI-pos) M+l = 585.4

[0938] Step C: A solution of tert-butyl (S)-2-(3-allyl-4-fluorophenyl)-3-[3-(3-allyl-6-methyl-2-pyridyl)-2-oxo-2,3-dihydro-lH-imidazol-l-yl]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (91 mg), Hoveyda-Grubbs II (50.4 mg, 80.4 pmol), and acetic acid (4.6 pL, 80.4 pmol) in 35 mL of DCE was bubbled with nitrogen for 5 minutes and heated to 40 °C overnight. The mixture was then concentrated and purified by silica gel chromatography (1-10% MeOH / DCM), to give tert-butyl (S)-26-fluoro-8, 17-dimethyl-30-oxo-2, 3,7,11,14,16-Attorney Docket No.: ABR-00125

[0939] hexaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaene-7-carboxylate (84 mg) as an oil. m / z (ESI-pos) M+l = 557.4

[0940] Step D: A solution of tert-butyl (S)-26-fluoro-8,17-dimethyl-30-oxo-2,3,7,ll,14,16-hexaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,22,25,27-decaene-7-carboxylate (81 mg, 146 pmol) and Pd / C 10%w / w (15.5 mg) in 1.5 mL of MeOH was sparged with hydrogen and then sealed and stirred for 1 hour. The solution was then filtered through celite, concentrated, and stirred in 0.5 mL of 4M HC1 in dioxane for 1 hour. The solution was then filtered and taken forward as the crude (S)-26-fluoro-8, 17-dimethyl-2,3,7, 11,14,16-hexaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaen-30-one hydrogen chloride (70 mg) as an oil. m / z (ESI-pos) M+l = 459.4

[0941] Step E: A solution of (S)-26-fluoro-8,17-dimethyl-2,3,7,ll,14,16-hexaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaen-30-one hydrogen chloride (65 mg, 131 pmol), 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (70.2 mg, 171 pmol), HATU (74.9 mg, 197 pmol), and DIEA (68.6 pL, 394 pmol) in 0.2 mL of DMF was stirred for 1 hour. The solution was then taken up in EtOAc and washed with water (3x). The organics were concentrated and purified by silica gel chromatography (1-10% MeOH / DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl } carbonyl)-26-fluoro-8, 17-dimethyl-2,3,7, 11,14,16-hexaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaen-30-one (35 mg, 38.6 pmol) as a white solid, m / z (ESI-pos) M+l = 852.6. 1H NMR (400 MHz, chloroform-D) δ 11.22 (t, J = 15.8 Hz, 1H), 8.00 (s, 1H), 7.56 (dd, J = 16.8, 8.1 Hz, 2H), 7.49 (d, J = 7.1 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.74 - 6.38 (m, 2H), 6.27 -6.06 (m, 1H), 5.87 - 5.68 (m, 1H), 4.54 - 4.35 (m, 1H), 3.83 (d, J = 13.7 Hz, 2H), 3.58 (dd, J = 24.1, 14.6 Hz, 1H), 3.36 (q, J = 7.2 Hz, 1H), 3.17 (s, OH), 3.00 (d, J = 12.4 Hz, 3H), 2.94 (s, 5H), 2.87 (d, J = 0.8 Hz, 3H), 2.56 - 2.43 (m, 3H), 2.32 (d, J = 17.0 Hz, 1H), 1.81 - 1.65 (m, 2H), 1.64 - 1.57 (m, 2H), 1.56 - 1.48 (m, 2H), 1.33 (d, J = 3.0 Hz, 3H), 1.27 (d, J = 3.7 Hz, 3H), 1.21 (dd, J = 21.2, 6.0 Hz, 3H).Attorney Docket No.: ABR-00125

[0942] Example 17 - Synthesis of Compound 17

[0943] Synthetic Scheme

[0944]

[0945] Procedure for Synthesis of Compound 17Attorney Docket No.: ABR-00125

[0946]

[0947] (Compound 17)

[0948] (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-24-thia-2,3,7,11,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaen-30-one

[0949] Step A: To a mixture of 3 -(o-bromophenyl)-l -propanol (5 g, 23.2 mmol) and perbromomethane (8.09 g, 24.4 mmol) in DCM (0.1 L) was added PPh3 (6.4 g, 24.4 mmol) at 0 °C in batches, and then stirred at room temperature for 16 h. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by column chromatography (PE / EtOAc = 100 / 1) to give o-bromo(3-bromopropyl)benzene (5.1 g, yield 79%) as a colorless oil. 1H NMR (400 MHz, CDC13) 8 7.54 (d, J = 8.0 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.12 - 7.05 (m, 1H), 3.43 (t, J = 6.8 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.25 - 2.13 (m, 2H).

[0950] Step B: To a solution of m-aminobenzenethiol (2.3 g, 18.3 mmol) in NaOH aqueous solution(50 mL. IM) and EtOH (100 mL) was added o-bromo(3-bromopropyl)benzene (5.1 g, 18.3 mmol) in EtOH (5 mL) dropwise at 0 °C and then stirred at room temperature for 2 h. The reaction mixture was diluted with water (200 mL), extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give a residue, which was purified by column chromatography (PE / EtOAc = 3 / 1) to give m-[3-(o-bromophenyl)propylthio]aniline (5 g) as a colorless oil. m / z (ESI-pos) M+l = 322.0 / 324.0

[0951] Step C: To a solution of m-[3-(o-bromophenyl)propylthio]aniline (4.5 g, 14 mmol) in aqueous HC1 (100 mL, 6 M) was added sodium nitrite (1.06 g, 15.4 mmol) in water (5 mL) at 0 °C and the reaction mixture was stirred at room temperature for 0.5 h. SnCl₂ in con. HC1 (10Attorney Docket No.: ABR-00125

[0952] mL) was added into the above reaction mixture at 0 °C and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was basified with NaOH solution (5 M) until pH 9 and the reaction mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography (PE / EtOAc=l / l) to give {m-[3-(o-bromophenyl)propylthio]phenyl}hydrazine (0.7 g, yield 15%) as light yellow oil. m / z (ESI-pos) M+l = 337.1

[0953] Step D: A mixture of {m-[3-(o-bromophenyl)propylthio]phenyl}hydrazine (0.7 g, 2.08 mmol) and tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (544 mg, 2.28 mmol) in ethanol (20 mL) was stirred at 80 °C under N2 atmosphere for 16 h. The reaction mixture was cooled to ambient temperature and then concentrated to give a residue, which was purified by column chromatography (PEZEtOAc = 3 / 1) to give tert-butyl (S)-3-amino-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (550 mg, yield 48%) as a light yellow solid, m / z (ESI-pos) M+l = 557.2 Step E: To a mixture of tert-butyl (S)-3-amino-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (550 mg, 986 pmol) and sodium hydrogencarbonate (249 mg, 2.96 mmol) in tetrahydrofuran (10 mL) was added benzyl chloroformate (232 mg, 1.48 mmol) at 0 °C under N2 and the mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was then filtered and the filtrate was concentrated to give tert-butyl (S)-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-4-methyl-3-[phenyl(oxycarbonylamino)]-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (0.7 g) as a brown oil. m / z (ESI-pos) M+l = 677.2 Step F: To a solution of tert-butyl (S)-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-4-methyl-3-[phenyl(oxycarbonylamino)]-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5 carboxylate (0.7 g, 1.03 mmol) in pyridine (10 mL) was added 2,2-dimethoxyethylamine (326 mg, 3.1 mmol) at 0 °C under N2 and the mixture was allowed to warm to ambient temperature and stirred for 4 h. The reaction was concentrated to give a residue which was purified by column chromatography (PE / EtOAc=l / l) to give tert-butyl (S)-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-3-[3-(2,2-dimethoxyethyl)ureido]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (430 mg, yield 64%) as a light yellow solid, m / z (ESI-pos) M+l = 688.2

[0954] Step G: To a solution of tert-butyl (S)-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-3-[3-(2,2-dimethoxyethyl)ureido]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (460 mg, 668 pmol) in tetrahydrofuran (25 mL) was added methanesulfonic acidAttorney Docket No.: ABR-00125

[0955] (64.2 mg, 668 pmol) at 0 °C under N2 and the mixture was warmed to 60 °C and stirred for 2 h. The reaction was quenched with NaHCO3aqueous solution (50 mL) and extracted with EtOAc (2x). The combined organics were washed with brine, dried over Na2SO4, filtered and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (PE / EtOAc=l / l) to give tert-butyl (S)-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (350 mg, yield 84%) as a light yellow solid. m / z (ESI-pos) M+l = 624.1

[0956] Step H: To a mixture of tert-butyl (S)-2-{m-[3-(o-bromophenyl)propylthio]phenyl}-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (0.3 g, 480 pmol), dipotassium carbonate (199 mg, 1.44 mmol) in N-methyl-2-pyrrolidone (30 mL) was added Cui (45.6 mg, 240 pmol) and (1R,2R)-1,2-bis(methylamino)cyclohexane (68.3 mg, 480 pmol) under N2 and the mixture was stirred at 100 °C for 16 h. The reaction was quenched with water and extracted with EtOAc (2x). The combined organics were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (PE / EtOAc=l / l) to give tert-butyl (S)-8-methyl-30-oxo-24-thia-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (0.1 g) as a light yellow solid, m / z (ESI-pos) M+l = 544.2; 1H NMR (400 MHz, CDC13) 87.54-7.49 (m, 1H), 7.36 (s, 1H), 7.29-7.26 (m, 1H), 7.25-7.17 (m, 4 H), 7.09 -7.02 (m, 1H), 6.29 (s, 1H), 6.11 (s, 1H), 5.29 (s, 1H), 4.60 - 4.23 (m, 1H), 3.19-3.05 (m, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H), 2.83-2.75 (m, 2H), 1.99-1.89 (m, 2H), 1.49 (s, 9H), 1.29-1.24 (m, 3H).

