5,6-bicyclic 5-HT2ar agonists and uses thereof

Abstract

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

Description

5, 6- BICYCLIC 5-HT2AR AGONISTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 704.677, filed October 8. 2024; U.S. Provisional Application No. 63 / 756.441, filed February 10. 2025; and U.S. Provisional Application No. 63 / 879, 126, filed September 10, 2025; the contents of each of which are herein incorporated by reference.TECHNICAL FIELD OF THE INVENTION

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

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

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

[0005] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, arc effective as agonists of 5-HT2AR. In some embodiments, the present disclosure provides a compound of formula I":1 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

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

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

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

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

[0011] In another aspect, the present disclosure provides methods of treating and / or preventing a410095-002WO (221369)BUSINESS.33570138.1neurological disease, disorder, or condition in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

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

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

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

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

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

[0017] The tenn “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that3 410095-002WO (221369)BUSINESS.33570138.1is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic G-C, hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of tire molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0018] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:4 410095-002WO (221369)BUSINESS.33570138.1

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

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

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

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

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

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

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

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

[0027] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy.” or410095-002WO (221369)BUSINESS.33570138.1“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to. phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and tire like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl).

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

[0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical.” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10- membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3.4-dihydro-2 / / pyrrolyl). NH (as in pyrrolidinyl), or+NR (as in6 410095-002WO (221369)BUSINESS.33570138.1' substituted pyrrolidinyl).

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

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

[0032] As described herein, compounds of the disclosure may contain “substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety of compounds are replaced with a suitable substituent. “Substituted”). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or410095-002WO (221369)BUSINESS.33570138.1more of the purposes disclosed herein.

[0033] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; (CI [?) >4F<OI -(CB I2)u4OR°: -0(CBl2)o 4R0, -O-(CBB2)CMC(O)OR°; - (CH2)CMCH(OR°)2; -(CH;)„ 4SR0; -(CHfr, 4 Ph. which may be substituted with R°; -(CH2)N40(CBl2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CBI2)OMO(C1-I2)O i- pyridyl which may be substituted with R°; -NCh; -CN; -N3; -(CH2)o^N(R°)2; -(CH2)0^N(R°)C(O)R°; - N(R°)C(S)R°; -(CH2)O4N(R°)C(0)NRO2; -N(RO)C(S)NR°2; -(CH2)OMN(R°)C(0)OR0;N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)„4C(O)R°; -C(S)R°; - (CH2)(I 4C(O)OR°; -(CH2)OMC(0)SR°; -(CH2)NJZ’(O)OSIR°3: -(CH2)0MOC(O)R°; -OC(O)(CH2)„4S R°; - (CH2)CMSC(O)R°; -(CH2)OMC(0)NR02; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)OMSSR°; -(CH2)O 4S(O)2R°; -(CH2)„4S(0)20RO; -(CH2)OMOS(0)2R°; -S(O)2NRO2; -(CH2)OMS(0)R°; -N(R°)S(O)2NRO2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CI I2)o4P(0)2R°; -(CH2)OMP(0)R02; -(CI k) .40P(0)R°2; - (CH2)CMOP(O)(OR°)2; SiR0?,; -(CM straight or branched alkylene)O-N(R°)2; or -(CIM straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-e aliphatic, -CH2Ph, 0(CB42)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

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

[0035] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0. =S. =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*. =NOR*, - O(C(R*2))2-3O-, or-S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen,8 410095-002WO (221369)BUSINESS.33570138.1Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-e aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

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

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

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

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

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i 4alkyl)4 salts. In some embodiments, the provided compounds are purified in salt form for9 410095-002WO (221369)BUSINESS.33570138.1convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromotagraphic purification are contemplated herein (e.g., diammonium salts) and are readily apparent to those having skill in the art.

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

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

[0043] In some embodiments, the present invention provides a compound of formula I":I" or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X3is N or CR3;X7is N or CR7; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR , -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-610 410095-002WO (221369)BUSINESS.33570138.1aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or each R5is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic or 3-to 8- membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R6is hydrogen or optionally substituted Ci.e aliphatic;R8is:Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl, or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl;Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom;Ring C is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl;Ring D is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having a single nitrogen heteroatom; each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; or two R9groups on the same or different atoms may be taken together to fonn an optionally substituted 3- to 8-membered saturated or partially unsaturated spiro, fused, or bridged carbocyclyl or spiro, fused, or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R10is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6 aliphatic;R11is hydrogen, halogen, -CN, -OR -NR2, or an optionally substituted Ci-6 aliphatic; each R12is independently hydrogen or optionally substituted C1.6 aliphatic; each R13is independently hydrogen or optionally substituted Ci-e aliphatic;11 410095-002WO (221369)BUSINESS.33570138.1each R is independently hydrogen or optionally substituted Ci.6 aliphatic;L1is a covalent bond or an optionally substituted bivalent C1.3 saturated or unsaturated, straight or branched, hydrocarbon chain; m is 0, 1, or 2; and n is 0, 1. 2, 3, 4, 5. 6, 7, or 8.

[0044] In some embodiments, the present invention provides a compound of formula I':or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X3is N or CR3;X7is N or CR7; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR?, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1-6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or each R5is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic or 3-to 8- membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R6is hydrogen or optionally substituted C1-6 aliphatic;R8is:Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl, or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl;12 410095-002WO (221369)BUSINESS.33570138.1Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom;Ring C is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl;Ring D is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having a single nitrogen heteroatom; each R9is independently selected from halogen, -CN, -OR, -NR:, or an optionally substituted Ci-e aliphatic; or two R9groups on the same or different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiro, fused, or bridged carbocyclyl or spiro, fused, or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R10is independently selected from halogen, -CN, -OR, -NR:, or an optionally substituted Ci-6 aliphatic;R11is hydrogen, halogen, -CN, -OR. -NR2, or an optionally substituted Ci-6 aliphatic; each R12is independently hydrogen or optionally substituted Ci-e aliphatic; each R13is independently hydrogen or optionally substituted Ci-e aliphatic; each R is independently hydrogen or optionally substituted Ci-e aliphatic; m is 0, 1, or 2; and n is 0, 1, 2, 3, 4, 5. 6, 7, or 8.

[0045] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X7is N or CR7; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR2, -C(O)R,13 410095-002WO (221369)BUSINESS.33570138.1-C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1.6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or each R5is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic or 3-to 8- membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R6is hydrogen or optionally substituted Ci-e aliphatic;R8is:each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6 aliphatic; or two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur: each R10is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic;R11is hydrogen, halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; each R12is independently hydrogen or optionally substituted Ci-e aliphatic; each R13is independently hydrogen or optionally substituted C1.6 aliphatic; each R is independently hydrogen or optionally substituted Ci-6 aliphatic; m is 0, 1, or 2; and ms 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0046] As defined above and described herein, X1is N or CR1. In some embodiments, X1is N. In some embodiments, X1is CR1.

[0047] As defined above and described herein, X3is N or CR3. In some embodiments. X3is N. In some embodiments, X3is CR3.

[0048] As defined above and described herein, X7is N or CR7. In some embodiments, X7is N. In some embodiments, X7is CR7.14 410095-002WO (221369)BUSINESS.33570138.1

[0049] As defined above and described herein, each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-mcmbcrcd saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] In some embodiments, R1is selected from halogen, -CN, -OR’, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Cue aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is fluoro. In some embodiments, R1is chloro. In some embodiments, R1is bromo. In some embodiments, R1is -CN.

[0052] In some embodiments, R1is -OR5. In some embodiments, R1is -OH. In some embodiments, R1is -OCH3. In some embodiments, R1is -OCH2CH3. In some embodiments, R1is -OCF3.

[0053] In some embodiments, R1is -NR2. In some embodiments, R1is -NH2. In some embodiments, R1is -NR2, wherein each R is independently Ci-e aliphatic.

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

[0055] In some embodiments, R1is -C(O)OR. In some embodiments, R1is -C(O)OH. In some embodiments, R1is -C(O)OR, wherein R is Ci e aliphatic.

[0056] In some embodiments, R1is -NRC(O)R. In some embodiments, R1is -NHC(O)R. In some embodiments, R1is -NHC(O)R, wherein R is C1-6 aliphatic.

[0057] In some embodiments, R1is -OC(O)R. In some embodiments. R1is -OC(O)R, wherein R is C1.6 aliphatic.

[0058] In some embodiments, R1is optionally substituted Ci-e aliphatic. In some embodiments, R1is C1-6 aliphatic. In some embodiments. R1is methyl. In some embodiments, R1is ethyl. In some15 410095-002WO (221369)BUSINESS.33570138.1embodiments, R1is n-propyl. In some embodiments, R1is isopropyl. In some embodiments, R1is n-butyl. In some embodiments, R1is s-butyl. In some embodiments, R1is t-butyL

[0059] In some embodiments, R1is Ci-e aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R1is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments. R1is -CH2F. In some embodiments, R1is -CHF2. In some embodiments, R1is -CF3. In some embodiments, R1is -CH2CF3. In some embodiments, R1is Ci-g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R1is - CH2OH.

[0060] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted cyclopropyl. In some embodiments, R1is an optionally substituted cyclobutyl. In some embodiments, R1is an optionally substituted cyclopentyl. In some embodiments, R1is an optionally substituted cyclohexyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclobutyl. In some embodiments, R1is cyclopentyl. In some embodiments. R1is cyclohexyl.

[0061] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0062] In some embodiments, R1is an optionally substituted phenyl. In some embodiments, R1is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] In some embodiments, R1is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3. or - OCF3.

[0064] In some embodiments, R1is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, - OCF3, or phenyl.

[0065] In some embodiments, R2is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Cue16 410095-002WO (221369)BUSINESS.33570138.1aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is selected from halogen, -CN, -OR’, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, or an optionally substituted group selected from Ci-g aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0066] In some embodiments, R2is hydrogen. In some embodiments, R2is halogen. In some embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is -CN.

[0067] In some embodiments, R2is -OR5. In some embodiments, R2is -OH. In some embodiments, R2is -OCH3. In some embodiments, R2is -OCH2CH3. In some embodiments, R2is -OCF3.

[0068] In some embodiments, R2is -NR2. In some embodiments, R2is -NH2. In some embodiments, R2is -NR2, wherein each R is independently C1.6 aliphatic.

[0069] In some embodiments, R2is -C(O)NR2. In some embodiments, R2is -C(O)NH2. In some embodiments, R2is -C(O)NR2, wherein each R is independently Ci-g aliphatic.

[0070] In some embodiments, R2is -C(O)OR. In some embodiments, R2is -C(O)OH. In some embodiments. R2is -C(O)OR. wherein R is Ci-6 aliphatic.

[0071] In some embodiments, R2is -NRC(O)R. In some embodiments, R2is -NHC(O)R. In some embodiments, R2is -NHC(O)R, wherein R is Ci-g aliphatic.

[0072] In some embodiments, R2is -OC(O)R. In some embodiments. R2is -OC(O)R, wherein R is Ci-6 aliphatic.

[0073] In some embodiments, R2is optionally substituted Ci.g aliphatic. In some embodiments, R2is Ci-6 aliphatic. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is n-propyl. In some embodiments, R2is isopropyl. In some embodiments, R2is n-butyl. In some embodiments, R2is s-butyl. In some embodiments. R2is t-butyl.

[0074] In some embodiments. R2is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1.6 aliphatic. In some embodiments, R2is Ci.e aliphatic, optionally substituted with halogen. In some embodiments, R2is -CH2F. In some embodiments, R2is -CHF2. In some embodiments, R2is -CF3. In some embodiments, R2is -CH2CF3. In some embodiments, R2is Ci.g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R2is - CH2OH.

[0075] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted 3- to 6-membered17 410095-002WO (221369)BUSINESS.33570138.1saturated or partially unsaturated carbocyclyL In some embodiments, R2is an optionally substituted cyclopropyl. In some embodiments, R2is an optionally substituted cyclobutyl . In some embodiments, R2is an optionally substituted cyclopentyl. In some embodiments, R2is an optionally substituted cyclohexyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is cyclobutyl. In some embodiments, R2is cyclopentyl. In some embodiments, R2is cyclohexyl.

[0076] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0077] In some embodiments, R2is an optionally substituted phenyl. In some embodiments. R2is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0078] In some embodiments, R2is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, or -OCF3.

[0079] In some embodiments, R2is selected from hydrogen, fluoro, chloro, -OCH3. -OCH2CH3, - OCF3, or phenyl.

[0080] In some embodiments, R3is selected from halogen, -CN, -OR’, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-mcmbcrcd saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-e aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is -CN.

[0082] In some embodiments, R3is -OR5. In some embodiments, R3is -OH. In some embodiments, R3is -OCH3. In some embodiments, R3is -OCH2CH3. In some embodiments, R3is -OCF3.

[0083] In some embodiments, R3is -NR2. In some embodiments, R3is -NH2. In some embodiments, R3is -NR2, wherein each R is independently Ci-e aliphatic.

[0084] In some embodiments, R3is -C(O)NR2. In some embodiments, R3is -C(O)NH2. In some18 410095-002WO (221369)BUSINESS.33570138.1embodiments, R3is -C(O)NR;, wherein each R is independently Ci .6 aliphatic.

[0085] In some embodiments, R3is -C(O)OR. In some embodiments, R3is -C(O)OH. In some embodiments, R3is -C(O)OR, wherein R is Ci-6 aliphatic.

[0086] In some embodiments, R3is -NRC(O)R. In some embodiments. R3is -NHC(O)R. In some embodiments. R3is -NHC(O)R. wherein R is Ci-6 aliphatic.

[0087] In some embodiments, R3is -OC(O)R. In some embodiments, R3is -OC(O)R, wherein R is Ci-6 aliphatic.

[0088] In some embodiments, R3is optionally substituted Ci-6 aliphatic. In some embodiments, R3is Ci-6 aliphatic. In some embodiments, R3is methyl. In some embodiments. R3is ethyl. In some embodiments, R3is n-propyl. In some embodiments, R3is isopropyl. In some embodiments, R3is n-butyl. In some embodiments, R3is s-butyl. In some embodiments, R3is t-butyl.

[0089] In some embodiments, R3is Ci-e aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R3is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments. R3is -CH2F. In some embodiments, R3is -CHF2. In some embodiments. R3is -CF3. In some embodiments, R3is -CH2CF3. In some embodiments, R3is Ci.g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or C1.6 aliphatic. In some embodiments, R3is - CH2OH.

[0090] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted cyclopropyl. In some embodiments, R3is an optionally substituted cyclobutyl. In some embodiments, R3is an optionally substituted cyclopentyl. In some embodiments, R3is an optionally substituted cyclohexyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0091] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0092] In some embodiments, R3is an optionally substituted phenyl. In some embodiments, R3is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0093] In some embodiments, R3is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, or -19 410095-002WO (221369)BUSINESS.33570138.1OCF3.

[0094] In some embodiments, R3is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, - OCF3, or phenyl.

[0095] In some embodiments, R4is selected from halogen, -CN, -OR5, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is selected from halogen, -CN, -OR5, -NR2. -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1.6 aliphatic, phenyl, or a 5- to 6- membered hetcroar l having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0096] In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is bromo. In some embodiments. R4is -CN.

[0097] In some embodiments, R4is -OR5. In some embodiments, R4is -OH. In some embodiments, R4is -OCH3. In some embodiments, R4is -OCH2CH3. In some embodiments, R4is -OCF3.