[0957] Step I: A solution of tert-butyl (S)-8-methyl-30-oxo-24-thia-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaene-7-carboxylate (0.1 g, 184 pmol) in HCl / l,4-di oxane (5 mL, 4 M) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give crude (S)-8-methyl-24-thia-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one hydrogen chloride (85 mg) as a light yellow solid, m / z (ESI-pos) M+l = 444.2 Step J: To a mixture of (S)-8-methyl-24-thia-2,3,7,ll,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-l(29),3,9,12,15,17,19,25,27-nonaen-30-one hydrogen chloride (85 mg, 192 pmol), 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-Attorney Docket No.: ABR-00125

[0958] indolecarboxylic acid (86.7 mg, 211 pmol) and DIEA (248 mg, 1.92 mmol) in DMF (10 mL) was added HATU (109 mg, 287 pmol) under N2 and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water and extracted with EtOAc (2x). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by Prep-HPLC [Waters MS-triggered Prep-LC with QDA detector, WELCH ultimate Cl 8 21.2*250mm lOum, eluted with 70-100 % ACN in H2O(0.1%FA), flow rate: 25 mL / min] to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-24-thia-2,3,7,l 1,14-pentaazahexacyclo[23.3.1.111,14.02,10.04,9.015,20]triaconta-1(29),3,9,12,15,17,19,25,27-nonaen-30-one (91.7 mg) as a white solid, m / z (ESI-pos) M+l = 837.3; 1H NMR (400 MHz, DMSO) 8 11.60 (s, 1H), 7.56 - 7.20 (m, 10.5H), 7.05 - 6.65 (m, 3.5H), 5.63 (s, 1H), 4.43 (s, 1H), 3.75 - 3.68 (m, 2H), 3.66 - 3.45 (m, 1H), 3.04 - 2.66 (m, 7H), 1.88 - 1.40 (m, 12H), 1.33- 1.10(m, 9H).Attorney Docket No.: ABR-00125

[0959] Example 18 - Synthesis of Compound 18

[0960] Synthetic Scheme

[0961] Isomer 1 'O'A-l!,o,,ler^

[0962]

[0963] Procedure for Synthesis of Compound 18Attorney Docket No.: ABR-00125

[0964]

[0965] (Compound 18)

[0966] (8S,23R)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8,23-dimethyl-22-oxa-2,3,7,11,14-pentaazahexacyclo[22.3.1.111,14.02,10.04,9.015,20]nonacosa-1(28),3,9,12,15,17,19,24,26-nonaen-29-one

[0967] Step A: To the solution of (R)-l-(3-nitrophenyl)ethan-l-ol (2 g, 12 mmol) in DMF (30 mL)

[0968] was added Sodium hydride (60%w / w, 957 mg, 23.9 mmol) at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min. Then l-bromo-2-(bromomethyl)benzene (2.99 g, 12 mmol) was added to the mixture and the mixture was allowed to warm to ambient temperature where it stirred for 2h. The reaction mixture was quenched with aq. NH4CI, diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (2x). The combined EtOAc layers were washed with brine, dried over Na2SO4filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-20% EtOAc in PE), to give (R)-l-bromo-2-((l-(3-nitrophenyl)ethoxy)methyl)benzene (4 g, 10.7 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.12 (d, J = 8.4Hz, 1H), 7.60 (d, J = 7.6Hz, 1H), 7.55 - 7.46 (m, 2H), 7.31 - 7.23 (m, 2H), 7.11-7.07 (m, 1H), 4.61 (s, 2H), 3.76 (t, J = 6.8Hz, 2H), 3.11 (t, J = 6.8Hz, 2H).

[0969] Step B: To the solution of (R)-l-bromo-2-((l-(3-nitrophenyl)ethoxy)methyl)benzene (4 g, 10.7 mmol) in EtOH (0.1 L) was added H2O (25 mL), iron (2.99 g, 53.5 mmol) and ammonium chloride (2.86 g, 53.5 mmol). The reaction mixture was stirred at 70 °C for 4 h. The mixture was cooled to ambient temperature and diluted with H2O, extracted with EtOAc (2x). The combined EtOAc layers were washed with brine, dried over Na2SO4filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-20%Attorney Docket No.: ABR-00125

[0970] EtOAc in PE) to give (R)-3-(l-((2-bromobenzyl)oxy)ethyl)aniline (3 g, 8.82 mmol) as a yellow oil. m / z (ESI-pos) M+l = 306.1 / 308.1.

[0971] Step C: To a solution of (R)-3-(l-((2-bromobenzyl)oxy)ethyl)aniline (3 g, 8.82 mmol) in cone. HC1 (25 mL) and H2O (25 mL) at 0 °C was added NaNO₂ (669 mg, 9.7 mmol) in H2O (5 mL) dropwise. After the addition, the mixture was stirred at 0 °C for 45 mins. Then a SnCl₂ (3.68 g, 19.4 mmol) solution in cone. HC1 (20 mL) and H2O (20 mL) was added dropwise. The mixture was stirred at ambient temperature for another 1 hour and then quenched with aq. NaOH (ION, 55 mL) to adjust pH to about 9. Then the mixture was extracted with EtOAc (3x), the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give (R)-(3-(1-((2-bromobenzyl)oxy)ethyl)phenyl)hydrazine (1.5 g, 4.2 mmol) as a yellow solid, m / z (ESI-pos) M+l = 321.1 / 323.1

[0972] Step D: To a solution of (R)-(3-(l-((2-bromobenzyl)oxy)ethyl)phenyl)hydrazine (1.5 g, 4.2 mmol) in EtOH (30 mL) was added tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (1.0 g, 4.2 mmol) and the mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure to get the crude product, which was purified by column chromatography (0-33% EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.7 g, 2.83 mmol) as ayellow solid, m / z (ESI-pos) M+l = 541.1 / 543.2.

[0973] Step E: To a solution of tert-butyl (S)-3-amino-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl) phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.7 g, 2.83 mmol) in tetrahydrofuran (40 mL) at 0 °C was added DIEA (1.1 g, 8.48 mmol) and benzyl chloroformate (885 mg, 5.65 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated to get crude tert-butyl (S)-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.65 g) as a yellow solid, which was used directly in next step, m / z (ESI-pos) M+l = 661.2 / 663.2.

[0974] Step F: To a solution of crude tert-butyl (S)-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (2.65 g, 2.8 mmol) in pyridine (20 mL) was added 2,2-dimethoxyethylamine (884 mg, 8.41 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated under vacuum. The obtained residue was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2,4,6,7-Attorney Docket No.: ABR-00125

[0975] tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.55 g) as a white solid, m / z (ESI-pos) M+l = 672.2 / 674.2

[0976] Step G: To a solution of tert-butyl (S)-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-3-(3-(2,2-dimethoxyethyl)ureido)-4-methyl-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.55 g, 2.07 mmol) in tetrahydrofuran (20 mL) was added methanesulfonic acid (239 mg, 2.49 mmol). The mixture was stirred at 60 °C for 1 hour and then cooled to ambient temperature. The reaction mixture was diluted with H2O, extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give tert-butyl (S)-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c] pyridine-5-carboxylate (1.3 g) as a white solid, m / z (ESI-pos) M+l = 608.2 / 610.2

[0977] Step H: To a solution of tert-butyl (S)-2-(3-((R)-l-((2-bromobenzyl)oxy)ethyl)phenyl)-4-methyl-3-(2-oxo-2, 3-dihydro-lH-imidazol-l-yl)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g, 1.92 mmol) in NMP (100 mL) was added copper iodide (183 mg, 961 pmol), (1R,2R)-N, N'-Dimethyl-1,2 cyclohexane diamine (273 mg, 1.92 mmol) and K2CO3(797 mg, 5.77 mmol). The mixture was stirred at 100 °C for 16 hours and then cooled to ambient temperature, diluted with H2O and extracted with EtOAc (2x). The combined EtOAc layers were washed with aqueous LiCl (2x). Dried over Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by column chromatography (0-50% EtOAc in PE) to give tert-butyl (8S,23R)-8,23-dimethyl-29-oxo-22-oxa-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (400 mg) as a white solid, m / z (ESI-pos) M+l = 528.3

[0978] Step I: A solution of tert-butyl (8S,23R)-8,23-dimethyl-29-oxo-22-oxa-2,3,7,11,14-pentaazahexacyclo[22.3.1.111,14.02,10.04,9.015,20]nonacosa-1(28),3,9,12,15,17,19,24,26-nonaene-7-carboxylate (180 mg, 307 μmol) in HCl / 1,4-dioxane (4M, 10 mL) was stirred at 20 °C for 1 hour. The mixture was directly concentrated under reduced pressure to give crude (8S,23R)-8,23-dimethyl-22-oxa-2,3,7,11,14-pentaazahexacyclo[22.3.1.111,14.02,10.04,9.015,20]nonacosa-1(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (144 mg) as a white solid, m / z (ESI-pos) M+1 = 428.2.

[0979] Step J: To a solution of (8S,23R)-8,23-dimethyl-22-oxa-2,3,7,11,14-pentaazahexacyclo[22.3.1.111,14.02,10.04,9.015,20]nonacosa-1(28),3,9,12,15,17,19,24,26-nonaen-29-one hydrogen chloride (144 mg, 303 μmol) in dimethylformamide (10 mL) was added 5-Attorney Docket No.: ABR-00125

[0980] [(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(2S)-2-methyl-l-(5-oxo-4,5 dihydro- 1,2, 4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (125 mg, 303 pmol) and DIEA (157 mg, 1.21 mmol). The mixture was stirred at 20 °C for 5 mins, then HATU (173 mg, 455 pmol) was added into the mixture and stirred at 20 °C for 16 hours. H2O was added and the mixture was extracted with EtOAc (2x). The combined EtOAc layers were washed with brine, then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (0-5% MeOH in DCM) to give (8S,23R)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8,23-dimethyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[22.3.1.111,14.02,1°.04,9.015,2O]nonacosa-l(28),3,9,12,15,17,19,24,26-nonaen-29-one (194 mg), which was further purified by prep-HPLC [Waters MS-triggered Prep-LC with QDA detector, WELCH Xtimate C18 21.2*250mm lOum, eluted with 70-100 % ACN in H2O (0.1%FA)] to give:

[0981] Isomer 1 (11.4 mg) as a white solid, m / z (ESI-pos) M+1 = 821.3. 1H NMR (400 MHz, DMSO) δ 11.54 (s, 1H), 7.63-7.61 (m, 1H), 7.52 - 7.44 (m, 6H), 7.41 (d, J = 8.4Hz, 1H), 7.31-7.30 (m, 2H), 7.25-7.22 (m, 1H), 6.87 (s, 1H), 6.57 (d, J = 2.4Hz, 1H), 6.39 (d, J = 2.8Hz, 1H), 5.66 (s, 1H), 4.65-4.60 (m, 1H), 4.42 (s, 1H), 4.12 (s, 2H), 3.73 - 3.71 (m, 2H), 3.57 (s, 1H), 3.01 -2.99 (m, 2H), 2.89-2.85 (m, 1H), 1.81-1.69 (m, 4H), 1.65 - 1.50 (m, 6H), 1.28 - 1.25 (m, 7H), 1.19 (s, 5H).

[0982] Isomer 2 (76.8 mg) as a white solid, m / z (ESI-pos) M+1 = 821.3; 1H NMR (400MHz, DMSO) δ 11.57 (s, 1H), 7.72-7.70 (m, 1H), 7.54 (s, 1H), 7.46 - 7.37 (m, 6H), 7.27 - 7.21 (m, 2H), 7.01 - 6.88 (m, 3H), 6.73 (s, 1H), 5.67 (s, 1H), 4.52-4.47 (m, 2H), 4.24 (d, J = 9.6Hz, 1H), 3.90 (d, J = 9.6Hz, 1H), 3.74- 3.72 (m, 2H), 3.56 (s, 1H), 3.04-3.00 (m, 2H), 2.94 - 2.88 (m, 1H), 1.74 - 1.54 (m, 7H), 1.51-1.47 (m, 3H), 1.35 (d, J = 6.4Hz, 3H), 1.28 (s, 3H), 1.20 (s, 6H).

[0983] (The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0984] Example 19 - Synthesis of Compound 19

[0985] Procedure for Synthesis of Compound 19Attorney Docket No.: ABR-00125

[0986]

[0987] (Compound 19)

[0988] (8S,23S)-7-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyllcarbonyl)-8,23-dimethyl-22-oxa- 2,3,7,ll,14-pentaazahexacyclor22.3.1.111,14.02,10.04,9.015,201nonacosa- 1 (28), 3,9, 12, 15, 17, 19,24,26-nonaen-29-one

[0989] Compound 19 was prepared following an analogous procedure to that used for Compound 18 except that (R)-l-(3-nitrophenyl)ethan-l-ol was replaced with (S)-l-(3-nitrophenyl)ethan-l-ol in Step A. The title compound was purified by prep-HPLC [Instrument: Waters Prep-LC with UV detector; Waters Luna C18 lOum 21.2*250mm; Gradient: 40-80 % ACN in H2O(0.1%FA) in 18min; Flow rate: 20mL / min] to give Isomer 1 (35.3 mg) and Isomer 2 (20.7 mg) as white solids. (The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[0990] Isomer 1: m / z (ESI-pos) M+l = 821.3;1H NMR (400 MHz, DMSO) 8 11.66(s, 1H), 7.61 (d, J = 4.8 Hz, 1H), 7.54 - 7.34 (m, 8H), 7.29 (d, J= 6.8 Hz, 1H), 7.22 (d, J= 8.8 Hz, 1H), 6.82 (s, 1H), 6.45(d, J= 54.8 Hz, 2H), 5.32 (s, 0.5H), 4.61 (d, J= 6.4 Hz, 1H), 4.55 - 4.21 (m, 0.5H), 4.09 (q, J= 8.8 Hz, 2H), 3.73-3.58 (m, 3H), 2.94 (d, J= 39.2 Hz, 3H), 1.79 -1.49 (m, 10H), 1.33 - 1.24 (m, 8H), 1.19 (s, 5H).

[0991] Isomer 2: m / z (ESI-pos) M+l = 821.3;1H NMR (400 MHz, DMSO) 6 11.56 (s, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.57 - 7.32 (m, 7H), 7.26 - 7.17 (m, 2H), 6.96 (s, 2H), 6.84 (s, 1H), 6.73 (s, 1H), 5.61 (s,lH), 4.53-4.38 (m, 2H), 4.17 (d, J = 10.0 Hz, 1H), 3.89 (d, J = 10.0 Hz, 1H), 3.71 (d, J= 7.6 Hz, 2H), 3.58 (s, 1H), 3.05 - 2.82 (m, 3H), 1.81 - 1.44 (m, 10H),1.36 (d, J = 6.4 Hz, 3H), 1.26 (d, J= 8.8 Hz, 4H), 1.18 (s, 5H).Attorney Docket No.: ABR-00125

[0992] Example 20 - Synthesis of Compound 20

[0993] Synthetic Scheme

[0994]

[0995] Procedure for Synthesis of Compound 20Attorney Docket No.: ABR-00125

[0996]

[0997] (Compound 20)

[0998] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyllcarbonyl)-8-methyl-2,3,7,l 1,14- pentaazahexacyclor21,3,1.111,14,02,10,04,9.015,2O]octacosa-l(27),3,9,12,15,17,19,23,25-nonaen- 28-one

[0999] Step A: To a suspension of sodium hydride (576 mg, 24 mmol) in dimethylformamide (15.8 mL) under N2 at 0 °C, was added diethyl phosphonate (2.76 g, 20 mmol). The mixture was stirred at 0 °C for 30 min, then o-bromo(bromomethyl)benzene (5 g, 20 mmol) was added to the mixture dropwise. The resulting mixture was stirred at 0 °C for 3h. The reaction was quenched with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (0-5% EtOAc in PE) to give diethyl [(o-bromophenyl)m ethyl] phosphonate (5 g, 13 mmol) as a white solid, m / z (ESI-pos) M+l = 307.1 / 309.1

[1000] Step B: To a solution of diethyl [(o-bromophenyl)methyl] phosphonate (5 g, 13 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (938 mg, 39.1 mmol) at -10°C under N2. Then a THF(10 mL) solution of m-nitrobenzaldehyde (1.38 g, 9.12 mmol) was added into the mixture dropwise over 2 mins. The mixture was allowed to warm to ambient temnperature and stirred for 3h. The reaction was quenched by pouring the mixture into ice water, extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4. Filtered and the filtrate was evaporated under reduced pressure. The crude compound was purified by column chromatography (0-5% EtOAc in PE) to give (E)-2-bromo-5'-nitrostilbene (3.1 g, 10.2 mmol) as a yellow solid. 1H NMR (400 MHz, CDC13) 6 8.43 - 8.33 (m, 1H), 8.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.70 - 7.51 (m, 4H), 7.35 (t, J = 8.0 Hz, 1H), 7.18 (td, J = 7.2, 1.6 Hz, 1H), 7.07 (d, J = 16.4 Hz, 1H).Attorney Docket No.: ABR-00125

[1001] Step C: To a solution of (E)-2-bromo-5'-nitrostilbene (3.5 g, 11.5 mmol) in tetrahydrofuran (87.5 mL) was added tosylhydrazine (10.7 g, 57.5 mmol) and sodium acetate (4.72 g, 57.5 mmol). The mixture was stirred at 90°C for 5h and the mixture was cooled to ambient temperature, diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4. Filtered and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-50% EtOAc in PE) to give o-bromo[2-(m-nitrophenyl)ethyl]benzene (2.8 g, 9.15 mmol) as a white solid. 1H NMR (400 MHz, CDC13) 6 8.10 - 8.04 (m, 2H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.46-7.41 (m, 1H), 7.23-7.19 (m, 1H), 7.15 -7.04 (m, 2H), 3.19 - 2.92 (m, 4H).