[0098] In some embodiments, R4is -NR2. In some embodiments, R4is -NH2. In some embodiments, R4is -NR2, wherein each R is independently C1-6 aliphatic.

[0099] In some embodiments, R4is -C(O)NR2. In some embodiments, R4is -C(O)NH2. In some embodiments, R4is -C(O)NR2, wherein each R is independently Ci-e aliphatic.

[0100] In some embodiments, R4is -C(O)OR. In some embodiments, R4is -C(O)OH. In some embodiments, R4is -C(O)OR, wherein R is C1-6 aliphatic.

[0101] In some embodiments, R4is -NRC(O)R. In some embodiments. R4is -NHC(O)R. In some embodiments, R4is -NHC(O)R, wherein R is C1-6 aliphatic.

[0102] In some embodiments, R4is -OC(O)R. In some embodiments, R4is -OC(O)R, wherein R is Ci -e aliphatic.

[0103] In some embodiments, R4is optionally substituted Ci-6 aliphatic. In some embodiments, R4is Ci-e aliphatic. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is n-propyl. In some embodiments, R4is isopropyl. In some embodiments, R4is n -butyl. In some embodiments, R4is s -butyl. In some embodiments, R4is t-butyl.

[0104] In some embodiments, R4is C1-6 aliphatic, optionally substituted with halogen or -OR°,20 410095-002WO (221369)BUSINESS.33570138.1wherein R° is hydrogen or Ci-s aliphatic. In some embodiments, R4is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R4is -CFFF. In some embodiments, R4is -CHF2. In some embodiments, R4is -CF3. In some embodiments, R4is -CH2CF3. In some embodiments, R4is Ci-g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci.g aliphatic. In some embodiments, R4is - CH2OH.

[0105] In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R4is an optionally substituted cyclopropyl. In some embodiments, R4is an optionally substituted cyclobutyl. In some embodiments, R4is an optionally substituted cyclopentyl . In some embodiments, R4is an optionally substituted cyclohexyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is cyclobutyl. In some embodiments, R4is cyclopentyl. In some embodiments, R4is cyclohexyl.

[0106] In some embodiments, R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R4is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0107] In some embodiments, R4is an optionally substituted phenyl. In some embodiments, R4is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0108] In some embodiments, R4is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, or - OCF3.

[0109] In some embodiments, R4is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, - OCF3, or phenyl.

[0110] In some embodiments, R7is selected from halogen, -CN, -OR5, -NR2. -C(O)R, -C(O)NR2, - C(O)OR, or an optionally substituted group selected from Ci.g aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is selected from hydrogen, halogen, - CN, -OR5, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is selected from halogen, -CN, -OR’, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, or an optionally substituted group selected from Ci-g aliphatic, phenyl, or a 5- to 6-21 410095-002WO (221369)BUSINESS.33570138.1membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] In some embodiments, R7is hydrogen. In some embodiments, R7is halogen. In some embodiments, R7is fluoro. In some embodiments, R7is chloro. In some embodiments, R7is bromo. In some embodiments, R7is -CN.

[0112] In some embodiments, R7is -OR3. In some embodiments, R7is -OH. In some embodiments, R7is -OCH3. In some embodiments, R7is -OCH2CH3. In some embodiments, R7is -OCF3.

[0113] In some embodiments, R7is -NR2. In some embodiments, R7is -NH2. In some embodiments, R7is -NR2, wherein each R is independently C1-6 aliphatic.

[0114] In some embodiments, R7is -C(O)NR2. In some embodiments, R7is -C(O)NH2. In some embodiments, R7is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0115] In some embodiments, R7is -C(O)OR. In some embodiments, R7is -C(O)OH. In some embodiments, R7is -C(O)OR, wherein R is Ci-g aliphatic.

[0116] In some embodiments, R7is -NRC(O)R. In some embodiments. R7is -NHC(O)R. In some embodiments. R7is -NHC(O)R. wherein R is Ci-6 aliphatic.

[0117] In some embodiments, R7is -OC(O)R. In some embodiments, R7is -OC(O)R, wherein R is Ci-e aliphatic.

[0118] In some embodiments, R7is optionally substituted Ci-6 aliphatic. In some embodiments, R7is Ci-6 aliphatic. In some embodiments, R7is methyl. In some embodiments. R7is ethyl. In some embodiments. R7is n-propyl. In some embodiments, R7is isopropyl. In some embodiments, R7is n-butyl. In some embodiments, R7is s-butyl. In some embodiments, R7is t-butyl.

[0119] In some embodiments, R7is Ci-e aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R7is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments. R7is -CH2F. In some embodiments, R7is -CHF2. In some embodiments. R7is -CF3. In some embodiments, R7is -CH2CF3. In some embodiments, R7is Ci.g aliphatic, optionally substituted with -OR0, wherein R° is hydrogen or Ci.g aliphatic. In some embodiments, R7is - CH2OH.

[0120] In some embodiments, R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R7is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R7is an optionally substituted cyclopropyl. In some embodiments, R7is an optionally substituted cyclobutyl . In some embodiments, R7is an optionally substituted cyclopentyl. In some embodiments, R7is an optionally substituted cyclohexyl.22 410095-002WO (221369)BUSINESS.33570138.1In some embodiments, R7is cyclopropyl. In some embodiments, R7is cyclobutyl. In some embodiments, R7is cyclopentyl. In some embodiments, R7is cyclohexyl.

[0121] In some embodiments, R7is an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur

[0122] In some embodiments, R7is an optionally substituted phenyl. In some embodiments, R7is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0123] In some embodiments, R7is selected from hydrogen, fluoro, chloro, -OCHs, -OCH2CH3. or - OCF3.

[0124] In some embodiments, R7is selected from hydrogen, fluoro, chloro, -OCH3, -OCH2CH3, - OCF3, or phenyl.

[0125] As defined above and described herein, each R5is independently hydrogen or an optionally substituted group selected from Cue aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0126] In some embodiments, R5is hydrogen or an optionally substituted C1-6 aliphatic, hi some embodiments. R5is hydrogen. In some embodiments, R is optionally substituted Ci-6 aliphatic. In some embodiments. R5is C1-6 aliphatic. In some embodiments, R’ is methyl. In some embodiments, R' is ethyl. In some embodiments, R5is n-propyl. In some embodiments, R5is isopropyl. In some embodiments, R5is n-butyl. In some embodiments, R’ is s-butyl. In some embodiments, R’ is t-butyl.

[0127] In some embodiments, R is C1-6 aliphatic, optionally substituted with one or more halogen (e.g., fluoro). In some embodiments, R5is -CF3.

[0128] In some embodiments, R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R is an optionally substituted 3-to 6-mcmbcrcd saturated or partially unsaturated carbocyclyl. In some embodiments, R5is an optionally substituted cyclopropyl. In some embodiments, R5is an optionally substituted cyclobutyl. In some embodiments, R’ is an optionally substituted cyclopentyl . In some embodiments, R5is an optionally substituted cyclohexyl. In some embodiments, R5is cyclopropyl. In some embodiments, R5is cyclobutyl. In some embodiments, R5is cyclopentyl. In some embodiments, R5is cyclohexyl.

[0129] In some embodiments, R5is an optionally substituted 3-to 8-membered saturated or partially23 410095-002WO (221369)BUSINESS.33570138.1unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0130] As defined above and described herein, each R6is independently hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, R6is hydrogen. In some embodiments, R6is optionally substituted Ci-e aliphatic. In some embodiments, R6is Ci-e aliphatic. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is n-propyl. In some embodiments, R6is isopropyl. In some embodiments, R6is n-butyl. In some embodiments, R6is s-butyl. In some embodiments, R6is t-butyl. In some embodiments, R6is hydrogen or methyl.

[0131] In some embodiments, R6is optionally substituted methyl. In some embodiments, R6is methyl, substituted with -(CH2)o-iPh. In some embodiments, R6is methyl, substituted with R°, wherein R° is phenyl. In some embodiments, R6is -CH;Ph.

[0132] In some embodiments, R6is hydrogen, methyl, or -CH2Ph.

[0133] As defined above and described herein, R8is:24 410095-002WO (221369)BUSINESS.33570138.1

[0135] In some embodiments,some embodiments, R8

[0136] As defined above and described herein, Ring A is a saturated or partially unsaturated 4- to 6- membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl, or a saturated or partially unsaturated 4- to 9-mcmbcrcd fused or bridged bicyclic carbocyclyl.

[0137] In some embodiments. Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 5-membered monocyclic carbocyclyl. In some embodiments, Ring A is cyclobutyl. In some embodiments, Ring A is cyclobutenyl. In some embodiments, Ringjn someembodiments, Ring A is, some embodiments, Ring A is cyclopcntyl.In some embodiments. Ring25 410095-002WO (221369)BUSINESS.33570138.1some embodiments, Ringsome embodiments, Ringsome embodiments, RingIn some embodiments, RingIn some embodiments, Ringsome embodiments, Ringsome embodiments, RingIn some embodiments, Ring A is cyclopentenyl. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is cyclohexenyl. In some embodiments,. In some embodiments,, In some embodiments, R8(R9)n(R9)„

[0138] In some embodiments. Ring A is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyL In some embodiments, Ring A is a saturated 7- to 8-membered bicyclic spirocyclic carbocyclyl. In some embodiments, Ring A is a saturated 7-membered bicyclic spirocyclic carbocyclyL In some embodiments, Ring A is spiro[3.3]heptanyl. In some embodiments, Ring A is26 410095-002WO (221369)BUSINESS.33570138.1In some embodiments, Ring A isIn some embodiments, Ring A isIn some embodiments, Ring A is a partially unsaturated 7-membered bicyclic spirocyclic carbocyclyl. In some embodiments. Ring A is a saturated 8- membered bicyclic spirocyclic carbocyclyl. some embodiments, Ring A is partially unsaturated 8- membered bicyclic spirocyclic carbocyclyl.

[0139] It will be understood, wherein n occurrence of R9may be attached to the structure within brackets,

[0140] In some embodiments, Ring A is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 4- membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 4-membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 4-membered fused bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 5 -membered fused or bridged bicyclic carbocyclyl. In some embodiments. Ring A is a saturated or partially unsaturated 5 -membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 5 -membered fused bicyclic carbocyclyl. In some27 410095-002WO (221369)BUSINESS.33570138.1embodiments, Ring

[0141] In some embodiments, Ring A is a saturated or partially unsaturated 6- to 9-membered fused or bridged bicyclic carbocyclyl.

[0142] In some embodiments, Ring A is a saturated or partially unsaturated 6-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 6- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 6-membered fused bicyclic carbocyclyl. In some embodiments, Ring A is bicyclohexanyl. In some embodiments. RingIn some embodiments. Ringsome embodiments, Ringembodiments, Ringsome embodiments. Ring

[0143] In some embodiments, Ring A is a saturated or partially unsaturated 7-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 7- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 7-membered fused bicyclic carbocyclyl. In some embodiments. Ring A is bicycloheptanyl. In28 410095-002WO (221369)BUSINESS.33570138.1some embodiments, Ringsome embodiments, RingIn some embodiments, Ring AIn some embodiments, Ring A is

[0144] In some embodiments, Ring A is a saturated or partially unsaturated 8-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 8- membered bridged bicyclic carbocyclyl. In some embodiments. Ring A is a saturated or partially unsaturated 8-membered fused bicyclic carbocyclyl. In some embodiments. Ring29 410095-002WO (221369)BUSINESS.33570138.1some embodiments, Ringembodiments, Ringsome embodiments, Ringsome embodiments, Ringsome embodiments, Ring

[0145] In some embodiments, Ring A is a saturated or partially unsaturated 9-membered fused or bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 9- membered bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 9-membered fused bicyclic carbocyclyl.

[0146] As defined above and described herein, Ring B a saturated or partially unsaturated 7- to 8- membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom.

[0147] In some embodiments, Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 7-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is 2-azaspiro[3.4]octanyl. In some embodiments, Ring B is 2-azaspiro[3.4]oct-6-enyl. In some embodiments, Ring B is, some embodiments, Ring B30 410095-002WO (221369)BUSINESS.33570138.1

[0148] In some embodiments. Ring B is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom.

[0149] In some embodiments, Ring B is a saturated or partially unsaturated 5-mcmbcrcd fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 5 -membered bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 5 -membered fused bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments. Ring B is 3- azabicyclo[3.1.0]hexanyl. In some embodiments, Ring.

[0150] In some embodiments, Ring B is a saturated or partially unsaturated 8- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments. Ring B is 2,3,3a,6,7,7a-hexahydro-lH-indolyl. In someembodiments, Ring B is R13In some embodiments, Ring B is R13In some embodiments, Ring

[0151] As defined above and described herein, Ring C is a saturated or partially unsaturated 4- to 6-31 410095-002WO (221369)BUSINESS.33570138.1membered monocyclic carbocyclyl. In some embodiments. Ring C is a saturated or partially unsaturated4-membered monocyclic carbocyclyl. In some embodiments, Ring C is a saturated or partially unsaturated5 -membered monocyclic carbocyclyl. In some embodiments, Ring C is a saturated or partially unsaturated6-membered monocyclic carbocyclyl. In some embodiments. Ring

[0152] In some embodiments, Ring C is a saturated 4- to 6-membered monocyclic carbocyclyl. In some embodiments, Ring C is a saturated 4-membered monocyclic carbocyclyl. In some embodiments, Ring C is a saturated 5-membered monocyclic carbocyclyl. In some embodiments, Ring C is a saturated6-membered monocyclic carbocyclyl. In some embodiments, Ring

[0153] As defined above and described herein, Ring D is a saturated or partially unsaturated 4- to 6- membered monocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring D is a saturated or partially unsaturated 4-membered monocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments. Ring D is a saturated or partially unsaturated 5 -membered monocyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring D is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having a single nitrogen heteroatom. In some32 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1In some embodiments, R8isIn some embodiments, R8isIn some embodiments,In some embodiments, R8isIn some embodiments,

[0157] As defined above and described herein, each R9is independently selected from halogen, -CN, -OR, -NR;, or an optionally substituted Ci -e aliphatic; or two R9groups on the same or different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiro, fused, or bridged carbocyclyl or spiro, fused, or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0158] In some embodiments, each R9is independently selected from halogen, -CN, -OR, -NR?, or an optionally substituted Ci-6 aliphatic; or two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R9is fluoro, -CN, -OR, -NR;, or an optionally substituted Ci-e aliphatic.

[0159] In some embodiments, each R9is independently selected from halogen, -CN, -OR, -NR;, or an optionally substituted Ci-6 aliphatic. In some embodiments, R9is halogen. In some embodiments, R9is fluoro. In some embodiments, R9is chloro. In some embodiments, R9is bromo. In some embodiments, R9is -CN. In some embodiments, R9is -OR. In some embodiments, R9is -OH. In some embodiments, R9is -OR, wherein R is Ci-e aliphatic. In some embodiments, R9is -NR;. In some embodiments, R9is -NH;. In some embodiments, R9is -NR;, wherein each R is independently Ci-6 aliphatic. In some embodiments, R9is an optionally substituted Ci-6 aliphatic. In some embodiments, R9is Ci-6 aliphatic. In some410095-002WO (221369)BUSINESS.33570138.1embodiments, R9is methyl. In some embodiments, R9is ethyl. In some embodiments, R9is n-propyl. In some embodiments, R9is isopropyl. In some embodiments, R9is n-butyl. In some embodiments, R9is s- butyl. In some embodiments, R9is t-butyl. In some embodiments, R9is cyclopropyl . In some embodiments, R9is cyclobutyl. In some embodiments, R9is cyclopentyl. In some embodiments, R9is cyclohexyl. In some embodiments, R9is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments. R9is Cue aliphatic, optionally substituted with fluoro. In some embodiments, R9is -CF3.