[1002] Step D: To a solution of o-bromo[2-(m-nitrophenyl)ethyl]benzene (2.8 g, 9.15 mmol) in ethanol (93.3 mL) and water (9.33 mL) was added iron powder (2.55 g, 45.7 mmol) and ammonium chloride (2.45 g, 45.7 mmol). The reaction mixture was stirred at 70°C for 2h. The reaction mixture was cooled to ambient temperature and quenched with H2O, extracted with ethyl acetate (2x). The combined EtOAc layers were washed with brine, dried over Na2SO4and concentrated. The crude product was purified by column chromatography (0-5% DCM in MeOH). to give m-[2-(o-bromophenyl)ethyl]aniline (2.3 g, 8.33 mmol) as a yellow oil. m / z (ESI-pos) M+l = 276.1 / 278.1

[1003] Step E: To a solution of m-[2-(o-bromophenyl)ethyl]aniline (2.3 g, 8.33 mmol) in 6M aq. HC1 at 0 °C was added a solution of sodium nitrite (575 mg, 8.33 mmol) in water (5 mL) dropwise. The mixture was then stirred at 0 °C for Ih, a solution of SnCl₂ (3.16 g, 16.7 mmol) in cone, hydrogen chloride (40 mL) was then added dropwise to the reaction mixture and then the mixture was allowed to warm to ambient temperature and stirred for 2 h. The pH was adjusted to about 14 with 4N aq. NaOH and the mixture extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution and dried over anhydrous Na2SO4. Filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (0-80% PE in EtOAc) to give {m-[2-(o-bromophenyl)ethyl]phenyl}hydrazine (1.8 g, 6.18 mmol) as a yellow oil. m / z (ESI-pos) M+l = 291.1 / 293.1

[1004] Step F: To a solution of {m-[2-(o-bromophenyl)ethyl]phenyl}hydrazine (1.8 g, 6.18 mmol) in ethanol (48 mL) at ambient temperature was added tert-butyl (2S)-3-cyano-2-methyl-4-oxo- 1 -piperidinecarboxylate (1.47 g, 6.18 mmol) and the mixture was stirred at 80 °C for 16Attorney Docket No.: ABR-00125

[1005] hours. The mixture was concentrated under reduced pressure to get crude product, which was purified by column chromatography (0-60% EtOAc in PE) to give tert-butyl (S)-3-amino-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (2.5 g, 4.89 mmol) as a yellow solid, m / z (ESI-pos) M+l = 511.2 / 513.2

[1006] Step G: To a solution of tert-butyl (S)-3-amino-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (2.5 g, 4.89 mmol) in tetrahydrofuran (50 mL) at 0 °C was added N-ethyldiisopropylamine (1.9 g, 14.7 mmol) and benzyl chloroformate (1.53 g, 9.78 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated to get crude tert-butyl (S)-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-4-methyl-3- [phenyl(oxycarbonylamino)]-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (3 g, 3.8 mmol) as a yellow solid, which was used directly in the next step, m / z (ESI-pos) M+l = 631.2 / 633.2

[1007] Step H: To a solution of crude tert-butyl (S)-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-4-methyl-3-[phenyl(oxycarbonylamino)]-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (3 g, 3.8 mmol) in pyridine (40 mL) was added 2, 2-dimethoxy ethylamine (2.5 g, 23.8 mmol). The mixture was stirred at ambient temperature for 2 hours and then concentrated under vacuum. The obtained residue was purified by column chromatography (0-80% EA in PE) to give tert-butyl (S)-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-3-[3-(2,2-dimethoxyethyl)ureido]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (2 g, 3.11 mmol) as a white solid, m / z (ESI-pos) M+l = 642.2 / 644.2

[1008] Step I: tert-butyl (S)-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-3-[3-(2,2-dimethoxyethyl)ureido]-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (2 g, 3.11 mmol) in tetrahydrofuran (40 mL) was added methanesulfonic acid (299 mg, 3.11 mmol). The mixture was stirred at 60 °C for 1 hour and then cooled to ambient temperature. The reaction mixture was diluted with H2O, extracted with EtOAc (2x). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum to get crude product, which was purified by column chromatography (0-80% EtOAc in PE) to give tertbutyl (S)-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (1.8 g, 3.11 mmol) as a white solid, m / z (ESI-pos) M+l = 578.2 / 580.2

[1009] Step J: To a solution of tert-butyl (S)-2-{m-[2-(o-bromophenyl)ethyl]phenyl}-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (0.9 g, 1.56 mmol) in N-methyl-2-pyrrolidone (36 mL) was added copper iodideAttorney Docket No.: ABR-00125

[1010] (296 mg, 1.56 mmol), (1R,2R)-1,2-bis(methylamino)cyclohexane (443 mg, 3.11 mmol) and dipotassium carbonate (415 mg, 3 mmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with aq. LiCl solution and dried over anhydrous Na2SO4. Filtered and the filtrate was evaporated under reduced pressure. The obtained residue was purified by column chromatography (0-80% EtOAc in PE) to give tert-butyl (S)-8-methyl-28-oxo-2,3,7,11,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa-1(27),3,9,12,15,17,19,23,25-nonaene-7-carboxylate (220 mg, 442 μmol) as yellow solid, m / z (ESI-pos) M+1 = 498.2

[1011] Step K: A solution of tert-butyl (S)-8-methyl-28-oxo-2,3,7,11,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa-1(27),3,9,12,15,17,19,23,25-nonaene-7-carboxylate (210 mg, 422 μmol) in HCl / 1,4-dioxane (4M, 2 mL) was stirred at ambient temperature for 1 hour. Then the mixture was directly concentrated under vacuum to give crude (S)-8-methyl-2,3,7,11,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa-1(27), 3, 9, 12, 15, 17,19,23,25-nonaen-28-one hydrogen chloride (180 mg, 453 μmol) as a white solid, m / z (ESI-pos) M+1 = 398.2

[1012] Step L: To a solution of (S)-8-methyl-2,3,7,11,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa-1(27),3,9,12,15,17,19,23,25-nonaen-28-one hydrogen chloride (180 mg, 453 μmol) in dimethylformamide (6 mL) was added 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-1-[(2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (186 mg, 453 μmol) and N-ethyldiisopropylamine (176 mg, 1.36 mmol). The mixture was stirred for 5 mins, then HATU (258 mg, 679 μmol) was added into and the mixture was stirred at ambient temperaturte for 16 hours. H₂O was added to quench the reaction and the mixture was extracted with EtOAc (2x). The combined EtOAc layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to get crude product, which was purified by column chromatography (0-5% MeOH in DCM) to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-2,3,7,11,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa-1(27), 3, 9, 12, 15, 17,19,23,25-nonaen-28-one (80 mg, 101 μmol) as a yellow solid, which was separated by SFC [Column: : Daicel CHIRALCEL IC, 250mm x 30 mm I.D., 10 μm :Attorney Docket No.: ABR-00125

[1013] Hex / EtOH[0.2%TFA]= 50 / 50] to get isomer 1 (12.2 mg) and isomer 2 (12.0 mg). (The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily) Isomer 1: m / z (ESI-pos) M+1 = 791.3; 1H NMR (400 MHz, DMSO) δ 11.49 (s, 1H), 7.49 (d, J = 7.6 Hz, 2H), 7.44 - 7.30 (m, 2H), 7.26 - 7.10 (m, 6H), 6.89 (dd, J = 14.0, 6.8 Hz, 3H), 6.53 (s, 1H),5.63 (s, 1H), 4.40 (s, 1H), 3.75 - 3.68 (m, 2H), 3.59 (s, 1H), 3.34 (dd, J = 39.2, 13.6 Hz, 2H), 2.99 (s, 2H), 2.90 (d, J = 7.2 Hz, 2H), 2.82 - 2.72 (m, 1H), 1.77 -1.48 (m, 9H), 1.22 (dd, J = 35.6, 10.8 Hz, 10H).

[1014] Isomer 2: m / z (ESI-pos) M+1 = 791.3; 1H NMR (400 MHz, DMSO) δ 11.58 (s, 1H), 7.55 - 7.46 (m, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.26-7.12 (m, 7H), 6.88 (d, J = 7.6 Hz, 2H),6.49 (s, 1H), 5.74 (s, 1H), 4.45 (s, 1H), 3.73 (dd, J = 12.0, 19.2 Hz, 2H), 3.56 (s, 1H), 3.44 - 3.22 (m, 2H), 3.01 (d, J = 3.6 Hz, 2H), 2.94 - 2.83 (m, 2H), 2.81 -2.71 (m, 1H), 1.80 - 1.46 (m, 9H), 1.36 - 1.11 (m, 10H).Attorney Docket No.: ABR-00125

[1015] Example 21 - Synthesis of Compound 21

[1016] Synthetic Scheme

[1017] 4 N HCI in dioxane 6oc

[1018]

[1019] Procedure for Synthesis of Compound 21Attorney Docket No.: ABR-00125

[1020]

[1021] (Compound 21)

[1022] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyllcarbonyl)-8-methyl-22-oxa-2,3,7,l 1,14- pentaazahexacyclor21,3,1.111,14,02,10,04,9.015,2O]octacosa-l(27),3,9,12,15,17,19,23,25-nonaen- 28-one

[1023] Step A: To the solution of 3 -nitrophenol (3 g, 21.6 mmol) in DMF (120 mL) was added sodium hydride (1.73 g, 43.1 mmol) at 0 °C under N2. The reaction was stirred at 0 °C for 30 min. Then l-bromo-2-(bromomethyl)benzene (6.47 g, 25.9 mmol) was added to the mixture. The reaction was allowed to warm to ambient temperature where it stirred for 2 h. The reaction mixture was quenched with saturated aq. NH4CI and extracted with ethyl acetate. The organic layer was washed with water (2x) and the aqueous layer was further extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (0-10% EtOAc in PE) to give l-bromo-2-((3-nitrophenoxy)methyl)benzene (6.7 g, 21.1 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO) 87.87-7.83 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.64-7.60 (m, 2H), 7.53-7.51 (m, 1H), 7.47.7.42 (m, 1H), 7.36-7.32 (m, 1H), 5.26 (s, 2H).

[1024] Step B: To a solution of l-bromo-2-((3 -nitrophenoxy )methyl)benzene (6.7 g, 21.7 mmol) in ethanol (100 mL) and water (20 mL) was added iron (6.0 g, 109 mmol) and ammonium chloride (11.6 g, 217 mmol). The reaction was stirred at 80 °C for 16 h. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give the crude compound. The crude compound wasAttorney Docket No.: ABR-00125

[1025] purified by column chromatography (0-6% MeOH in DCM) to give 3 -((2-bromobenzyl)oxy)aniline (5.2 g, 17.8 mmol) as a yellow oil. m / z (ESI-pos) M+l = 278.1 / 280.0 Step C: To a solution of 3-((2-bromobenzyl)oxy)aniline (5.2 g, 18.77 mmol) in 6M aq. HC1 at 0 °C was added a solution of sodium nitrite (1.42 g, 20.64 mmol) in water (10 mL) dropwise. The mixture was then stirred at 0 °C for Ih. A solution of SnCl₂ (7.1 g, 37.54 mmol) in con. HC1 (30 mL) was added dropwise to the reaction mixture and then the mixture was allowed to warm to ambient temoerature and stirred for 2h. The pH was adjusted to ~14 with 4N aq. NaOH. The mixture was diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution, and dried over anhydrous Na2SO4., filtered and evaporated under reduced pressure. The residue was purified by column chromatography (0-10% MeOH in DCM) to give (3-((2-bromobenzyl)oxy)phenyl)hydrazine (3.05 g) as a yellow oil. m / z (ESI-pos) M+l = 293.0 / 295.0

[1026] Step D: To a solution of (3-((2-bromobenzyl)oxy)phenyl)hydrazine (3.05 g, 10.44 mmol) in Ethanol (50 mL) was added tert-butyl (2S)-3-cyano-2-methyl-4-oxo-l-piperidinecarboxylate (2.48 g, 10.44 mmol). The resulting mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (0-6% MeOH in DCM) to give tert-butyl (S)-3-amino-2-(3-((2-bromobenzyl)oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5 -carboxylate (3.34 g, 5.85 mmol) as a yellow oil. m / z (ESI-pos) M+l = 513.1 / 515.1 Step E: To a solution of tert-butyl (S)-3-amino-2-(3-((2-bromobenzyl)oxy)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.0 g, 3.90 mmol) and NaHCO₃ (982 mg, 11.7 mmol) in tetrahydrofuran (30 mL) was added benzyl chloroformate (761 mg, 7.81 mmol). The reaction was stirred at 25 °C for 2 hr. The reaction mixture was concentrated to give tert-butyl (S)-2-(3-((2-bromobenzyl)oxy)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.2 g) as a crude yellow oil, which was used directly for the next step without any further purification, m / z (ESI-pos) M+l = 633.1 / 635.1

[1027] StepF: Crude tert-butyl (S)-2-(3-((2-bromobenzyl)oxy)phenyl)-4-methyl-3-((phenoxy carbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.2 g crude, 3.90 mmol) was dissolved in pyridine (50 mL), to which 2, 2-dimethoxy ethylamine (1.23 g, 11.7 mmol) was added. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was concentrated under reduced pressure and the crude compound was purified by column chromatography (0-5% MeOH in DCM) to give tert-butyl (S)-3-{3-[2,2-Attorney Docket No.: ABR-00125

[1028] bi s(methylamino)ethyl]urei do } -2-(m- [ [(o-bromophenyl)methoxy]methyl [phenyl )-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (1.5 g, 1.86 mmol) as ayellow oil. m / z (ESI-pos) M+l = 644.2 / 646.2

[1029] Step G: To a solution of tert-butyl (S)-3-{3-[2,2-bis(methylamino)ethyl]ureido}-2-(m-{[(o-bromophenyl)methoxy]methyl}phenyl)-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (1.5 g, 2.33 mmol) in tetrahydrofuran (50 mL) was added methanesulfonic acid (291 mg, 3.03 mmol). The mixture was stirred at 60 °C for 2 hr. Aqueous K3PO4 was added to adjust the pH to ~9, and then Boc2O (507 mg, 2.33 mmol) was added. The resulting mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with IN aq. HC1 (20 mL), followed by brine and then dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography (0-80% EtOAc in PE) to give tert-butyl (S)-2-(3-((2-bromo benzyl)oxy)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (850 mg, 1.32 mmol) as a yellow solid, m / z (ESI-pos) M+l = 580.1 / 582.1

[1030] Step H: To a solution of tert-butyl (S)-2-(3-((2-bromobenzyl)oxy)phenyl)-4-methyl-3-(2-oxo-2,3-dihydro-lH-imidazol-l-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1360 mg, 2.34 mmol) in N-methyl-2-pyrrolidone (80 mL) was added dipotassium carbonate (972 mg, 7.04 mmol), (1R,2R)-1,2-bis(methylamino)cyclohexane (332 mg, 2.34 mmol), copper iodide (445 mg, 2.34 mmol) at 25 °C under N2. The resulting mixture was stirred at 130 °C for 16 hr. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate, washed with water (2x) and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with aq. LiCl solution and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The obtained residue was purified by column chromatography (0-80% EtOAc in PE) to give tert-butyl (S)-8-methyl-28-oxo-22-oxa-2,3,7,l 1,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa l(27),3,9,12,15,17,19,23,25-nonaene-7-carboxylate (120 mg) as a yellow solid, m / z (ESI-pos) M+l = 500.1

[1031] Step I: tert-butyl (S)-8-methyl-28-oxo-22-oxa-2,3,7,ll,14-pentaazahexacyclo [21.3.1.111,14.02,10.04,9.015,20]octacosa l(27),3,9,12,15,17,19,23,25-nonaene-7-carboxylate (120 mg, 240 pmol) was dissolved in HCl / l,4-di oxane (4M, 5 mL) and stirred at 25 °C for Ih. The reaction mixture was directly concentrated to give the crude (S)-8-methyl-22-oxa-2,3,7,l 1,14-Attorney Docket No.: ABR-00125

[1032] pentaazahexacyclo[21.3.1.111,14.02,1°.04,9.015,2O]octacosa-l(27),3,9,12,15,17,19,23,25-nonaen-28-one hydrogen chloride (112 mg) as a yellow solid, which was used to the next step directly. m / z (ESI-pos) M+l = 400.2

[1033] Step J: To a solution of 5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolecarboxylic acid (115 mg, 280 pmol), DIEA (109 mg, 841 pmol) in DMF (5 mL) was added HATU (160 mg, 421 pmol). The mixture was stirred at 25 °C for 20 minutes and (S)-8-methyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[21.3.1.111,14.02,10.04,9.015,20]octacosa-l(27),3,9,12,15,17,19,23,25-nonaen-28-one hydrogen chloride (112 mg, 280 pmol) was added. The resulting mixture was stirred at 25 °C for 16 hr, then diluted with ethyl acetate, washed with water (2x). The aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with brine solution, then dried over anhydrous Na2SO4, filtered and the filtrate was evaporated under reduced pressure to give the crude compound which was purified by column chromatography (0-10% MeOH in DCM) to give the desired product (130 mg), which was further purified by prep-HPLC [Instrument: GILSON Prep LC with UV detector; Column: XBridge Prep C18 19*150mm 5um; Gradient: eluted with 70-95 % ACN in H2O(0.1%NH4HCO3) in 10 mins; Flow rate: 15ml / min] to give (S)-7-({5-[(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-[(lS,2S)-2-methyl-l-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)cyclopropyl]-2-indolyl}carbonyl)-8-methyl-22-oxa-2,3,7,ll,14-pentaazahexacyclo[21.3.1.111,14.02,1°.04,9.015,2O]octacosa-l(27),3,9,12,15,17,19,23,25-nonaen-28-one (30 mg) as yellow solid, which was dissolved in MeOH (100 mL) and separated by chiral supercritical fluid chromatography (separation condition: Daicel CHIRALPAK IC_3, 4.6mm*250mm 5um; Mobile Phase: MeOH-DCM-DEA at 1 mL / min; Temp: 30 °C; Wavelength: 254 nm) to afford Isomer 1 (13.8 mg) and Isomer 2 (11.4 mg) as white solids. (The absolute configuration was unknown, the configuration of two atropisomers were assigned arbitrarily).