[0160] In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0161] In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiro carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiro carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to fonn an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated spiro heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0162] In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to fomi an optionally substituted 3- to 8-membered saturated or partially unsaturated fused carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated fused carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3 -membered saturated or partially unsaturated fused carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to fonn an optionally substituted 4-mcmbcrcd saturated or partially unsaturated fused carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 5- membered saturated or partially unsaturated fused carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 6-membered saturated or partially35 410095-002WO (221369)BUSINESS.33570138.1unsaturated fused carbocyclyl.

[0163] In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated bridged carbocyclyl. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to fomi an optionally substituted 3- membered saturated or partially unsaturated fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 4-membered saturated or partially unsaturated fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 5- membered saturated or partially unsaturated fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on different atoms may be taken together to form an optionally substituted 6-membered saturated or partially unsaturated fused heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0164] In some embodiments, R8and R9form. In some embodiments, R8and R9form (R )2 . in some embodiments, R8and R9form (R h .

[0165] In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl. In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.36 410095-002WO (221369)BUSINESS.33570138.1

[0166] In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged hctcrocyclyl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated fused or bridged carbocyclyl. In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 3- to 6-membered saturated or partially unsaturated fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0167] In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 5 -membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 5-membered saturated or partially unsaturated fused or bridged carbocyclyl. In some embodiments, an R9and an R13group may be taken together to form an optionally substituted 5 -membered saturated or partially unsaturated fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0168] As defined above and described herein, each R10is independently selected from halogen, -CN, -OR, -NR?, or an optionally substituted C1-6 aliphatic.

[0169] In some embodiments, R10is halogen. In some embodiments, R10is fluoro. In some embodiments, R10is chloro. In some embodiments, R10is bromo. In some embodiments, R10is -CN. In some embodiments. R10is -OR. In some embodiments, R10is -OH. In some embodiments, R10is -OR, wherein R is Ci-e aliphatic. In some embodiments, R10is -NR2. In some embodiments, R10is -NH2. In some embodiments, R10is -NR2, wherein each R is independently C1-6 aliphatic. In some embodiments, R10is an optionally substituted Ci-e aliphatic. In some embodiments, R10is Ci-s aliphatic. In some embodiments, R10is methyl. In some embodiments, R10is ethyl. In some embodiments, R10is n-propyl. In some embodiments, R10is isopropyl. In some embodiments, R10is n-butyl. In some embodiments, Rwis s-butyl. In some embodiments, R10is t-butyl. In some embodiments. R10is cyclopropyl. In some embodiments, R10is cyclobutyl. In some embodiments, R10is cyclopentyl. In some embodiments, R10is cyclohexyl . In some embodiments, R10is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R10is Cue aliphatic, optionally substituted with fluoro. In some embodiments, R10is -CF3.

[0170] As defined above and described herein, each R11is selected from hydrogen, halogen, -CN, - OR, -NR2. or an optionally substituted C1-6 aliphatic.

[0171] In some embodiments, each R11is selected from hydrogen, fluoro, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic.37 410095-002WO (221369)BUSINESS.33570138.1

[0172] In some embodiments, R11is hydrogen. In some embodiments, R11is halogen. In some embodiments, R11is fluoro. In some embodiments, R11is chloro. In some embodiments, R11is bromo. In some embodiments, R11is -CN. In some embodiments, R11is -OR. In some embodiments, R11is -OH. In some embodiments, R11is -OR, wherein R is Ci-6 aliphatic. In some embodiments. R11is -NR2. In some embodiments, R11is -NH2. In some embodiments, R11is -NR2, wherein each R is independently C1-6 aliphatic. In some embodiments, R11is an optionally substituted Cns aliphatic. In some embodiments, R11is Cue aliphatic. In some embodiments, R11is methyl. In some embodiments, R11is ethyl. In some embodiments, R11is n-propyl. In some embodiments, R11is isopropyl. In some embodiments, R11is n- butyl. In some embodiments, R11is s-butyl. In some embodiments, R11is t-butyl. In some embodiments, R11is cyclopropyl. In some embodiments, R11is cyclobutyl. In some embodiments. R11is cyclopentyl. In some embodiments. R11is cyclohexyl. In some embodiments, R11is Cue aliphatic, optionally substituted with halogen. In some embodiments, R11is C1-6 aliphatic, optionally substituted with fluoro. In some embodiments, R11is -CF3.

[0173] As defined above and described herein, L1is a covalent bond or an optionally substituted bivalent C1-3 saturated or unsaturated, straight or branched, hydrocarbon chain. In some embodiments, L1is a covalent bond. In some embodiments, L1is an optionally substituted bivalent C1.3 saturated or unsaturated, straight or branched, hydrocarbon chain. In some embodiments, L1is a bivalent C1.3 saturated straight hydrocarbon chain. In some embodiments, L1is -CH2-. In some embodiments, L1is a covalent bond or -CH2-.

[0174] As defined above and described herein, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0175] As defined above and described herein, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8.

[0176] As defined above and described herein, each R12is independently hydrogen or optionally substituted Ci-e aliphatic. In some embodiments, R12is hydrogen. In some embodiments, R12is optionally substituted Ci-c aliphatic. In some embodiments, R12is Ci-c aliphatic. In some embodiments, R12is methyl. In some embodiments, R12is ethyl. In some embodiments, R12is n-propyl. In some embodiments, R12is isopropyl. In some embodiments. R12is n-butyl. In some embodiments, R12is s-butyl. In some embodiments, R12is t-butyl. In some embodiments. R12is hydrogen or methyl.

[0177] As defined above and described herein, each R13is independently hydrogen or optionally substituted Ci-e aliphatic. In some embodiments, R13is hydrogen. In some embodiments, R13is optionally38 410095-002WO (221369)BUSINESS.33570138.1substituted Ci-s aliphatic. In some embodiments, R13is Ci.s aliphatic. In some embodiments, R13is methyl. In some embodiments, R13is ethyl. In some embodiments, R13is n-propyl. In some embodiments, R13is isopropyl. In some embodiments, R13is n-butyl. In some embodiments, R13is s-butyl. In some embodiments, R13is t-butyl. In some embodiments, R13is hydrogen or methyl.

[0178] As defined above and described herein, each R is independently hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted Ci e aliphatic. In some embodiments, R is Ci-e aliphatic. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is n-propyl. In some embodiments, R is isopropyl. In some embodiments, Ris n-butyl. In some embodiments, R is s-butyl. In some embodiments, R is t-butyl.

[0179] In some embodiments, the compound is not

[0180] In some embodiments, the present disclosure provides a compound of formulae I-a, I-a-1, 1-a-2, 1-b, I-b-1, 1-b-2, 1-c, I-c-1, or Lc-2:39 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1I-c-1 I-c-2 or a pharmaceutically acceptable salt thereof, wherein each of X1, X7, R2, R3, R4, R6, R9, R10, R11, R12. R13, m. and n is defined and described in classes and subclasses herein, both singly and in combination.

[0181] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae I-a, I-a-1, 1-a-2, 1-b, I-b-1, 1-b-2, 1-c, I-c-1, or I-c-2, embodiments of variables X1, X7, R2, R3, R4, R6, R9, R10, Rn, R12, R13, m, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae I-a, I-a-1, 1-a-2. 1-b, I-b-1, 1-b-2, 1-c. I-c-1, or I-c-2, both singly and in combination.

[0182] In some embodiments, the present disclosure provides a compound of formulae I-d, I-d-1, 1- d-2, 1-e, I-e-1, I-e-2, 1-e-3, or I-e-4:41 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of X1, X7. R2, R3, R4, R6, R9. R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0183] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae I-d, I-d-1, 1-d-2, 1-e, I-e-1, 1-e-2, 1-e-3, or I-e-4, embodiments of variables X1, X7, R2, R3, R4, R6, R9. R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae I-d, I-d-1, 1-d-2, 1-e, I-e-1, 1-e-2, 1-e-3, or I-e-4, both singly and in combination.

[0184] In some embodiments, the present disclosure provides a compound of formulae Il-a, II-a-1,II-a-2, Il-b, II-b-1, II-b-2, Ill-a, III-a-1, III-a-2, IILb, III-b-1, or III-b-2:42 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of X1, X7, R2, R3, R4, R6, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0185] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Il-a, II-a-1, ILa-2, ILb, II-b-1, ILb-2, Ill-a, III-a-1, IILa-2, Ill-b, III-b-1, or IILb-2, embodiments of variables X1, X7, R2, R3, R4, R6, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae Il-a, II-a-1, II-a-2, Il-b, II-b-1, II-b-2, Ill-a, III-a-1, III-a-2, Ill-b, III-b-1, or III-b-2, both singly and in combination.44 410095-002WO (221369)BUSINESS.33570138.1

[0186] In some embodiments, the present disclosure provides a compound of formulae IV-a, IV-a-1 ,IV-a-2, IV-b, IV-b-1, IV-b-2, IV-c, IV-c-1, or IV-c-2:45 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R7, R2, R3, R4, R6, R9, R1C, R11, R12, R13, m and n is defined and described in classes and subclasses herein, both singly and in combination.[001871 It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV-a, IV-a-1, IV-a-2, IV-b, IV-b-1, IV-b-2, IV-c, IV-c-1, or IV-c-2, embodiments of variables R1, R7, R2, R3, R4, R6, R9, R10, R11, R12, R13, m and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a, IV-a-1, IV-a-2, IV-b, IV-b-1, IV-b-2, IV-c, IV-c-1, or IV-c-2, both singly and in combination.46 410095-002WO (221369)BUSINESS.33570138.1

[0188] In some embodiments, the present disclosure provides a compound of formulae IV-d, IV-d-1 ,IV-d-2, IV-e, IV-e-1, IV-e-2, IV-e-3, or IV-e-4:IV-e-3 IV-e-4 or a pharmaceutically acceptable salt thereof, wherein each of R1, R2. R3, R4, Rb, R7, R9. R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0189] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV-d, IV-d-1, IV-d-2, IV-e, IV-e-1, IV-e-2, IV-e-3, or IV-e-4, embodiments of variables R1, R2, R3, R4, R6, R7, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-d, IV-d-1, IV-d-2, IV-e, IV-e-1, IV-e-2, IV-e-3, or IV-e-4. both singly and in combination.

[0190] In some embodiments, the present disclosure provides a compound of formulae V-a, V-a-1, V- a-2, V-b, V-b-1, V-b-2, V-c, V-c-1, or V-c-2:47 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R6, R9, R10, R11, R12, R13, m and n is defined and described in classes and subclasses herein, both singly and in combination.[001911 It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae V-a, V-a-1, V-a-2, V-b, V-b-1, V-b-2, V-c, V-c-1, or V-c-2, embodiments of variables R1, R2, R3, R4, R6, R9, R10, R11, R12, R13, m and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae V-a, V-a-1, V-a-2, V-b, V-b-1, V-b-2, V-c, V-c-1, or V-c-2, both singly and in combination.49 410095-002WO (221369)BUSINESS.33570138.1

[0192] In some embodiments, the present disclosure provides a compound of formulae V-d, V-d-1 , V- d-2, V-e, V-e-1, V-e-2, V-e-3, or V-e-4:V-e-3 V-e-4 or a pharmaceutically acceptable salt thereof, wherein each of R1. R2. R3, R4, R6, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0193] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae V-d, V-d-1, V-d-2, V-e, V-e-1, V-e-2, V-e-3, or V-e-4, embodiments of variables R1, R2, R3, R4, R6, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae V-d, V-d-1, V-d-2, V-e, V-e-1, V-e-2, V-e-3, or V-e-4. both singly and in combination.[00194J In some embodiments, the present disclosure provides a compound of formulae Vl-a, VI-a-1,VI-a-2, Vl-b, VI-b-1, VI-b-2, VI-c, VI-c-1, or VI-c-2:50 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1VI-c-1 VI-c-2 or a pharmaceutically acceptable salt thereof, wherein each of R7, R2. R3. R4. R6, R9, R10. R11, R12, R13. m and n is defined and described in classes and subclasses herein, both singly and in combination.

[0195] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae Vl-a, VI-a-1, VI-a-2, Vl-b, VI-b-1, VI-b-2, VI-c, VI-c-1, or VI-c-2, embodiments of variables R7, R2, R3. R4, R6, R9, R10. R11, R12, R13, m and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae Vl-a, VI-a-1, VI-a-2, Vl-b, VI-b-1, VI-b-2. VI-c, VI-c-1. or VI-c-2, both singly and in combination.

[0196] In some embodiments, the present disclosure provides a compound of formulae Vl-d, VI-d-1,410095-002WO (221369)BUSINESS.33570138.1VI-d-2, Vl-e, VI-e-1, VI-e-2, VI-e-3, or VLe-4:VI-e-3 VI-e-4 or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, R6, R7, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0197] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vl-d, VI-d-1, VI-d-2, Vl-e, VI-e-1, VI-e-2, VI-e-3, or VI-e-4, embodiments of variables R2, R3, R4, R6, R7, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae Vl-d, VI-d-1, VI-d-2, Vl-e, VI-e-1, VI-e-2, VI-e-3, or VI-e-4, both singly and in combination.

[0198] In some embodiments, the present disclosure provides a compound of fonnulae VH-a, Vll-a-1, VII-a-2, Vll-b, VII-b-1, VILb-2, VII-c, VILc-l, or VII-c-2:53 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1VII-c-1 VII-c-2 or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, R6, R9. R10, R11, R12, R13. m and n is defined and described in classes and subclasses herein, both singly and in combination.

[0199] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae VH-a, VII-a-1, VII-a-2, Vll-b, VII-b-1, VII-b-2, VII-c, VD-c-1, or VII-c-2, embodiments of variables R2, R3, R4, Rb, R9, R10, R11, R12, R13, m and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae VH-a, VII-a-1, VII-a-2. Vll-b, VII-b-1, Vll-b- 2, VII-c, VII-c-1, or VII-c-2, both singly and in combination.

[0200] In some embodiments, the present disclosure provides a compound of formulae VTI-d, Vll-d-410095-002WO (221369)BUSINESS.33570138.11, VII-d-2, VH-e, VII-e-1, VII-e-2, VII-e-3, or VILe-4:VII-e-3 VII-e-4 or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, R6, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.[002011 It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VH-d, VII-d-1, VII-d-2, VILe, VII-e-1, VILe-2, VII-e-3, or VII-e-4, embodiments of variables R2, R3, R4, Rb, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae Vll-d, VII-d-1, VII-d-2, VH-e, VII-e-1, VII-e-2, VII-e-3, or VII-e-4, both singly and in combination.

[0202] In some embodiments, the present disclosure provides a compound of formulae Vlll-a, VIII- a-1, VIII-a-2, Vlll-b, VIII-b-1, or VIII-b-2:56 410095-002WO (221369)BUSINESS.33570138.1VIILb410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R\ R4, R6, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0203] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vlll-a, VIII-a-1, VIII-a-2, VIII-b, VIII-b-1, or VIII-b-2, embodiments of variables R1, R2, R3, R4, R6, and R7as defined above and described in classes and subclasses herein, also apply to compounds of formulae VUI-a, VIII-a-1, VIII-a-2, VIII-b, VIII-b-1, or VIII-b-2, both singly and in combination.