[1034] Isomer 1: m / z (ESI-pos) M+l = 793.3; 1H NMR (400 MHz, DMSO) 8 11.67 (s, 1H), 7.74-6.69 (m, 1H), 7.53-7.41 (m, 4H), 7.38-7.34 (m, 1H), 7.26-7.17 (m, 3H), 7.11-7.02 (m, 2H), 6.87 (s, 1H), 6.66-6.61 (m, 1H), 6.18 (s, 1H), 5.83-5.66 (m, 1H), 5.54 (d, J = 13.2 Hz, 1H), 4.94 (d, J = 13.6 Hz, 1H), 4.54-4.38 (m, 1H), 3.73 (d, J = 7.6 Hz, 2H), 3.60-3.49 (m, 1H), 3.00- 2.87 (m, 2H), 1.86-1.50 (m, 11H), 1.28 (s, 3H), 1.24-1.12(m, 6H).

[1035] Isomer 2: m / z (ESI-pos) M+l = 793.3; 1H NMR (400 MHz, DMSO) 6 11.59 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.50-7.38 (m, 4H), 7.35-7.26 (m, 2H), 7.24-7.17 (m, 2H), 7.13-7.08 (m, 1H), 6.96 (s, 1H), 6.87 (s, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.78-5.52 (m, 2H), 4.95 (d, JAttorney Docket No.: ABR-00125

[1036] = 13.6 Hz, 1H), 4.51-4.34 (m, 1H), 3.76-3.70 (m, 2H), 3.63-3.51 (m, 1H), 2.99-2.83 (m, 2H), 1.76-1.49 (m, 11H), 1.27 (s, 3H), 1.24-1.12 (m, 6H).

[1037] Example 22 - Synthesis of Compound 22

[1038] Synthetic Scheme

[1039] o

[1040] Boc

[1041]

[1042] Boc HAttorney Docket No.: ABR-00125

[1043]

[1044] Procedure for Synthesis of Compound 22

[1045]

[1046] (Compound 22)

[1047] (S)-7-(15-r(S)-2,2-dimethyltetrahydro-4H-pyran-4-yl]-l-r(lS,2S)-2-methyl-l-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-yl)cvclopropyl1-2-indolyl}carbonyl)-8-methyl-21-oxa-2,3,7,l 1,14- pentaazahexacyclor21,3,1.111,14,02,10,04,9.015,2O]octacosa-l(27),3,9,12,15,17,19,23,25-nonaen- 28-one

[1048] Step A: To a solution of (3-aminophenyl)methanol (4 g, 32.5 mmol) in cone. HC1 (15 mL) and H2O (15 mL) at 0 °C was added NaNCh (2.47 g, 35.7 mmol) in H2O (5 mL), dropwise. After the mixture was stirred at 0 °C for 45 min, SnCl₂ (13.5 g, 71.5 mmol) in cone. HC1 (15 mL) and H2O (15 mL) was added dropwise and the mixture was stirred for 1 hour. The reaction was quenched with aqueous NaOH (ION, 35 mL) to adjust the pH to about 9. Then the mixture was extracted with EtOAc (3x) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in PE) to give (3-hydrazinylphenyl)methanol (1.8 g, 11.7 mmol) as a yellow solid, m / z (ESI-pos) M+l = 139.1Attorney Docket No.: ABR-00125

[1049] Step B: To a solution of (3-hydrazinylphenyl)methanol (1.8 g, 11.7 mmol) in EtOH (40 mL) was added tert-butyl (2S)-3-cyano-2-methyl-4-oxopiperidine-l-carboxylate (2.79 g, 11.7 mmol). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography (0-100 EtOAc in PE) to give tert-butyl (S)-3-amino-2-(3-(hydroxymethyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.4 g, 8.54 mmol) as a yellow solid, m / z (ESI-pos) M+l = 359.2.

[1050] Step C: To a solution of tert-butyl (S)-3-amino-2-(3-(hydroxymethyl)phenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (3.4 g, 8.54 mmol) in DCM (50 mL) at 0 °C was added imidazole (1.16 g, 17.1 mmol) and tert-butyl(chloro)bis(phenyl)silane (2.58 g, 9.39 mmol). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with ELO and extracted with DCM (2x). The combined organics were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (0-25% EtOAc in PE) to give tert-butyl (S)-3-amino-2-(m-{[tert-butylbis(phenyl)siloxy] methyl}phenyl)-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (5 g, 7.54 mmol) as a yellow solid, m / z (ESI-pos) M+l = 597.3.

[1051] Step D: To a solution of tert-butyl (S)-3-amino-2-(m-{[tert-butylbis(phenyl)siloxy]methyl} phenyl)-4-methyl-l,2,5-triaza-2,4,6,7-tetrahydro-5H-indene-5-carboxylate (5 g, 7.54 mmol) in tetrahydrofuran (50 mL) at 0 °C was added DIEA (2.92 g, 22.6 mmol) and benzyl chloroformate (2.36 g, 15.1 mmol). The mixture was stirred at ambient temperature for 2 hours. Then the mixture was concentrated to get crude tert-butyl (S)-2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (7.7 g, 7.52 mmol) as a yellow solid, that was used directly in the subsequent step, m / z (ESI-pos) M+l = 717.3.

[1052] Step E: To a solution of tert-butyl (S)-2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)-4-methyl-3-((phenoxycarbonyl)amino)-2, 4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (7.7 g, 7.52 mmol) in pyridine (50 mL) was added 2,2-dimethoxyethylamine (2.37 g, 22.6 mmol) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (0-50% EtOAc inAttorney Docket No.: ABR-00125

[1053] PE) to giv...

Claims

Attorney Docket No.: ABR-00125ClaimsWe claim:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof; wherein,A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;B is –(alkylene)O(alkylene)–, alkylene, haloalkylene, alkenylene, –O(alkylene)–, –(alkylene)O–, –O(alkylene)O–,–O(alkylene)O(alkylene)–, –(alkylene)O(alkylene)O–,–S(alkylene)–, –(alkylene)S–, –(alkylene)S(alkylene)–, –S(alkylene)S–, –S(alkylene)S(alkylene)–, –(alkylene)S(alkylene)S– –NH(alkylene)–, –(alkylene)NH–, –(alkylene)NH(alkylene)–, –NH(alkylene)NH– –NH(alkylene)NH(alkylene)–, –(alkylene)NH(alkylene)NH–, –N(alkyl)(alkylene)–, –(alkylene)N(alkyl)–, or is a bond;C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;orRing Z is heterocycloalkylene or heteroarylene;R1is independently for each occurrence alkyl, alkoxy, or halo; or two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring;R2is independently for each occurrence alkyl, alkoxy, or halo;663Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125R3is haloalkyl, unsubstituted cycloalkyl, cycloalkyl substituted with alkyl, cycloalkyl substituted with haloalkyl, cycloalkyl substituted with halo, unsubstituted heteroaryl, heteroaryl substituted with alkyl, heteroaryl substituted with halo, unsubstituted heterocycloalkyl, heterocycloalkyl substituted with alkyl, heterocycloalkyl substituted with halo, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;R4is independently for each occurrence alkyl, alkoxy, or halo;k is an integer selected from 0-2;m is an integer selected from 0-6;n is an integer selected from 0-4;p is an integer selected from 0-4; andq is an integer selected from 0-2.