[0204] In some embodiments, the present disclosure provides a compound of fonnulae VUI-d, VIII- d-1, VIII-d-2, Vlll-e, VIII-e-1, VIII-e-2, VIII-e-3, or VIILe-4:369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R6, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0205] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VII d, VIII-d-1, VIII-d-2, VUI-e, VIII-e-1, VIII-e-2, VIII-e-3, or VIII-e-4, embodiments of variables R1, R2, R3, R4, R6, and R7as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae Vlll-d, VIII-d-1. VIII-d-2, Vlll-e. VIII-e-1. VIII-e-2. VIII-e-3, or VIII- e-4, both singly and in combination.

[0206] In some embodiments, the present disclosure provides a compound of formulae IX-a, IX-a-1, IX-a-2, IX-b, IX-b-1, or IX-b-2:59 410095-002WO (221369)BUSINESS.33570138.1IX-b-1 IX-b-2 or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, and R6is defined and described in classes and subclasses herein, both singly and in combination.

[0207] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IX-a, IX-a-1, IX-a-2, IX-b, IX-b-1, or IX-b-2, embodiments of variables R1, R2, R3, R4, and R6as defined above and described in classes and subclasses herein, also apply to compounds of formulae IX-a, IX-a-1, IX-a-2, IX-b, IX-b-1, or IX-b-2, both singly and in combination.

[0208] In some embodiments, the present disclosure provides a compound of fonnulae IX-d. IX-d-1,IX-d-2, IX-e, IX-e-1, IX-e-2, IX-e-3, or IX-e-4:60 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R1. R2, R3, R4, and R6is defined and described in classes and subclasses herein, both singly and in combination.[00209J It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IX-d, IX-d-1, IX-d-2, IX-e, IX-e-1, IX-e-2, IX-e-3, or IX-e-4, embodiments of variables R1, R2, R3, R4, and R6as defined above and described in classes and subclasses herein, also apply to compounds of formulae IX-d, IX-d-1, IX-d-2, IX-e, IX-e-1, IX-e-2, IX-e-3, or IX-e-4, both singly and in combination.

[0210] In some embodiments, the present disclosure provides a compound of formulae X-a. X-a-1, X- a-2, X-b, X-b-1, or X-b-2:X-a61 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, R6, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0211] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae X-a, X-a-1. X-a-2, X-b, X-b-1. or X-b-2, embodiments of variables R2, R3, R4, R6. and R7as defined above and described in classes and subclasses herein, also apply to compounds of formulae X-a, X-a-1, X-a-2, X-b, X-b-1, or X-b-2, both singly and in combination.

[0212] In some embodiments, the present disclosure provides a compound of formulae X-d, X-d-1, X-d-2, X-e, X-e-1, X-e-2, X-e-3, or X-e-4:410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, R6, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0213] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae X-d, X-d-1, X-d-2. X-e, X-e-1. X-e-2, X-e-3, or X-e-4, embodiments of variables R2, R3, R4, R6, and R7as defined above and described in classes and subclasses herein, also apply to compounds of formulae X-d, X-d-1, X-d-2, X-e, X-e-1, X-e-2, X-e-3, or X-e-4, both singly and in combination.

[0214] In some embodiments, the present disclosure provides a compound of formulae Xl-a, XI-a-1, XI-a-2, Xl-b, XI-b-1, or XI-b-2:63 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R2. R3. R4. and R6is defined and described64 410095-002WO (221369)BUSINESS.33570138.1in classes and subclasses herein, both singly and in combination.

[0215] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulac Xl-a, XI-a-1, XI-a-2, Xl-b, XI-b-1, or XI-b-2, embodiments of variables R2, R3, R4, and R6as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae XI- a, XI-a-1, XI-a-2. Xl-b. XI-b-1, or XI-b-2, both singly and in combination.

[0216] In some embodiments, the present disclosure provides a compound of formulae Xl-d, XI-d-1, XI-d-2, Xl-e, XI-e-1, XI-e-2, XI-e-3, or XI-e-4:XI-e-3 XI-e-4 or a pharmaceutically acceptable salt thereof, wherein each of R2. R3, R4, and R6is defined and described in classes and subclasses herein, both singly and in combination.

[0217] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Xl-d, XI-d-1, XI-d-2, Xl-e, XI-e-1, XI-e-2, XI-e-3, or XI-e-4, embodiments of variables R2, R3, R4, and R6as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae Xl-d, XI-d-1, XI-d-2, Xl-e, XI-e-1, XI-e-2, XI-e-3, or XI-e-4, both singly and in combination.65 410095-002WO (221369)BUSINESS.33570138.1

[0218] In some embodiments, the present disclosure provides a compound of formulae XTI-a, XIT-b,XII-c, Xll-d, or XII-e:XII-e or a pharmaceutically acceptable salt thereof, wherein each of X1, X3, X7, R2, R4, R6. Ring A, Ring B, Ring C, Ring D, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0219] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XH-a, XH-b, XII-c, Xll-d, or XII-e, embodiments of variables X1, X3, X7, R2, R4, R6, Ring66 410095-002WO (221369)BUSINESS.33570138.1A, Ring B, Ring C, Ring D, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XH-a, Xll-b, XII-c, Xll-d, or Xll-e, both singly and in combination.

[0220] In some embodiments, the present disclosure provides a compound of formulae Xlll-a, XIII- b, XIII-c, or Xlll-d:or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R7, R2, R4, Rb, Ring A, Ring B, Ring C, Ring D, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0221] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Xlll-a, Xlll-b. XIII-c, or Xlll-d, embodiments of variables R1, R3, R7. R2. R4. R6, Ring A, Ring B. Ring C. Ring D, R9, R13. and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XUI-a, XITI-b, XIII-c, or XTIT-d, both singly and in combination.

[0222] In some embodiments, the present disclosure provides a compound of formulae XlV-a, XIV- b, XIV-c, or XIV-d:67 410095-002WO (221369)BUSINESS.33570138.1XIV-c XlV-d or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R2, R4, R6, Ring A, Ring B, Ring C, Ring D, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0223] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XlV-a, XlV-b, XIV-c, or XlV-d, embodiments of variables R1, R3, R2, R4, R6, Ring A, Ring B, Ring C, Ring D, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XlV-a, XlV-b, XIV-c, or XlV-d, both singly and in combination.

[0224] In some embodiments, the present disclosure provides a compound of formulae XV-a, XV-b,XV-c. or XV-d:68 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R3, R7, R2, R4, R6, Ring A, Ring B, Ring C, Ring D, R9. R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0225] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XV-a, XV-b, XV-c, or XV-d, embodiments of variables R3, R7, R2, R4, R6, Ring A, Ring B, Ring C, Ring D, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of fonnulae XV-a, XV-b, XV-c, or XV-d. both singly and in combination.

[0226] In some embodiments, the present disclosure provides a compound of formulae XVI-a, XVI- b, XVI-c, or XVI-d:69 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, wherein each of R3, R2, R4, R6, Ring A, Ring B, Ring C, Ring D, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0227] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XVI-a, XVI-b, XVI-c, or XVI-d, embodiments of variables R3, R2, R4, Rb, Ring A, Ring B, Ring C, Ring D. R9. R13. and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XVI-a, XVI-b, XVI-c, or XVI-d, both singly and in combination.

[0228] In some embodiments, the present disclosure provides a compound of formulae XVII-a, XVII- b, XVII-c, XVII-d, or XVII-e:70 410095-002WO (221369)BUSINESS.33570138.1XVII-e or a pharmaceutically acceptable salt thereof, wherein each of R2, R4, Rb, Ring A, Ring B. Ring C. Ring D, R9, R13, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0229] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae XVII-a, XVII-b, XVII-c, XVII-d, or XVII-e, embodiments of variables R2, R4, R6, Ring A, Ring B, Ring C. Ring D, R9, R13, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae XVII-a, XVII-b, XVII-c. XVII-d, or XVII-e, both singly and in combination.

[0230] In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1, or a pharmacally acceptable salt thereof.71 410095-002WO (221369)BUSINESS.33570138.172 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.177 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.180 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.183 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.1BUSINESS.33570138.1

[0231] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above.4. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0232] According to another embodiment, the invention provides a composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmacally acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate 5-HT2AR, or a mutant thereof, in a biological sample or in a patient. In some embodiments, a composition of this invention is formulated for administration to a patient in need of such composition.

[0233] In some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmacally acceptable carrier, adjuvant, or vehicle. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a pharmacal composition comprising a compound set forth in Table 1 above, or a pharmacally acceptable salt thereof, together with a pharmacally acceptable carrier, adjuvant, or vehicle.

[0234] The term ‘'patient” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0235] The term “pharmacally acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is fonnulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate.88 410095-002WO (221369)BUSINESS.33570138.1lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0236] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intraliepatic. intralesional and intracranial injection or infusion techniques. Preferably, tire compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0237] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, for the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0238] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers may be included. Lubricating agents are also typically added. For oral administration in a capsule fonn, diluents may be included. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention arc administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0239] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a89 410095-002WO (221369)BUSINESS.33570138.1suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.

[0240] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of tire eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0241] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdennal patches may also be used.

[0242] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing tire active components suspended or dissolved in one or more pharmaceutically acceptable carriers

[0243] For ophthalmic use. provided pharmaceutically acceptable compositions may be fonnulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative . Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment .

[0244] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0245] Tire amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.

[0246] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. Tire amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.90 410095-002WO (221369)BUSINESS.33570138.1Uses of Compounds and Pharmaceutically Acceptable Compositions

[0247] In some embodiments, provided compounds and compositions are for use in medicine.

[0248] Compounds and compositions described herein are generally useful as agonists of 5-HT2AR.

[0249] According to one embodiment, the invention relates to a method of activating 5-HT2AR. or a mutant thereof, in a biological sample comprising contacting said biological sample with a provided compound, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

[0250] Tire term “biological sample’’, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, 5-HT2AR is from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0251] Activation of 5-HT2AR, or a mutant thereof, in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[0252] In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for activating 5-HT2AR, or a mutant thereof, as described herein.

[0253] In some embodiments, the invention also provides a compound described herein, or a pharmacally acceptable salt thereof, or pharmacal compositions described herein, for use in a method for selectively activating 5-HT2AR, or a mutant thereof, (e.g.. over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) as described herein. In some embodiments, such methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound selectively binds to 5-HT2AR over 5-HT2BR and / or 5-HT2CR. The method of selectively agonizing 5-HT2AR, or a mutant thereof, can be used to treat, ameliorate, and / or prevent disorders that are affected by, associated with, or would benefit from selective activation of 5-HT2AR. In selectively binding to and activating 5-HT2AR, or a mutant thereof, over the 5-HT2BR and / or 5-HT2CR. or one or more mutants thereof, the method provides, for example, reduced side effects such as, but not limited to, drug- induced valvular heart disease associated with binding and activating 5-HT2BR. In some embodiments, a provided compound is a 5-HT2BR, or a mutant thereof, antagonist. In some embodiments, a provided compound is a 5-HT2CR, or a mutant thereof, antagonist.

[0254] In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for treating a 5-HT2AR-mediated disorder as described herein. Such disorders are described in detail herein.

[0255] G protein-coupled receptors (GPCRs) signal through numerous pathways, including disease-91 410095-002WO (221369)BUSINESS.33570138.1associated but also non-disease-associated pathways, and as a result modulation of GPCRs can cause undesired side effects. Modulators of GPCRs can bind and preferentially activate specific pathways over others, often referred to as ligand-mediated bias or pathway bias. 5-HT2AR may interact with multiple signaling pathways upon ligand binding, e.g., pathways that engage with G proteins or [3-arrestins. See Kossatz. E., et al. Nature Communications 2024, 15:4307. In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for binding 5-HT2AR, or a mutant thereof, resulting in increased (“biased”) activation of a particular signaling pathway (e.g., a G protein signaling pathway) over others (e.g., a -arrestin signaling pathway). In some embodiments, provided methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound binds to 5-HT2AR and results in increased (“biased”) activation of a G protein signaling pathway over a P-arrestin signaling pathway. In some embodiments, provided methods include administering to a patient a provided compound, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized in that, upon binding 5-HT2AR, or a mutant thereof, the compound effects increased (“biased”) activation of a G protein signaling pathway over a P-arrestin signaling pathway.

[0256] In some embodiments, provided methods include increasing activation of a G protein signaling pathway associated with 5-HT2AR over a P-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0257] In some embodiments, G protein signaling pathways arc evaluated through detection of calcium, e.g., as described in Example 22. In some embodiments, p-arrestin signaling pathways are evaluated as described in Example 23.

[0258] In some embodiments, a G protein signaling pathway is increased by at least 50%, at least 100%, at least 500%, at least 1,000%, at least 5,000%, or at least 10,000% (e.g., as measured in Example 22) as compared to P-arrestin signaling pathways (e.g., as measured in Example 23).

[0259] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, may exhibit anxiolytic, anti-depressive, and antidrug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions. For example, a provided compound, or a pharmaceutically acceptable salt thereof, may confer antidepressant like activities without incurring psychedelic drug-like actions. For example, in some embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, may be safe and effective for use in a method described herein, yet lack the hallucinogenic effects of known psychedelics such as. for example, DMT and psilocybin. In some embodiments, a patient does not experience a hallucinogenic effect as a result of the activating or treating.92 410095-002WO (221369)BUSINESS.33570138.1

[0260] The activity of a compound, or a pharmaceutically acceptable salt thereof, utilized in this invention as an activator of 5-HT2AR, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine activation and / or the subsequent functional consequences of activated 5-HT2AR. or a mutant thereof. Alternate in vitro assays quantitate the ability of the agonist to bind to 5-HT2AR. or a mutant thereof. Agonist binding may be measured by radiolabeling the compound prior to binding, isolating the compound / 5-HT2AR complex and determining the amount of radiolabel bound. Alternatively, agonist binding may be determined by running a competition experiment where additional agonists are incubated with 5-HT2AR, or a mutant thereof, bound to known radioligands. Detailed conditions for assaying a compound utilized in this invention as an agonist of 5-HT2AR, or a mutant thereof, are set forth in the Examples below.

[0261] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0262] Provided compounds are agonists of 5-HT2AR, or a mutant thereof, and are therefore useful for treating one or more disorders associated with activity of 5-HT2AR. In some embodiments, the present invention provides a method for treating a 5-HT2AR-mediated disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0263] As used herein, the term “5-HT2AR-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which 5-HT2AR, or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which 5-HT2AR, or a mutant thereof, are known to play a role.

[0264] In some embodiments, the present invention provides a method for treating a neurological disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0265] Non-limiting examples of a neurological disease or disorder include depression, anxiety, substance abuse, and headaches. Headaches that can be treated with the methods herein include, but are not limited to. migraine headaches and cluster headaches.

[0266] In some embodiments, the present invention provides a method for treating a depressive disease, disorder, or condition comprising administering to a patient in need thereof provided compound,93 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the depressive disorder is a major depressive disorder. In other embodiments, the depressive disorder includes treatment resistant depressions.

[0267] In some embodiments, the present invention provides a method for treating an anxiety disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the anxiety disorder is generalized anxiety disorder. In other embodiments, the anxiety disorder is social anxiety disorder.

[0268] In some embodiments, the present invention provides a method for treating trauma and / or stress disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, such a disorder is post-traumatic stress disorder. In other embodiments, such a disorder is an adjustment disorder.

[0269] In some embodiments, tire present invention provides a method for treating an obsessive- compulsive disorder, e.g., body dysmorphic disorder, comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof.

[0270] In some embodiments, the present invention provides a method for treating an eating disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof, hr some embodiments, the eating disorder is anorexia. In other embodiments, the eating disorder is bulimia.

[0271] In some embodiments, the present invention provides a method for treating a sleep-wake disorder, e.g., insomnia, comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0272] In some embodiments, the present invention provides a method for treating a psychotic disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the psychotic disorder is schizophrenia. In other embodiments, the psychotic disorder is schizoaffective disorder. In still other embodiments, the psychotic disorder is schizotypal personality disorder.

[0273] In some embodiments, tire present invention provides a method for treating a substance-related and / or addictive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, such a disorder is an alcohol use disorder. In other embodiments, such a disorder is an opioid use disorder. In still other embodiments, such a disorder is a94 410095-002WO (221369)BUSINESS.33570138.1tobacco use disorder. For example, in some embodiments provided compound, or a pharmaceutically acceptable salt thereof, may be usefill in facilitating smoking cessation.

[0274] In some embodiments, the present invention provides a method for treating a ncurocognitivc disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the neurocognitive disorder includes those due to a primary neurodegenerative disease, for example, Alzheimer's disease or Parkinson’s disease.

[0275] In some embodiments, the present invention provides a method for treating a personality disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0276] In some embodiments, the present invention provides a method for treating an autism spectrum disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0277] In some embodiments, the present invention provides a method for treating a bipolar disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the bipolar disorder is bipolar I disorder. In some embodiments, the bipolar disorder is bipolar II disorder.

[0278] In some embodiments, the present invention provides a method for treating a pain disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmacally acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, the pain disorder is neuropathic pain. In some embodiments, the pain disorder is migraine. In some embodiments, the pain disorder is a cluster headache. In some embodiments, the pain disorder is a trigeminal neuralgia. In some embodiments, the pain disorder is cancer pain. In some embodiments, the pain disorder is a regional pain disorder. In some embodiments, the pain disorder is phantom limb pain. In some embodiments, a contemplated pain disorder is a chronic pain.EXAMPLES

[0279] As depicted in tire Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.95 410095-002WO (221369)BUSINESS.33570138.1

[0280] Exemplary General Scheme 196 410095-002WO (221369)BUSINESS.33570138.1

[0281] Exemplary General Scheme 297 410095-002WG (221369)BUSINESS.33570138.1

[0283] Exemplary General Scheme 4Eluting fraction 2

[0285] Step 1. To a stirred solution of tert-butyl 3 -bromo-5 -fluoro- IH-indazole-l -carboxylate (1.0 g, 3.17 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) cyclohex-3 -en-l-yl) (1.54 g, 4.76 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) was added K3PO4) (2.02 g, 9.52 mmol). The reaction410095-002WO (221369)BUSINESS.33570138.1mixture was purged withN2 for 30 min and Pd(dppf)C12.DCM complex (0.26 g, 0.32 mmol) was added at RT. The reaction mixture was allowed to stir at 100 °C for 16 h. Tire reaction was monitored by TLC using 30% EA in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with EA (3 x 50 mL). Tire combined organic layers were dried over sodium sulfate and concentrated. Hie obtained crude material was purified by flash column chromatography on silica gel using 12% EA in hexane to afford tert-butyl 3 -(4-((tert-butoxy carbonyl) amino) cyclohex-l-en-l-yl)-5-fluoro-lH-indazole-l-carboxylate, (1.02 g, 74%). LCMS (m / z): 432.3 [M+H]+.

[0286] Step 2. To a stirred solution of tcrt-butyl 3-(4-((tcrt-butoxycarbonyl) aminocyclohcx-l-cn-1- yl)-5-fluoro-lH-indazole-l-carboxylate (0.95 g, 2.20 mmol) in DCM (0.95 mL) was added 4 M HC1 in 1,4- dioxane (0.95 mL) at 0 °C. The resulting mixture stirred at RT for 2 h. The reaction was monitored by TLC using 10% MeOH in DCM and LCMS analysis. The reaction mixture was concentrated under reduced pressure to obtain solid material which was triturated with n-pentane (3 x 30 mL) to obtain 4-(5 -fluoro- 1H- indazol-3-yl) cyclohex-3 -en-1 -amine hydrochloride (1-16) (0.58 g, 98%). LCMS (m / z): 232.2 [M+H]+; 'H NMR (400 MHz, DMSO-r / g): 5 13.10 (bs, 1H), 8.14 (bs, 3H), 7.75 (dd, J 9.8, 2.2 Hz, 1H), 7.56 (dd, J 9.0, 3.4, 1H), 7.26 (td, J 9.0, 2.3 Hz, 1H), 6.45-6.43 (m, 1H), 3.40-3.34 (m, 1H), 2.90-2.83 (m, 1H). 2.69-2.55 (m, 2H). 2.37-2.28 (m, 1H), 2.15-2.10 (m. 1H), 1.82-1.72 (m, 1H).

[0287] Step 3. The isolated 0.58 g racemic material was submitted to chiral prep HPLC purification. (Column: CHIRALPAK IG (250mm x 50mm x 5pm; Mobile Phase A: 0.1% methanolic ammonia in n- hcxanc, Mobile Phase B: 0.1% methanolic ammonia in McOH / tcrt-butyl methyl ether (50-50); Flow rate: 40 mL / min; Gradient: 75% A to 75% A in 55 min; Wave Length: 210 nm; RTl(min) 42.9; RT2(min): 50.0; Sample Solvent: MeOHmobile phase; Sample loading: 25 mg; Number Of Runs: 23).

[0288] Eluting fraction 1: 4-(5-fluoro-lH-indazol-3-yl)cyclohex-3-en-l-amine (1-17) (0.13 g, 22%, white solid). LCMS (m / z): 232.1 [M+H]+; ’H NMR (400 MHz, DMSO-r / fi): 8 13.1 l(bs 1H), 7.71 (dd, J 9.8, 1.8 Hz, 1H), 7.54 (dd, J 9.0, 4.6 Hz, 1H), 7.24 (td, J 9.0, 2.3 Hz, 1H), 6.43-6.41 (m, 1H), 3.58-3.54 (m, 1H), 3.11-3.04 (m, 1H), 2.84-2.76 (m, 1H), 2.58-2.53 (m. 1H), 2.10-2.04 (m, 1H), 1.99-1.93 (m, 1H), 1.59-1.49 (m, 1H). (-NH2 signal is not distinguishable)

[0289] Eluting fraction 2: 4-(5-fluoro-lH-indazol-3-yl)cyclohex-3-en-l-amine (1-18) (0.13 g, 22% white solid). LCMS (m / z): 232.1 [M+H]+; ’H NMR (400 MHz, DMSO-r / 6): 8 13.02 (bs 1H), 7.71 (dd, J 10.0, 2.0 Hz, 1H), 7.53 (dd, J 8.8, 4.4 Hz, 1H), 7.24 (td, J 9.0, 1.2 Hz, 1H), 6.43-6.41 (m, 1H), 3.63-3.57 (m, 1H). 3.03-2.96 (m, 1H), 2.83-2.74 (m, 1H), 2.49-2.45 (m, 1H), 2.05-1.88 (m, 2H), 1.53-1.43 (m, 1H). (-NH2 signal is not distinguishable)99 410095-002WO (221369)BUSINESS.33570138.1

[0290] Additional Exemplary Compounds Prepared via Example 1 Methods100 410095-002WO (221369)BUSINESS.33570138.1

[0291] Example Method 2 (1-19)

[0292] Step 1. To a stirred solution of tert-butyl 3-(4-((tert-butoxycarbonyl)amino) cyclohex- 1-en-l- yl)-5-fluoro-lH-indazole-l-carboxylate (intermediate prepared in example method 1. 0.05 g, 0.12 mmol) in dimethylformamide (0.5 mL) was added methyl iodide (0.05 mL) and sodium hydride (0.01 g, 0.35 mmol) at 0 °C. The resulting mixture stirred at RT for 16 h. The reaction was monitored by TLC using 10% EA in hexane and LCMS analysis. After completion of the reaction, the reaction mixture quenched with water (20 mL) and extracted with EA (3 x 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The obtained crude material was purified by reverse phase preparative HPLC to afford tert-butyl 5-fluoro-3-(4-(methylamino)cyclohex-l-en-l-yl)-lH-indazole-l- carboxylate solid material as a white solid (0.02 g, 50%).

[0293] Step 2. To a stirred solution of 4-(5-fluoro-lH-indazol-3-yl)-N-methylcyclohex-3-en-l -amine hydrochloride (0.01 g, 0.03 mmol) in DCM (0.1 mL) was added 4 M HC1 in 1,4-dioxane (0.1 mL) at 0 °C. Tire resulting reaction mixture stirred at RT for 1 h. The reaction was monitored by TLC using 10% McOH101 410095-002WO (221369)BUSINESS.33570138.1in DCM and LCMS analysis. The reaction mixture was concentrated under reduced pressure to obtain solid material which was triturated with diethyl ether (3 x 5mL) to afford 4-(5-fluoro-lH-indazol-3-yl)-N- methylcyclohex-3-en-l -amine hydrochloride as a white solid (1-19) (4 mg, 56%). LCMS (m / z): 246.2 [M+H]+; 'HNMR (400 MHz, DMSO-fi): 5 7.98 (bs, 2H), 7.76 (dd, J 9.8, 1.8 Hz,lH), 7.69 (dd, J 9.2, 4.4 Hz, 1H). 7.33 (td, J 9.0, 2.4 Hz, 1H), 6.45-6.43 (m, 1H), 4.01 (s, 3H). 3.41-3.37 (m. 1H), 2.88-2.80 (m, 1H), 2.65-2.57 (m. 2H). 2.32-3.26 (m. 1H), 2.13-2.07 (m, 1H), 1.79-1.68 (m, 1H). (-NH signal is not distinguishable).

[0294] Example Method 3 (1-8 and 1-9)Eluting fraction 1 +Eluting fraction 2

[0295] Step 1. To a stirred solution of 3-bromo-4-methoxy-lH-indazole (0.2 g, 0.88 mmol) in DCM (2 mL) was added triethylamine (0.27 g, 2.64 mmol) and 4-dimethyl aminopyridine (0.01 g). Tire reaction mixture was stirred for 10 min and BOC-anhydride (0.29 g, 1.32 mmol) was added at RT. Tire reaction mixture was further allowed to stir at RT for 1-2 h. The reaction was monitored by TLC using 30% EA in hexane and LCMS analysis. Tire reaction mixture was quenched with water (50 mL) and extracted with EA (2 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The obtained crude material was purified by flash column chromatography on silica gel using 20% EA in102 410095-002WO (221369)BUSINESS.33570138.1hexane to get tert-butyl 3-bromo-4-methoxy-lH-indazole-l -carboxylate (0.28 g, 97%) as a light-yellow solid.

[0296] Step 2. To a stirred solution oftcrt-butyl 3 -bromo-4-mcthoxy- IH-indazolc- 1 -carboxylate (0.28 g, 0.86 mmol) and tert-butyl (4-(4,4.5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)cyclohex-3-en-l- yl)carbamate (0.28 g, 0.86 mmol) in 1,4 dioxane (2.8 mL) and water (0.28 mL) was added K3PO4 (0.55 g, 2.58 mmol). The reaction mixture was purged with N2for 15 min and Pd(dppf)C12.DCM complex (0.07 g, 0.09 mmol) was added at RT. The reaction mixture was further allowed to stir at 100 °C for 2 h. Tire reaction was monitored by TLC using 30% EA in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with EA (2 x 50 mL). Tire combined organic layers were dried over sodium sulfate and concentrated under vacuum. Tire obtained crude material was purified by flash column chromatography on silica gel using 26% EA in hexane to afford tert-butyl 3- (4-((tert-butoxycarbonyl)amino)cyclohex- 1 -en- 1 -yl)-4-methoxy- 1 H-indazole- 1 -carboxylate (0.22 g, 58%) as light yellow solid.

[0297] Step 3. The isolated racemic material of tert-butyl 3-(4-((tert- butoxycarbonyl)amino)cyclohex-l-en-l-yl)-4-methoxy-lH-indazole-l -carboxy late (0.22 g) was submitted to chiral prep HPLC purification. (Column: CHIRALPAK IG (250mm x 50mm x 5pm; Mobile Phase A: Liquid CO2. Mobile Phase B: 0: 0.1% methanolic ammonia in MeOH-ACN (50:50): Flow rate: 150 mL / min; Gradient: 80% A to 80% A in 13 min; Wave Length: 300 nrn; RTl(min) 9.4; RT2(min): 10.8: Sample Solvent: ACN:DCM; Sample loading (mg): 3, Number Of Runs: 101). Eluting isomer 1 (29.1 mg, off-white solid) and eluting isomer 2 (44.2 mg, off-white solid) were obtained.

[0298] Step 4. To a stirred solution of tert-butyl 3-(4-((tert-butoxycarbonyl)amino)cyclohex-l-en-l- yl)-4-methoxy-lH-indazole-l -carboxylate eluting fraction 1 (0.08 g, 0.18 mmol) in DCM (0.8 mL) was added 4 M HO in 1,4-dioxane (0.4 mL) at 0 °C. The resulting reaction mixture was stirred at RT for 2 h. The reaction was monitored by TLC using 5% MeOH in DCM and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The isolated solid material was further triturated with diethyl ether (2 x 10 mL) and dried under vacuum to afford 4-(4-methoxy-lH- indazol-3-yl)cyclohex-3-en-l-amine hydrochloride (1-8) (0.029 g. 57%). LCMS (m / z): 244.2 | M+H| : 'H NMR (400 MHz, DMSO-5): 5 12.97 (bs. 1H), 8.21 (s, 3H), 7.25 (t, J 8.0 Hz. 1H), 7.04 (d. J 8.4 Hz, 1H), 6.54 (d, J 7.6 Hz, 1H), 6.40-6.38 (m, 1H), 3.88 (s, 3H), 3.38-3.32 (m, 1H), 2.83-2.76 (m, 1H), 2.65-2.54 (m, 2H), 2.35-2.28 (m, 1H), 2.14-2.09 (m, 1H), 1.82-1.72 (m, 1H).

[0299] Step 5. To a stirred solution of tert-butyl 3-(4-((tert-butoxycarbonyl)amino)cyclohex-l-en-l- yl)-4-methoxy-lH-indazole-l -carboxylate eluting fraction 2 (0.072 g, 0.16 mmol) in DCM (0.72 mL) was added 4 M HC1 in 1,4 dioxane (0.36 mL) at 0°C. The resulting mixture was stirred at RT for 2 h. The reaction was monitored by TLC using 5% MeOH in DCM and LCMS analysis. After completion of103 410095-002WO (221369)BUSINESS.33570138.1reaction, the reaction mixture was concentrated under reduced pressure. The isolated solid material was further triturated with diethyl ether (2 x 10 mL) and dried under vacuum to afford 4-(4-methoxy-lH- indazol-3-yl)cyclohex-3-en-l-amine hydrochloride (1-9) (0.044 g, 97%). LCMS (m / z): 244.2 | M+H| : 'H NMR (400 MHz, DMSO-r / g): 5 12.92 (bs, 1H), 8.08 (s, 3H), 7.25 (t, J 8.0 Hz, 1H), 7.05 (d, J 8.0 Hz, 1H), 6.54 (d, J 7.6 Hz, 1H), 6.40-6.38 (m, 1H), 3.88 (s, 3H), 3.39-3.33 (m, 1H), 2.83-2.75 (m, 1H). 2.65-2.54 (m, 2H). 2.33-2.24 (m, 1H). 2.14-2.08 (m. 1H), 1.80-1.71 (m, 1H).