2. The compound of claim 1, wherein the compound is represented by formula (I-a):or a pharmaceutically acceptable salt thereof; wherein,A is optionally substituted arylene, heteroarylene, or heterocycloalkylene;B is alkylene, haloalkylene, alkenylene, -O(alkylene)-, -(alkylene)O-, -(alkylene)O(alkylene)-,-O(alkylene)O-, -O(alkylene)O(alkylene)-, -(alkylene)O(alkylene)O-,-S(alkylene)-, -(alkylene)S-, -(alkylene)S(alkylene)-, -S(alkylene)S-,-S(alkylene)S(alkylene)-, -(alkylene)S(alkylene)S-, -NH(alkylene)-, -(alkylene)NH-, -(alkylene)NH(alkylene)-, -NH(alkylene)NH-664FoleyHoagUS 13278104.2Attorney Docket No.: ABR-00125-NH(alkylene)NH(alkylene)-, -(alkylene)NH(alkylene)NH-,-N(alkyl)(alkylene)-, -(alkylene)N(alkyl)-, or is a bond;C is optionally substituted arylene, heteroarylene, or heterocycloalkylene;Ring Z is heteroarylene or heterocycloalkylene;R1is independently for each occurrence alkyl, alkoxy, or halo; ortwo occurrences of R1taken together with the atom(s) to which they are attached form an optionally substituted cycloalkyl ring;R2is independently for each occurrence alkyl, alkoxy, or halo;R3is haloalkyl, unsubstituted cycloalkyl, cycloalkyl substituted with alkyl, cycloalkyl substituted with haloalkyl cycloalkyl substituted with halo, unsubstituted heteroaryl, heteroaryl substituted with alkyl, heteroaryl substituted with halo, unsubstituted heterocycloalkyl, heterocycloalkyl substituted with alkyl, heterocycloalkyl substituted with halo, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;R3ais independently for each occurrence alkyl, alkoxy, halo, haloalkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkoxy, -NH2, -NH(alkyl), or -N(alkyl)2;R4is independently for each occurrence alkyl, alkoxy, or halo;k is an integer selected from 0-2;m is an integer selected from 0-6;n is an integer selected from 0-4;p is an integer selected from 0-4; andq is an integer selected from 0-2.

3. The compound of claim 1 or 2, wherein k is 1.665Foley HoagUS 13278104.2Attorney Docket No.: ABR-001254. The compound of any one of claims 1-3, wherein the compound is represented by formula (I-b):(RA)r(I-b)or a pharmaceutically acceptable salt thereof; wherein,RAis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl; andr is an integer selected from 0-4.666Foley HoagUS 13278104.2Attorney Docket No.: ABR-001255. The compound of any one of claims 1-3, wherein the compound is represented by formula (I-c):(R ')mR3(R3a)P(I-c)or a pharmaceutically acceptable salt thereof; wherein,Rcis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl; ands is an integer selected from 0-4.667Foley HoagUS 13278104.2Attorney Docket No.: ABR-001256. The compound of any one of claims 1-3, wherein the compound is represented by formula (I-d):or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1-3 and 6, wherein the compound is represented by formula (I-e):or a pharmaceutically acceptable salt thereof.668Foley HoagUS 13278104.2Attorney Docket No.: ABR-001258. The compound of claim 4, wherein the compound is represented by formula (I-f):(RA)ror a pharmaceutically acceptable salt thereof.

9. The compound of claim 5, wherein the compound is represented by formula (I-g):or a pharmaceutically acceptable salt thereof.669Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012510. The compound of any one of claims 1-9, wherein the compound is represented by formula (I-h):N II (RNR3Z7“(R:(i-h);or a pharmaceutically acceptable salt thereof; wherein,RAis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl;R^C is independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO₂, -N3, aryl, or heteroaryl;r is an integer selected from 0-4; ands is an integer selected from 0-4.670Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012511. The compound of any one of claims 1-3, 5-7, and 9, wherein A is optionally substituted phenylene, pyridinylene, pyridazinylene, pyrimidinylene, or pyrazinylene.

12. The compound of claim 11, wherein A is optionally substituted phenylene.

13. The compound of claim 11 or 12, wherein A is optionally substituted by one or more RA, wherein RAis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl), -S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO2, -N3, aryl, or heteroaryl.

14. The compound of any one of claims 4, 8, 10, and 13, wherein each RAis independently alkyl, haloalkyl, cycloalkyl, alkoxy, or halo.

15. The compound of claim 14, wherein each RAis independently methyl, trifluoromethyl, cyclopropyl, methoxy, fluoro, or chloro.

16. The compound of claim 14 or 15, wherein each RAis independently methyl, fluoro, or chloro.

17. The compound of any one of claims 4, 8, 10, and 14-16, wherein r is an integer selected from 1 or 2.

18. The compound of any one of claims 4, 8, and 10, wherein r is 0.671Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012519. The compound of any one of claims 1-3, 5-7, 9, and 11-15, wherein -A-* isF FClCl Clwherein the asterisk (*) indicates the point of attachment to B.Cl20. The compound of claim 19, wherein -A-* isClwherein the asterisk (*) indicates the point of attachment to B.

21. The compound of any one of claims 1-3, 5-7, 9, and 11-20 wherein B is*-CH2CH2-, *-CH2CH2CH2-,*-CH2CH2CH2CH2-, *-CH2CH2CH2CH2CH2-*-CF2CH2CH2CH2-, *-CH(CH3)OCH2- *-OCH2-,*-CH2O-, *-OCH2CH2-*-CH2OCH2-, *-CH2CH2O-,*-OCH2CH2CH2-, *-CH2OCH2CH2-, *-CH2CH2OCH2-*-CH2CH2CH2O-, *-OCH2CH2O-, *-OCH2CH2CH2CH2-, *-CH2OCH2CH2CH2-*-CH2CH2OCH2CH2-,*-CH2CH2CH2OCH2-, *-CH2CH2CH2CH2O-, *-SCH2-, *-CH2S-*-SCH2CH2-,*-CH2SCH2-, *-CH2CH2S-, *-SCH2CH2CH2-, *-CH2SCH2CH2-*-CH2CH2SCH2-,*-CH2CH2CH2S-, *-SCH2CH2S-, *-SCH2CH2CH2CH2-*-CH2SCH2CH2CH2-, *-CH2CH2SCH2CH2-,*-CH2CH2CH2SCH2-672FoleyHoagUS 13278104.2Attorney Docket No.: ABR-00125*-CH2CH2CH2CH2S-, *-CH=CH- *-CH=CHCH2- *-CH2CH=CH- *-CH=CHCH2CH2- *-CH2CH=CHCH2- *-CH2CH2CH=CH- *-CH=CHCH2CH2CH2- *-CH2CH=CHCH2CH2- *-CH2CH2CH=CHCH2- *-CH2CH2CH2CH=CH- *-N(CH3)CH2CH2- or *-CH2CH2N(CH3)-;wherein the asterisk (*) indicates the point of attachment to A.

22. The compound of claim 21, wherein B is *-CH2CH2- *-CH2CH2CH2- *-CH2CH2CH2CH2- *-CF2CH2CH2CH2- *-CH=CHCH2- *-CH2CH=CHCH2- *-CH2O- *-OCH2- *-CH2OCH2- *-OCH2CH2- *-OCH2CH2CH2- *-CH2OCH2CH2-, *-CH2CH2OCH2- *-CH2CH2CH2O- *-OCH2CH2O- *-CH(CH3)OCH2- *-N(CH3)CH2CH2- *-SCH2CH2- *-SCH2CH2CH2-;wherein the asterisk (*) indicates the point of attachment to A.

23. The compound of claim 21 or 22, wherein B iswherein the asterisk (*) indicates the point of attachment to A.

24. The compound of claim 21 or 22, wherein B is *-CH2OCH2-;wherein the asterisk (*) indicates the point of attachment to A.

25. The compound of any one of claims 1-4, 6-8, and 11-24, wherein C is optionally substituted phenylene, pyridinylene, pyridazinylene, pyrimidinylene, pyrazinylene, indolylene, indazolylene, benzimidazolylene, or 2-hydroxybenzimidazolylene.

26. The compound of claim 25, wherein C is optionally substituted phenylene.

27. The compound of claim 25 or 26, wherein C is optionally substituted by one or more Rc, wherein Rcis independently for each occurrence alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, silyl, -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, hydroxyalkyl, alkoxy, -SH, -S-alkyl, -S-S-alkyl, halo, haloalkyl, haloalkoxy, -C(O)H, -C(O)-alkyl, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)2, -C(O)N(alkyl)(cycloalkyl), -C(O)OH, -OC(O)-alkyl, -C(O)O-alkyl, -C(O)S-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2-cycloalkyl, -S(O)2NH2, -S(O)2NH(alkyl),673Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125-S(O)2N(alkyl)2, -S(O)NH2, -S(O)NH(alkyl), -S(O)N(alkyl)2, -S(=O)(=NH)(-alkyl), -S(=O)(=N-alkyl)(-alkyl), -CH2S(O)2(alkyl), -OP(O)(O-alkyl)2, -P(O)(alkyl)2, -CN, -NO2, -N3, aryl, or heteroaryl.

28. The compound of any one of claims 5, 9-24, and 27, wherein each Rcis independently alkyl, alkoxy, halo, -C(O)NH(alkyl), -C(O)N(alkyl)(cycloalkyl), -S(O)2-alkyl, -S(O)2-cycloalkyl, -CN, or heterocycloalkyl.

29. The compound of claim 28, wherein each Rcis independently methyl, methoxy,30. The compound of claim 28 or 29, wherein Rcis fluoro.

31. The compound of any one of claims 5, 9-24, and 28-30, wherein s is an integer selected from 1 or 2.

32. The compound of any one of claims 5 and 9-24, wherein s is 0.

33. The compound of any one of claims 1-4, 6-8, 11-25, and 27-29, wherein *-C- is674Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125wherein the asterisk (*) indicates the point of attachment to B.