[0300] Additional Exemplary Compounds Prepared via Example 3 Methods104 410095-002WO (221369)BUSINESS.33570138.1

[0301] Example Method 4 (1-2 and 1-3) +

[0302] Step 1. To a stirred solution of 7-fluoro-lH-indole (0.5 g. 3.69 mmol) in DMF (5 mL) was added N-bromo succinimide (0.66 g, 3.69 mmol) was added at 0 °C. The reaction mixture was allowed to stir at RT for 30 min. Tire reaction was monitored by TLC using 10% EA in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was poured into ice cold water (50 mL). The precipitated solid was filtered and dried well under vacuum to afford crude 3-bromo-7-fluoro-lH-indole (0.50 g, 63%).

[0303] Step 2. To a stirred solution of 3-bromo-7-fluoro-lH-indole (0.50 g, 2.34 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (1.13 g, 3.50 mmol) in 1,4- dioxane (5 mL) and water (0.5 mL) was added K3PO4 (0.74 g, 3.50 mmol). Tire reaction mixture was purged withNi for 15 min and Pd(dppf)C12.DCM complex (0.19 g, 0.234 mmol) was added at RT. The reaction mixture was allowed to stir at 100 °C for 1 h. The reaction was monitored by TLC using 20% EA in hexane and LCMS analysis. After completion of the reaction, the reaction mixture quenched by water ( 100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The obtained crude material was purified by reverse phase column410095-002WO (221369)BUSINESS.33570138.1chromatography using 60% ACN in water. The pure fractions were lyophilized to get tert-butyl (4-(7-fluoro- lH-indol-3-yl) cyclohex-3-en-l-yl) carbamate (0.16 g, 21%).

[0304] Step 3. The isolated racemic material of tert-butyl (4-(7-fluoro-lH-indol-3-yl) cyclohcx-3-cn- 1-yl) carbamate (0.16 g) was submitted to chiral prep HPLC purification. (Column: CHIRALPAK IG (250mm x 50mm x 5pm: Mobile Phase A: Liquid CO2, Mobile Phase B: 0.1% methanolic ammonia in MeOH-ACN (50-50); Flow rate: 150 mL / min; Gradient: 75% A to 75% A in 30 min; Wave Length: 210 nm; RTl(min) 11.5; RT2(min): 13.5; Sample Solvent: MeOH; Sample loading: 10 mg; Number Of Runs: 15). Eluting fraction 1: tert-butyl (4-(7-fluoro-lH-indol-3-yl) cyclohex-3 -en-l-yl) carbamate (50 mg, off- white solid) and eluting fraction 2: tert-butyl (4-(7-fluoro-lH-indol-3-yl) cyclohex-3-en-l-yl) carbamate (50 mg, off-white solid) were obtained.

[0305] Step 4. To a stirred solution of tert-butyl (4-(7-fluoro-lH-indol-3-yl) cyclohex-3 -en-l-yl) carbamate eluting isomer 1 (0.05 g, 0.151 mmol) in DCM (0.5 mL) was added 4 M HO in 1 ,4 dioxane (0.25 mL, 5.0 vol) at 0 °C. The resulting mixture stirred at RT for 1 h. Tire reaction was monitored by TLC using 10% MeOH in DCM and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain solid material which was purified by reverse phase preparative HPLC purification. The pure fractions were lyophilized to afford 4-(lH-pyrrolo[2,3-b]pyridin- 3-yl)cyclohex-3-en-l-amine (1-2) (1.8 mg) as white solid. LCMS (m / z): 231.2 [M+H]+; H NMR (400 MHz, DMSO-cL): 5 11.65 (s, 1H), 8.40 (s, 1H), 7.61 (d, J 7.6 Hz, 1H), 7.44 (s, 1H), 7.01-6.90 (m, 3H), 6.11-6.09 (m, 1H), 3.29-3.24 (m, 1H), 2.62-2.48 (m, 3H), 2.27-2.19 (m, 1H), 2.09-2.03 (m, 1H), 1.78-1.69 (m, 1H). (-NH3+signal is not fully distinguishable)

[0306] Step 5. To a stirred solution of tert-butyl (4-(7-fluoro-lH-indol-3-yl) cyclohex-3 -en-l-yl) carbamate eluting isomer 2 (0.05 g. 0.151 mmol) in DCM (0.5 mL) was added 4 M HC1 in 1,4 dioxane (0.25 mL, 5.0 vol) at 0 °C. The resulting mixture stirred at RT for Ih. The reaction was monitored by TLC using 10% MeOH in DCM and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain solid material which was purified by preparative HPLC to afford 4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine (1-3) (0.013 g) as a white solid. LCMS (m / z): 231.2 | M+H| : 'H NMR (400 MHz, DMSO-t / 6): 5 11.66 (s, IH), 8.45 (s, IH), 7.62 (d. J 7.6 Hz, IH), 7.44 (s, IH), 7.02-6.92 (m, 2H), 6.11-6.09 (m, IH). 3.24-3.18 (m, IH). 2.62-2.47 (m, 3H). 2.23-2.15 (m, IH), 2.07-2.01 (m, IH), 1.72-1.63 (m, IH). (-NH;, signal is not fully distinguishable)106 410095-002WO (221369)BUSINESS.33570138.1

[0307] Additional Exemplary Compounds Prepared via Example 4 Methods107 410095-002WO (221369)BUSINESS.33570138.1108 410095-002WO (221369)BUSINESS.33570138.1

[0308] Example Method 5 (1-37 and 1-38)

[0309] Step 1. A solution of tert-butyl (4-( IH-pyrrolo [2.3 -b]pyridin-3 -yl)cyclohex-3-en- 1 - yl)carbamate (intermediate prepared in example method 1, 68 mg, 0.22 mmol) in MeOH / THF (5 / 5 mb) and Pd(OH)2-Pd / C (8mg / 8mg) was stirred at RT for 2 days with H2balloon. The mixture was directly fdtered, the fdtrate was directly concentrated under vacuum. The residue was purified by column chromatography (PE / EA=10 / l-5 / l-l / l-DCM / MeOH=50 / l-30 / l-20 / l) followed by chiral preparative- HPLC (Column: CHIRALCEL AD-H (250mm x 4.6mm x 5pm; Mobile Phase A: n-hexane. Mobile Phase B: ethanol; Flow rate: 1 mL / min; Gradient: 70% A to 70% A in 30 min: Wave Length: 214 nm: RTl(min) 6.3; RT2(min): 17.9; Sample Solvent: MeOH:Ethanol (50:50) Sample concentration: 1.0 mg / mL) to afford tert-butyl to afford tert-butyl ((ls,4s)-4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohexyl)carbamate (25 mg, 36%, eluting fraction 1) as an off-white solid and tert-butyl ((lr,4r)-4-(lH-pyrrolo[2,3-b]pyridin-3- yl)cyclohexyl)carbamate (30 mg, 44%, eluting fraction 2) as an off-white solid. LCMS (m / z): 316.2 | M+111 for both isomers.[00310J Step 2. A solution of tert-butyl ((ls,4s)-4-(lH-pyrrolo[2,3-b]pyridin-3- yl)cyclohexyl)carbamate (25 mg, 0.079 mmol) in 4 M HCl / dioxane (2 mL) was stirred at RT for 2 h. The reaction was directly concentrated under vacuum. Tire residue was triturated with hexane to give (ls,4s)-4- (lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohexan-l-amine hydrochloride (1-38) (18 mg, 98%) as an off-white solid. LCMS (m / z): 216.0 [M+H]+; ’HNMR (400 MHz, DMSO L) 5 12.24 (s, 1H), 8.54 (d, J 7.8 Hz, 1H), 8.35 (d, J 5.2 Hz, 1H), 8.15 (bs, 3H), 7.51 (s. 1H), 7.34-7.28 (m, 1H), 3.37-3.33 (m, 1H), 3.07-3.00 (m, 1H), 2.05-1.94 (m, 2H), 1.87-1.76 (m, 6H).

[0311] Step 3. A solution of tert-butyl ((lr,4r)-(4-(lH-pyrrolo[2,3-b]pyridin-3- yl)cyclohexyl)carbamate (25 mg, 79.26 umol) in 4 M HCl / dioxane (5 mL) was stirred at RT for 2 h. The reaction was directly concentrated under vacuum. Tire residue was purified by trituration (hexane) to give109 410095-002WO (221369)BUSINESS.33570138.1(lr,4r)-4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohexan-l-amine (1-37) (18 mg, 98%) as an off-white solid. LCMS (m / z): 216.2 [M+H]+; 'HNMR (400 MHz, DMSO-A) 5 12.04 (s, 1H), 8.43 (d, J 7.8 Hz, 1H), 8.32 (d, J 5.2 Hz, 1H), 8.08 (m, 3H), 7.38-7.36 (m, 1H), 7.26 (dd, J 8.0, 5.2 Hz, 1H), 3.11-3.07 (m, 1H), 2.83-2.76 (m, 1H), 2.09-2.01 (m, 4H), 1.64-1.49 (m, 4H).

[0312] Example Method 6 (1-11 and 1-12)

[0313] Step 1. To a solution of lH-indol-5-ol (2.0 g, 15.02 mmol) in i-PrOH (20 mL) was added Rh on AI2O3 (1.0 g) and the mixture was stirred at 80 °C for 48 h under a 0.4 MPa H2atmosphere. The mixture was filtered and concentrated to afford a yellow oil, which was used directly without purification. To a solution of above crude material in DCM (20 mL) was added di-tert-butyldicarbonate (9.8 g, 45 mmol) and DIEA (9.7 g, 75 mmol). The mixture was stirred at RT for 4 h. Hie mixture was diluted with water (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over Na-’SOi. filtered and concentrated. The residue was purified by column (PE:EA=20: 1-5: 1) to afford tertbutyl 5 -hydroxyoxooctahydro- IH-indole-l -carboxylate (1.1 g, 31%) as a yellow solid. LCMS (m / z): 242.1 [M+H]+.110 410095-002WG (221369)BUSINESS.33570138.1

[0314] Step 2. The solution of tert-butyl 5-hydroxyoxooctahydro-lH-indole-l -carboxylate (500 mg, 2.07 mmol) in acetone (15 mL) at 0 °C was added Jones’ reagent (2N, 1.3 mL) and the mixture was stirred at 0 °C for 4 h. The mixture was diluted with McOH (5 mL) and H2O (200 mL), extracted with EA (100 ml x 3). Tire combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated in vacuum to afford tert-butyl 5-oxooctahydro-lH-indole-l-carboxylate (400 mg, 81%) as yellow oil, which was used directly into next step.

[0315] Step 3. To a solution of tert-butyl 5-oxooctahydro-lH-indole-l-carboxylate (400 mg, 1.67 mmol) in anhydrous THF (15 mL) at -78 °C was added LiHMDS (1 N, 4.2 mL). After stirring at -78 °C for 10 min, l,Ll-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (717 mg, 2.0 mmol) was added and the mixture was stirred at 0 °C for 4 h. The mixture was diluted with iced NlLCl (aq.) (200 mL), extracted with EA (100 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to afford tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)- 2,3,3a,6,7,7a-hexahydro-lH-indole-l-carboxylate (400 mg, 65%) as a yellow oil, which was used directly into next step.

[0316] Step 4. To a solution of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-2,3,3a.6.7,7a-hexahydro- IH-indole-l -carboxylate (700 mg, 1.88 mmol) in 1.4-dioxane / H2O (12 mL / 3 mL) ) was added tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (779 mg, 2.26 mmol), Pd(PPh2)4 (108.9 mg, 0.09 mmol) and K2CO2(520 mg, 3.77 mmol). The mixture was stirred was stirred at 120 °C overnight underN2. The mixture was diluted with water (200 mL), extracted with EA (70 ml x 3). The combined organic layers were washed with brine, dried overNa2SC>4, filtered and concentrated. The residue was purified by prep-HPLC and chiral-HPLC to give tert-butyl tert-butyl 5-(lH-pyrrolo[2,3- b]pyridin-3-yl)-2,3,3a.6.7.7a-hexahydro-lH-indole-l-carboxylate (eluting isomer 1, 14 mg) as a white solid and tert-butyl tert-butyl 5-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2,3,3a,6,7,7a-hexahydro-lH-indole-l- carboxylate (eluting isomer 2, 17 mg) as a white solid. LCMS (m / z): 340.1 [M+H]+for eluting isomer 1, 340.2 [M+H]+for eluting isomer 2.

[0317] Step 5. To a solution of tert-butyl 5-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2,3,3a.6.7,7a-hexahydro- IH-indole-l -carboxylate eluting isomer 1 (26 mg, 0.08 mmol) in DCM (3 mL) was added 4 M HC1 / 1.4- dioxane (1 mL) and the mixture was stirred at RT for 2 h. The mixture was concentrated under vacuum and the residue was triturated to give 3-(2,3,3a,6,7,7a-hexahydro-lH-indol-5-yl)-lH-pyrrolo[2,3-b]pyridine hydrochloride (1-11) (17 mg, 93%) as a yellow solid. LCMS (m / z): 240.1 [M+H]+;]H NMR (400 MHz, DMSO-r / 6) 5 12.44-12.25 (m, 1H), 9.97-9.69 (m, 1H), 9.11-8.80 (m, 1H), 8.61-8.47 (m, 1H), 8.35 (d, J 4.0 Hz, 1H). 7.71-7.65 (m, 1H). 7.35-7.25 (m, 1H). 6.22-6.12 (m, 1H). 3.85-3.81 (m, 1H), 3.25-3.14 (m, 2H). 3.07-2.98 (m, 1H), 2.72-2.63 (m. 1H), 2.48-2.32 (m. 1H), 2.28-2.19 (m, 1H). 2.08-1.98 (m, 1H), 1.97-1.79 (m, 2H).111 410095-002WO (221369)BUSINESS.33570138.1

[0318] Step 6. To a solution oftert-butyl 5-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2,3,3a,6,7,7a-hexahydro- IH-indole-l -carboxylate eluting isomer 2 (34 mg, 0.10 mmol) in DCM (3 mL) was added 4 M HC1 / 1.4- dioxanc ( 1 mL) and the mixture was stirred at RT for 2h. The mixture was concentrated under vacuum and the residue was triturated to give 3-(2,3,3a,6,7,7a-hexahydro-lH-indol-5-yl)-lH-pyrrolo[2,3-b]pyridine hydrochloride (1-12) (22 mg, 92%) as a yellow solid. LCMS (m / z): 240.1 [M+H]1; ’H NMR (400 MHz, DMSO-iL) 5 12.18 (s, lH), 9.70 (bs, 1H), 8.86 (bs, 1H), 8.47 (d, J 8.0 Hz, 1H), 8.32 (dd, J 5.2, 1.4 Hz, 1H), 7.66 (d, J 2.6 Hz, 1H), 7.25 (dd, J 8.0, 5.0 Hz, 1H), 6.20-6.15 (m, 1H), 3.87-3.78 (m, 1H), 3.20 (quin, J 6.4, Hz, 2H), 3.07-2.98 (m, 1H), 2.72-2.62 (m, 1H), 2.48-2.33 (m, 1H), 2.28-2.19 (m, 1H), 2.07-1.97 (m, 1H), 1.95-1.79 (m, 2H).

[0319] Example Method 7 (1-35)B2(pin)2

[0320] Step 1. A solution of tert-butyl 3-bromo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (2 g, 6.73 mmol), B2(pin)2 (3.42 g, 13.46 mmol), KOAc (1.32 g, 13.46 mmol) and Pd(dppf)Cl2(493 mg, 0.673 mmol) in 1,4-dioxane (30 mL) was stirred at 80 °C for 16 h undcrN;. The mixture was diluted with water (30 mL), extracted with EA (3 x 30 mL). Tire combined organic layers were washed with water (30 mL) and brine (30 mL), dried over Na2SO4. filtered and concentrated. The residue was purified by silica gel chromatography (PE-PE / EA=50 / 1 -30 / 1) to afford tert-butyl 3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (960 mg, 53%) as a light yellow solid. LCMS (m / z): 345.2 [M+H]+.

[0321] Step 2. To a solution of LiHMDS (22 mL, 22.00 mmol) in dry THF (22 mL) was added a solution of tert-butyl methyl(4-oxocyclohexyl)carbamate (2.00 g. 8.80 mmol) in dry THF (22 mL) at -78 °C. After stirring at -78 °C for 15 min, a solution of l,l,l-trifhioro-N-phenyl-N-((trifluoromethyl)sulfonyl)112 410095-002WO (221369)BUSINESS.33570138.1methane-sulfonamide (3.77 g, 10.6 mmol) in dry THF (10 mL) was added at -78 °C, the mixture was stirred from -78 °C to 0 °C for 1 h. The mixture was quenched with water (50 mL), extracted with EA (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (PE-PE / EA=50 / l-30 / l) and reverse phase chromatography (column: C18 column; Gradient: 63% ACN in water) to afford 4-((tert-butoxycarbonyl)(methyl)amino)cyclohex-l-en-l- yl trifluoromethanesulfonate (1.36 g, 56%) as a yellow oil. LCMS (m / z): 304.1 [M+H]+.

[0322] Step 3. A solution of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (100 mg, 0.29 mmol), 4-((tert- butoxycarbonyl)(methyl)amino)cyclohex-l-en-l-yl trifluoromethanesulfonate (105 mg, 0.29 mmol), K2CO3 (80 mg, 0.58 mmol) and Pd(PPh;,)4 (17 mg, 0.014 mmol) in l,4-dioxane / H2O (1.2 mL / 0.6 mL) was stirred at 120 °C for 16 h in sealed tube. The mixture was diluted with water (15 mL), extracted with EA (3 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=20 / l) and prep-HPLC (column: C18 column; Gradient: ACN in water with 53% modifier (0.1%formic acid)) to afford tert-butyl (4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3- en-l-yl)(methyl)carbamate (10 mg, 8%) as an off-white solid. LCMS (m / z): 328.1 [M+H]+.

[0323] Step 4. A solution of tert-butyl (4-(lH-pyrrolo[2.3-b]pyridin-3-yl)cyclohex-3-en-l- yl)(methyl)carbamate (10 mg. 30.5 umol) in 4 M HCl / dioxane (2 mL) was stirred at RT for 2 h. The reaction mixture was directly concentrated under vacuum, the residue was purified by trituration (ether) to afford N-methyl-4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine (1-35) (6.4 mg, 91%) as ayellow solid. LCMS (m / z): 228.1 [M+H]+; 'HNMR (400 MHz, DMSO-cL) 5 11.90 (s, 1H), 8.86 (bs, 2H), 8.33 (d, J 7.8 Hz, 1H), 8.27 (d, J 4.8 Hz, 1H), 7.58 (d, J 2.4 Hz, 1H), 7.27 (dd, J 8.0, 4.8 Hz, 1H). 6.16-6.14 (m, 1H), 3.34-3.23 (m, 1H), 2.71-2.58 (m. 5H), 2.58-2.53 (m. 1H), 2.39-2.29 (m, 1H), 2.24-2.16 (m, 1H). 1.83- 1.71 (m, 1H).113 410095-002WO (221369)BUSINESS.33570138.1

[0324] Example Method 8 (1-27 and 1-28)Eluting fraction 1 + Eluting fraction 2

[0325] Step 1. A mixture of tert-butyl 3-bromo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (3 g, 10.09 mmol), Pinfh (5.1 g, 20.19 mmol), Pd(dppf)C12 (738 mg. 1.0 mmol) and CHsCOOK (1.98 g. 20.2 mmol) in dioxane (30 mL) was stirred at 80 °C overnight under N2. The reaction mixture was diluted with water (300 mL), extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over ISh^SCL, filtered and concentrated to crude product. Tire residue was purified by column (PE:EA=20: l —15: 1) to give tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3- b]pyridine-l -carboxylate (3.65 g, purity: 50%) as a colorless oil. LCMS (m / z): 345.3 [M+H]+.

[0326] Step 2. A mixture of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (3.65 g, 10.53 mmol), l-(5-bromothiophen-2-yl)ethan-l-one (1.8 g, 8.77 mmol), Pd(PPli3)4 (507 mg, 0.43 mmol) and K2CO3 (3.6 g, 26.3 mmol) in 1,4-dioxane / water (15 mL / 3mL) was stirred at 80 °C overnight under N2. Tire reaction mixture was diluted with water (200 mL), extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over Na2SO4. filtered and concentrated to crude product. The residue was purified by column (PE:EA=20: 1-15: 1) to give tert-butyl 3-(5-acetylthiophen-2-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (1 g, 33%) as a yellow solid. LCMS (m / z): 343.0 [M+H]+.

[0327] Step 3. To a solution of tert-butyl 3-(5-acetylthiophen-2-yl)-lH-pyrrolo[2,3-b]pyridine-l- carboxylate (900 mg, 2.62 mmol) in THF / MeOH (4 mL / 4 ML) at 0 °C was added NaBIL (0.2 g, 5.2 mmol). The mixture was stirred at RT. for 1 h. Tire mixture was diluted with water (100 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The residue114 410095-002WO (221369)BUSINESS.33570138.1was purified by prep-TLC (PE / EA=2 / 1) to give tert-butyl 3-(5-(l-hydroxyethyl)thiophen-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (710 mg, 78%) as a yellow oil. LCMS (m / z): 345.2 [M+H]+.

[0328] Step 4. To a solution of tcrt-butyl 3-(5-(l-hydroxycthyl)thiophcn-2-yl)-lH-pyrrolo[2,3- b]pyridine-l -carboxylate (700 mg, 2.03 mmol), isoindoline-1, 3-dione (448 mg, 3.04 mmol) and PPI13 (799 mg, 3.04 mmol) in dry THF (8 mL) was added DEAD (530 mg, 3.04 mmol) at 0 °C. The mixture was stirred at RT for 6 h. The mixture was diluted with water (100 mL) and extracted with EA (40 mL x 3). The combined organic layers were dried over Na2SO 4, filtered and concentrated. The residue was purified by silica column chromatography (PE / EA= 10 / 1-5 / 1) to give tert-butyl 3-(5-(l-(l,3-dioxoisoindolin-2- yl)ethyl)thiophen-2-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (560 mg, 58%) as an off-white solid. LCMS (m / z): 475.2 [M+H]+.

[0329] Step 5. A solution of tert-butyl 3-(5-(l-( L3-dioxoisoindolin-2-yl)ethyl)thiophen-2-yl)-lH- pyrrolo[2,3-b]pyridine-l -carboxylate (560 mg, 1.18 mmol) and hydrazine hydrate (592 mg, 11 .8 mmol) in EtOH / DCM (8 / 8 mL) was stirred at 60 °C for 1 h. The mixture was filtered, the filtrate was concentrated and purified by pre-TLC (DCM / MeOH=10 / l+NH3.H2O) to give l-(5-(lH-pyrrolo[2,3-b]pyridin-3- yl)thiophen-2-yl)ethan- 1 -amine (170 mg), then further isolated by chiral resolution (Column: CHIRALCEL OD-H (250mm x 4.6mm x 5pm: Mobile Phase A: n-hexane, Mobile Phase B: ethanol; Flow rate: 1 mL / min; Gradient: 70% A to 70% A in 30 min; Wave Length: 214 nm; RTl(min) 11.2; RT2(min): 12.7: Sample Solvent: MeOFLEthanol (50:50) Sample concentration: 1.3 mg / mL).

[0330] l-(5-(lH-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl)propan-l-amine (1-27) (eluting isomer 1, 42.6 mg) and l-(5-(lH-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl)propan-l-amine (1-28) (eluting isomer 2, 44.9 mg) were obtained as a white solids.

[0331] Eluting fraction 1 (1-27) : LCMS (m / z): 227.0 [M-NH2]+: H NMR (400 MHz, DMSO-rk) 8 11.87 (s, 1H), 8.27 (dd, J 4.6, 1.4 Hz, 1H), 8.23 (dd, J 8.0, 1.4 Hz, 1H), 7.75 (s, 1H), 7.18-7.14 (m, 2H), 6.90 (d, J 3.4 Hz, 1H), 4.23 (q, J 6.4 Hz, 1H), 2.12 (bs, 2H), 1.37 (d, J 6.4 Hz, 3H).

[0332] Eluting fraction 2 (1-28): LCMS (m / z): 227.0 [M-NH2]+; ’H NMR (400 MHz, DMSO-6) 8 11.87 (s, 1H), 8.27 (dd, J 4.6, 1.4 Hz. 1H), 8.23 (dd, J 8.0, 1.4 Hz, 1H), 7.75 (s, 1H), 7.18-7.14 (m, 2H), 6.90 (d, J 3.4 Hz, 1H), 4.23 (q, J 6.4 Hz, 1H), 2.12 (bs, 2H), 1.37 (d, J 6.4 Hz, 3H).115 410095-002WO (221369)BUSINESS.33570138.1

[0333] Additional Exemplary Compounds Prepared via Example 8 Methods116 410095-002WO (221369)BUSINESS.33570138.1

[0334] Example MethodPdCI2(PPh3)2NaH Cui

[0335] Step 1. To a stirred solution of 3-iodo-lH-pyrrolo[2,3-b]pyridine (10 g, 40.9 mmol) in THF (200 mL) at 0 °C was added NaH (1.96 g, 49.2 mmol, 60% in oil) slowly. After stirring at 0 °C for 0.5 h, SEMCI (10.2 g. 61.5 mmol) was added. The mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (2 x 300mL), dried over Na2SO4, filtered and concentrated. The residue was purified by117 410095-002WO (221369)BUSINESS.33570138.1column chromatography (DCM) to give 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridine (15 g, 99%) as a yellow oil. LCMS (m / z) 374.9 [M+H]+.

[0336] Step 2. A mixture of 3-iodo-l-((2-(trimcthylsilyl)cthoxy)mcthyl)-lH-pyrrolo[2,3-b]pyridinc (6 g, 16 mmol), prop-2-yn-l-ol (2 eq.), Pd(PPli3)2C12 (280 mg, 0.4 mmol), Cui (152 mg, 0.80 mmol) and triethylamine (4.8 g, 48 mmol) in THF (40 mL) was stirred at 70 °C for 4 h under N2. The mixture was diluted with water (500 mL) and exacted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The mixture was purified by column chromatography (DCM / MeOH, 1:0) to afford 3-(l-((2-(trimethylsilyl)ethoxy)-methyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)prop- 2-yn-l-ol (2.6 g, 54%) as a brown oil. LCMS (m / z) 303.2 [M+H]+.

[0337] Step 3. To a stirred solution of 3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)prop-2-yn-l-ol (2.6 g. 8.59 mmol) in DCM (30 mL) at 0 °C was added Dess-Martin periodinane (5.46 g, 12.9 mmol). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with aq. NaHCOs (500 mL) and exacted with DCM (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried overNa2SO4, filtered and concentrated. The mixture was purified by column chromatography (DCM) to afford 3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)propiolaldehyde (2.1 g. 81%) as a yellow oil. LCMS (m / z) 301.1 [M+H]L

[0338] Step 4. To a stirred solution of allylmagnesium bromide (IM in THF, 10.5 mL) at 0 °C was added a solution of 3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-3- yl)propiolaldehyde (2.1 g, 6.98 mmol) in THF (5 mL). The reaction mixture was stirred at 0 °C for 2 h. The mixture was diluted with water (100 mL) and exacted with ethyl acetate (3 x 30 mL). Tire combined organic layers were washed with brine (3 x 40 mL) and dried over ISfeSCL, filtered and concentrated. Hie mixture was purified by column (DCM / MeOH=100: 1) to afford 1 -(1 -((2-(trimethylsilyl)ethoxy)m ethyl)- 1H- pyrrolo[2,3-b]pyridin-3-yl)hex-5-en-l-yn-3-ol (1.9 g, 79%) as a yellow oil. LCMS (m / z) 343.2 [M+H]+.

[0339] Step 5. A mixture of l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-3- yl)hex-5-en-l-yn-3-ol (1.9 g, 5.54 mmol) and Pt Cl 2 (74 mg, 0.27 mmol) in toluene (20 mL) was stirred at 80 °C overnight under N2 in a sealed tube. Hie mixture was filtered and concentrated. The mixture was purified by column (DCM / MeOH=100: 1) to afford l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-one (1.04 g, 54%) as a yellow solid. LCMS (m / z) 343.3 [M+H]+.

[0340] Step 6. A mixture of l-(l-((2-(trimcthylsilyl)ctlioxy)mcthyl)-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]-hexan-3-one (640 mg, 1.86 mmol) and ammonium fomiate (1.44 g, 18.6 mmol) in MeOH (15 mL) was stirred at RT for 1 h. NaBHsCN (940 mg, 14.9 mmol) was added. The mixture was stirred at 60 °C for 4 h. The mixture was concentrated, diluted with water (60 mL) and exacted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 40 mL) and dried over Na2SCL, filtered118 410095-002WO (221369)BUSINESS.33570138.1and concentrated. The mixture was purified by prep-TLC (DCM / MeOH=15: 1) to afford l-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1 ,0]hexan-3 -amine (379 mg, 59%) as a yellow oil. LCMS (m / z) 344.2 [M+H]+.

[0341] Step 7. A mixture of l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2.3-b]pyridin-3- yl)bicyclo[3.1.0]-hexan-3 -amine (300 mg. 0.87 mmol) in DCM (10 mL) and TFA (3 mL) was stirred at RT for 2 h. The mixture was concentrated, diluted with water (8 mL) and exacted with DCM (3 x 5 mL). The water phases were adjusted pH 7~8 and concentrated to ~3 mL volume, then THF (12 mL) and K2CO3 (965 mg, 6.97 mmol) was added, the mixture was stirred at RT for 2 h to form l-(lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-amine. The reaction mixture was used into next step without purification. LCMS (m / z) 214.1 [M+H]+

[0342] Step 8. To a stirred solution of l-(lH-pyrrolo[2.3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine (185 mg, 0.8 mmol) was added BOC2O (571 mg, 2.6 mmol). The reaction mixture was stirred at RT for 2 h. The mixture was diluted with water (40 mL) and exacted with DCM (3 x 30 mL). Tire combined organic layers were washed with brine (3 x 40 mL) and dried over Na2SCL, filtered and concentrated. The mixture was purified by prep-TLC (DCM / MeOH=20: 1) to afford tert-butyl 3-(3-((tert- butoxycarbonyl)amino)bicyclo[3.1.0]hexan-l-yl)-lH-pyrrolo[2.3-b]pyridine-l-carboxylate (76 mg, 20%) as a yellow oil. LCMS (m / z) 414.2 [M+H]+.