34. The compound of claim 33, wherein *-C- iswherein the asterisk (*) indicates the point of attachment to B.

35. The compound of any one of claims 1-34, wherein ring Z is heterocycloalkylene.

36. The compound of claim 35, wherein ring Z is tetrahydropyranyl ene, morpholinylene, 8-oxa-3-azabicyclo[3.2.1]octanylene, 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinylene, 6,7-dihydro-5H-cyclopenta[b]pyridinylene, 2-oxa-6-azaspiro[3.3]heptanylene, or 1,4-oxazepanylene.

37. The compound of claim 35 or 36, wherein ring Z is morpholinylene.

38. The compound of any one of claims 1-34, wherein ring Z is heteroarylene.

39. The compound of claim 38, wherein ring Z is pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, imidazolylene, 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazinylene, 6,7-dihydro-5H-cyclopenta[b]pyridinylene, lH-pyrrolo[2,3-b]pyridinylene, 1,2,3-triazolylene, or pyrazolylene.

40. The compound of claim 38 or 39, wherein ring Z is pyridinylene.

41. The compound of any one of claims 1-40, wherein R3is -NH2, -N(Me)(Et), NMe2,-CHF2, -CF3, -CH2CF3, -CF2CH3, -CF2CF3, -0CHF2, -OCF3,675Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012542. The compound of claim 41, wherein R3is CF3, -CF2CH3, or43. The compound of any one of claims 1-42, wherein R3ais alkyl or halo.

44. The compound of claim 43, wherein R3ais methyl or fluoro.

45. The compound of any one of claims 1-44, wherein p is 1.

46. The compound of any one of claims 1-42, wherein p is 0.676Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012549. The compound of any one of claims 1-6 and 11-48, wherein R1is alkyl.

50. The compound of any one of claim 49, wherein R1is methyl.

51. The compound of any one of claims 1-5 and 11-48, wherein two geminal occurrences of R1taken together with the carbon atom to which they are attached form an optionally substituted spirocyclic cycloalkyl ring.

52. The compound of claim 51, wherein two geminal occurrences of R1taken together with the carbon atom to which they are attached form a spirocyclic cyclopropyl ring.

53. The compound of any one of claims 1-5 and 11-50, wherein m is an integer selected from 1-3.

54. The compound of claim 53, wherein m is 1.

55. The compound of any one of claims 1-6 and 11-54, wherein R2is alkyl.

56. The compound of claim 55, wherein R2is methyl.

57. The compound of any one of claims 1-5 and 11-56, wherein n is 1.

58. The compound of any one of claims 1-5 and 11-57, wherein q is 0.

59. The compound of any one of claims 1, 11-13, 19-27, and 33-58, wherein ring D is677Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012560. The compound of claim 1, wherein the compound is selected from:678Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125679Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125680Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125 / ) z= / a \ zO J VA. o J / AA "zX) ^°\AA 'Ct,uA’ / \) \ z>5S5 / <z( / =\ / z= / o \ z<A A f^ V°z■ ft xiI7C AXQ^Oor a pharmaceutically acceptable salt thereof.681Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012561. The compound of claim 1, wherein the compound is selected from:682Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125683Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125684Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125685Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125686Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125687Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125688Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125689Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125690Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125691Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125692Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125693Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125694Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125695Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125696Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125697Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125698Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125699Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125or a pharmaceutically acceptable salt thereof.

62. A compound, wherein the compound is selected from:700Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125701Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125702Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125703Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125or a pharmaceutically acceptable salt thereof.704 Foley HoagUS 13278104.2Attorney Docket No.: ABR-0012563. A compound, wherein the compound is selected from:X X ) AIN^NX) ^i\rdb-dN^NHF — o / ^ O / SQN' N JI J } N-N JI ] jdb < 7 d b -<5 N^NH'°4 bAoF / (DN -N |l I |l X X J 'd b (? d N^NHb ■ d N^NH bAobA0705Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125706Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125707Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125708Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125709Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125710Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125711Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125712Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125713Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125714Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125715Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125716Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125717Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125718Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125719Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125720Foley HoagUS 13278104.2Attorney Docket No.: ABR-00125or a pharmaceutically acceptable salt thereof.

64. A pharmaceutical composition comprising a compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

65. A method of inducing GLP-1R activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 64.

66. A method of treating a GLP-1 -associated disease, disorder, or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 64.

67. The method of claim 66, wherein the GLP-1 -associated disease, disorder, or condition is type I diabetes mellitus, type 2 diabetes mellitus, early onset type 2 diabetes mellitus, idiopathic type I diabetes mellitus (Type lb), youth onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), latent autoimmune diabetes in adults (LADA), obesity, weight gain from use of other agents, idiopathic intracranial hypertension, Wolfram syndrome, gout, excessive sugar craving, hypertriglyceridemia, dyslipidemia, hyperlipidemia, malnutrition-related diabetes, gestational diabetes, kidney disease, adipocyte dysfunction, sleep apnea, obstructive sleep apnea, visceral adipose deposition, eating disorders, cardiovascular disease, congestive heart failure, myocardial infarction, left ventricular721FoleyHoagUS13278104.2Attorney Docket No.: ABR-00125hypertrophy, peripheral arterial disease, stroke, hemorrhagic stroke, ischemic stroke, transient ischemic attacks, atherosclerotic cardiovascular disease, traumatic brain injury, peripheral vascular disease, endothelial dysfunction, impaired vascular compliance, vascular restenosis, thrombosis, hypertension, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, hyperglycemia, hyperosmolar hyperglycemic state, post-prandial lipemia, metabolic acidosis, diabetic ketoacidosis, ketosis, hyperinsulinemia, impaired glucose metabolism, insulin resistance, hepatic insulin resistance, alcohol use disorder, chronic renal failure, metabolic syndrome, syndrome X, smoking cessation, premenstrual syndrome, anginapectoris, diabetic nephropathy, impaired glucose tolerance, neuropathy, diabetic neuropathy, neuropathy of eight cranial nerve, neuropathic pain, diabetic retinopathy, macular degeneration, cataract, glomerulosclerosis, arthritis, primary and secondary osteoarthritis, psoriatic arthritis, rheumatoid arthritis, osteoporosis, treatment of addiction, cocaine dependence, bipolar disorder, major depressive disorder, cognitive dysfunction in major depressive disorder, persistent depressive disorder (dysthymia), skin and connective tissue disorders, foot ulcerations, foot ulcers, pressure ulcers, psoriasis, primary polydipsia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, inflammatory bowel disease, colitis, irritable bowel syndrome, Crohn' s disease, short bowel syndrome, Parkinson's disease, Alzheimer's disease, Huntington’s disease, impaired cognition, schizophrenia, Polycystic Ovary Syndrome (PCOS), peri- and post-menopausal symptom regulation, peri- and post-menopausal hormone regulation, gambling disorder, hypersexuality, adrenaline addiction, tobacco-use disorder, substance use disorder, metabolic dysfunction-associated steatotic liver disease (MASLD), spinal stenosis, degenerative disc disease, fractures, major and mild neurocognitive disorder, multiple sclerosis, Addison’s disease, celiac disease, Grave’s disease, Hashimoto’s thyroiditis, myasthenia gravis, pernicious anemia, Sjogren’s syndrome, systemic lupus erythematosus, cancer, cholecystitis, coronary artery disease, cardiac fibrosis, atrial fibrillation, arrythmia, renal fibrosis, asthma, restrictive lung disease, erectile dysfunction, infertility, glaucoma, macular edema, diabetic papillopathy, nyctalopia, sensorineural hearing loss, auditory neuropathy spectrum disorder, auditory processing disorder, malignant otitis externa, meniere’s disease, gastroparesis, gastroesophageal reflux disease, hepatic fibrosis, chronic and acute pancreatitis, infection-associated chronic condition (long COVID), cellulitis (bacterial and fungal), periodontal disease, HIV lipohypertrophy, necrobiosis lipoidica, acanthosis nigricans, diabetic dermopathy, scleroderma-type skin changes, scleroderma diabetocorum, bullosis diabeticorum, ichthyosiform changes of the shins, xerosis, acquired perforating dermatosis,722FoleyHoagUS13278104.2Attorney Docket No.: ABR-00125eruptive xanthomas, acrochordons, diabetes-associated pruritis, Huntley’s papules, keratosis pilaris, pigmented purpuric dermatosis, palmar erythema, periungual telangi ectasias, rubeosis faciei, onychocryptosis, generalized granuloma annulare, vitiligo, hidradenitis supparativa, glucagonoma, all-cause mortality, sedentary lifestyle, body dysmorphic disorder, inferiority complex, or any combination thereof.

68. The method of claim 67, wherein the GLP-1 -associated disease, disorder, or condition is obesity.

69. The method of claim 67, wherein the GLP-1 -associated disease, disorder, or condition is cancer.

70. The method of claim 67, wherein the cancer is endometrial cancer, breast cancer, colorectal cancer, prostate cancer, liver cancer, gallbladder cancer, kidney cancer, ovarian cancer, esophageal cancer, meningioma cancer, stomach cancer, or pancreatic cancer.723FoleyHoagUS13278104.2

Images