[0343] Step 9. A mixture of tert-butyl 3-(3-((tert-butoxycarbonyl)amino)bicyclo[3.1.0]hexan-l-yl)- lH-pyrrolo[2,3-b]pyridine-l-carboxylate (68 mg, 0.16 mmol) and NaOH (68 mg, 1.6 mmol) in MeOH / water (4 mL / 4 mL) was stirred at RT for 2 h. Tire mixture was concentrated, diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (3 x 40 mL) and dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-HPLC to afford tert-butyl (l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate (eluting isomer 1, 14 mg) and (eluting isomer 2, 13 mg) as a white solid. LCMS (m / z): 314.1 [M+H]+for both isomers.

[0344] Step 10. To a solution of tert-butyl (l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3- yl)carbamate eluting isomer 1 (14 mg, 0.04 mmol) in DCM (3 mL) was added 4 M HC1 in 1,4-dioxane (0.3 mL).The reaction mixture was stirred at RT for 1 h. Tire mixture was concentrated and triturated with hexane (4 mL) to afford l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine hydrochloride (1-48) (8.5 mg) as a yellow solid. LCMS (m / z) 214.1 [M+H]+; ’HNMR (400 MHz, DMSO / ) 8 11.91-11.80 (m, 1H), 8.31-8.28 (m, 1H), 8.23-8.16 (m, 1H), 8.01 (bs, 3H), 7.39-7.36 (m, 1H), 7.24-7.18 (m, 1H), 4.06-3.96 (m, 1H), 2.67-2.56 (m, 2H), 2.16-2.09 (m, 1H), 1.82-1.74 (m, 1H), 1.70-1.63 (m, 1H), 1.27-1.22 (m, 1H), 1.06- 1.00 (m. 1H).

[0345] Step 11. To a solution of tert-butyl (l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3- yljcarbamate eluting isomer 2 (13 mg, 0.04 mmol) in DCM (3 mL) was added 4 M HC1 in 1,4-dioxane (0.3119 410095-002WO (221369)BUSINESS.33570138.1mL).The reaction mixture was stirred at RT for 1 h. The mixture was concentrated and triturated with hexane (4 mL) to afford l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine hydrochloride (1-49) as a yellow solid. LCMS (m / z) 214.1 [M+H]+; 'H NMR (400 MHz, DMSO-iL) 5 11.71 (s, IH), 8.29-8.25 (m, 2H), 8.11 (bs, 3H), 7.33 (d, J 2.4 Hz, IH), 7.19-7.12 (m, IH), 3.38-3.32 (m, IH), 2.42 (dd, J 12.2, 7.4 Hz, IH). 2.26-2.09 (m, 3H), 1.60 (dt, J 8.4, 4.4 Hz, IH), 0.92 (dd, J 8.0, 5.4 Hz, IH), 0.88 (t, J 4.8 Hz, IH).

[0346] Example Method 10 (1-54)

[0347] Step 1. To a solution of tert-butyl (3-oxocyclopentyl)carbamate (5.0 g. 25 mmol ) in THF (70 mL) was added LiHMDS (63 mL, 63 mmol ) at -78 °C and the mixture was stirred at -78 °C for 1 h. A mixture of 1, 1, l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (10.7 g, 30.1 mmol) in THF (30 mL) was added and the reaction solution was stirred at 0 °C for another Ih. The mixture was diluted with ice NFLC1 (aq.) (300 mL) and extracted by EtOAc (150 ml x 3). The combined organic layers were washed with brine, dried overNa2SO4, filtrated and concentrated. The residue was purified by column chromatography on silica gel (eluent: Pet. Ether : EtOAc = 100: 1 -50: 1) to afford 4-((tert- butoxycarbonyl)amino)cyclopent-l-en-l-yl trifluoromethanesulfonate (5.0 g, 63%) as a yellow oil.120 410095-002WG (221369)BUSINESS.33570138.1

[0348] Step 2. To a solution of 3-bromo-lH-pyrrolo[2,3-b]pyridine (20 g, 0.1 mol ) in DCM (300 mL) was added TEA (30.8 g, 0.3 mol), di-tert-butyl dicarbonate (44.3 g, 0.2 mmol ) and DMAP (1.2 g, 0.01 mmol) at 0 °C and the mixture was stirred at RT for 2 h. The mixture was diluted with DCM (200 mL), washed with water (200 ml x 3) and brine (100 mL). Tire organic phase was dried over NazSCL, filtered and concentrated. The residue was purified by column (PE:EA=100: 1-80: 1) to afford tert-butyl 3-bromo-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (22 g, 73 %) as a yellow oil. LCMS (m / z): 297.0 [M+H]+.

[0349] Step 3. To a solution of tert -butyl 3-bromo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (5.0 g, 16.83 mmol), B2PUI2 (6.4 g, 25.24 mmol ) in 1,4-dioxane (50 mL) was added Pd(dppf)CL (615.6 mg, 0.84 mmol) and KO Ac (4.95 g, 50.48 mmol). The mixture was stirred at 80 °C for 16 h under N2. Tire mixture was diluted with water (300 mL). extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated. Tire mixture was purified by column chromatography on silica gel (eluent: Pet. Ether : EtOAc = 100: 1 -50: 1) to afford tert-butyl 3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (3.0 g, 51.7 %) as a yellow oil. LCMS (m / z): 345.2 [M+H]+.

[0350] Step 4. To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrrolo[2.3-b]pyridine-l-carboxylate (3.0 g, 8.72 mmol). 4-((tert-butoxycarbonyl)amino)cyclopent-l-en- 1-yl trifluoromethanesulfonate (2.9 g, 8.72 mmol) in l A-dioxanc / FLO (30 mL / 6 mL) ) was added Pd(dppf)Ch (318.9 mg, 0.44 mmol) and K2CO3 (3.6 g, 26.15 mmol). The mixture was stirred was stirred at 110 °C overnight under N2. The mixture was diluted with water (300 mL), extracted with EtOAc (100 ml*3). Tire combined organic layers were washed with brine, dried over Na2SO4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: Pet. Ether: EtOAc = 20: 1 -5: 1) and prep-HPLC to give tert-butyl (3-( lH-pyrrolo[2.3-b]pyridin-3-yl)cyclopent-3-en-l-yl)carbamate (80 mg) as a yellow solid. LCMS (m / z): 300.1 [M+H]+.

[0351] Step 5. To a solution of tert-butyl (3-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopent-3-en-l- yl)carbamate (80 mg, 0.27 mmol) in DCM (5 mL) was added TFA (0.5 mL), and the mixture was stirred at RT for 30 min. The mixture was removed under vacuum and the residue was purified by prep-HPLC to give 3-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclopent-3-en-l-amine (1-54) (34 mg, TFA salt ,42%) as a yellow solid. LCMS (m / z): 200.1 [M+H]’; 'H NMR (400 MHz, DMSO-rfc) 5 11.80 (s, 1H), 8.40 - 8.11 (m, 2H), 8.10 - 7.88 (m, 3H), 7.55 (s, 1H), 7.26 - 7.07 (m, 1H), 6. 11 (s, 1H), 3.95 (s, 1H), 3. 11 (dd, J = 16.5, 8.0 Hz, 1H), 2.94 (dd, J = 17.5, 8.0 Hz, 1H), 2.83 - 2.68 (m, 1H), 2.60 - 2.51 (m, 1H).121 410095-002WO (221369)BUSINESS.33570138.1

[0352] Example Method 11 (1-57)

[0353] Step 1. To a solution of lH-pyrrolo[2.3-b]pyridine-3-carbaldehyde (4.5 g, 34.21 mmol, 1 equiv) in toluene (60mL) was added 4-(cyclopent-l-en-l-yl)morpholine (14.15 g,102.63 mmol, 3 equiv) and the mixture was stirred at 90 °C for 18 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 4). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, fdtrated and concentrated. The residue was purified by column (Gradient: PE / EA=l / 2)) to get (E)-2-((lH-pyrrolo[2,3-b]pyridin-3-yl)methylene)cyclopentan-l-one (3.24 g, 49%) as a yellow solid. LCMS (m / z): 213.5 [M+H]+.

[0354] Step 2. At 0 °C, to a solution of (E)-2-((lH-pyrrolo[2,3-b]pyridin-3- yl)methylene)cyclopentan-l-one (3.42 g, 16.11 mmol, 1.00 equiv) in THF / MeOH (20 mL / 20 mL) was added NaBEL (1.42 g, 32.23 mmol, 2 equiv). Tire reaction mixture was stirred at RT for 2 h. The mixture was filtrated and concentrated. The mixture was triturated by DCM to afford (E)-2-((lH-pyrrolo[2,3- b]pyridin-3-yl)methylene)cyclopentan-l-ol (1.17 mg, 33%) as ayellow solid. LCMS (m / z): 215.1 [M+H]+.

[0355] Step 3. To a solution of (E)-2-((lH-pyrrolo[2,3-b]pyridin-3-yl)methylene)cyclopentan-l-ol (1.17 g, 5.64 mmol, 1.00 equiv) in THF (3 mL) was added isoindoline- 1,3 -di one (964.10 mg, 6.55 mmol, 1.2 equiv), PPIv (2.15 g, 8.19 mmol, 1.5 equiv) and DEAD (1.43 g, 8.19 mmol, 1.5 equiv). The reaction mixture was stirred at RT overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (100ml x 4). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, fdtrated and concentrated. The mixture was purified by column (Gradient: PE / EA=1 / 1)) and RP-column (60% MeCN in water) to afford (E)-2-(2-((lH-pyrrolo[2,3-b]pyridin-3-122 410095-002WO (221369)BUSINESS.33570138.1yl)methylene)cyclopentyl)isoindoline- 1,3 -dione (450 mg, 23%) as a yellow solid. LCMS (m / z): 344.1 [M+H]+.

[0356] Step 4. To a solution of (E)-2-(2-((lH-pyrrolo[2,3-b]pyridin-3- yl)methylene)cyclopentyl)isoindoline- 1.3 -dione (450 mg, 1.13mmol, 1.00 equiv) in EtOH / DCM (4 mL / 4mL) was added hydrazine hydrate (656.04 mg, 13.10mmol. 10.00 equiv). and the reaction mixture was stirred at 60 °C for 1 h. The mixture was concentrated and tire crude was purified by prep-HPLC to afford (E)-2-((lH-pyrrolo[2,3-b]pyridin-3-yl)methylene)cyclopentan-l-amine (1-57) (11 mg, 3%) as a yellow solid. LCMS (m / z): 214.1 [M+H]+. 'H NMR (400 MHz, DMSO-6) 8 12.35 (s, 1H), 8.44 (s, 3H), 8.37 - 8.29 (m, 2H), 7.58 (d, J = 2.5 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.20 (s, 1H), 4.17 (s, 1H), 2.57 - 2.52 (m, 2H), 2.12 - 1.94 (m, 2H). 1.82 - 1.68 (m. 2H).123 410095-002WO (221369)BUSINESS.33570138.1

[0357] Example Method 12 (1-59, T-60, 1-61 , & T-62)From eluting fractions 1-4

[0358] Step 1. To a solution of 3-iodo-lH-pyrrolo[2,3-b]pyridine (3 g, 12.29 mmol) in dry DMF (30 mL) was added NaH (60%, 738 mg, 18.44 mmol). Hie reaction mixture was stirred at 0 °C for 30 min under N2. TsCI (2.81 g, 14.75 mmol) was added, and the reaction mixture was stirred at RT for Ih. The mixture was diluted with water (100 mL) and exacted with EtOAc (80 mL x 3). The combined organic layers were washed with water (100 mL x 4) and brine ( 100 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet. ether: EtOAc=80: 1 -124 410095-002WO (221369)BUSINESS.33570138.120: 1) to afford 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (4.4 g, 89%) as an off-white solid. LCMS (m / z): 399.0 [M+H]+.

[0359] Step 2. To a solution of 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridinc (10 g, 25.11 mmol), 4, 4,5,5- tetramethyl-2-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l,3,2-dioxaborolane (8.02 g, 30.13 mmol), Pd(dppf)C12 (1.84 g, 2.51 mmol) and K2CO3 (10.41 g. 75.34 mmol) in 1,4-dioxane (100 mL) and H2O (25 mL) was stirred at 60 °C overnight under N2. The mixture was diluted with water (100 mL) and exacted with EtOAc (200 mL x 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na2SCL, filtered and concentrated. Tire mixture was purified by column chromatography on silica gel (Pet.ether: EtOAc=10: l - 2: 1) to afford 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l-tosyl-lH-pyrrolo[2,3- b]pyridine (5.4 g, 52%) as a light-yellow solid. LCMS (m / z): 411.2 [M+H]+.

[0360] Step 3. To a solution of CH2I2 (35.23 g, 131.55 mmol) in dry DCM (7 mL) at -78 °C was added a solution of Et2Zn (1 M, 66 mL, 65.78 mmol) in hexane under N2. After stirring at -78 °C for 30 min under N2, a solution of 3-(l,4-dioxaspiro[4.5]dec-7-en-8-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.7 g, 6.58 mmol) in dry DCM (20 mL) was added, and the reaction mixture was stirred at RT overnight. The mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL). dried over Na2SO4. filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.ether: EtOAc=5: 1 - 3: 1) to afford 3-(spiro[bicyclo[4.1 0]heptane-3,2'-[l,3]dioxolan]-6-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (1.14 g, 44%) as a light-yellow solid. LCMS (m / z): 425.1 [M+H]+.

[0361] Step 4. To a solution of 3-(spiro[bicyclo[4.1.0]heptane-3,2'-[l,3]dioxolan]-6-yl)-l-tosyl-lH- pyrrolo[2,3-b]pyridine (1.24 g, 2.92 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxane (30 mL). The reaction mixture was stirred at RT for 4 h. The reaction mixture was adjusted pH to 9-10 with K2CO3 solid. The mixture was diluted with water (50 mL) and exacted with DCM (100 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over NaiSCL, filtered and concentrated. Tire mixture was purified by column chromatography on silica gel (Pet.ether: EtOAc=4: 1 - 2: 1) to afford 6-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[4.1.0]heptan-3-one (840 mg, 75%) as an off-white solid. LCMS (m / z): 381.1 [M+H]+.

[0362] Step 5. To a solution of 6-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[4.1.0]heptan-3-one (674 mg, 1.77 mmol) in MeOH (14 mL) was added ammonium formate (1.12 g, 17.72 mmol). Hie reaction mixture was stirred at RT for 1 h. NaBH3CN (891 mg, 14.17 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with water (50 mL) and exacted with EtOAc (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4. filtered and concentrated to afford crude 6-(f-tosyl-lH-pyrrolo[2.3-b]pyridin-3- yl)bicyclo[4. 1 0]heptan-3-amine, which was used directly without purification.125 410095-002WO (221369)BUSINESS.33570138.1

[0363] Step 6. To a solution of 6-( l -tosyl- lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[4.1.0]heptan-3- amine (674 mg, 1.77 mmol) and TEA (536 mg, 5.3 mmol) in DCM (12 mL) was added BOC2O (674 mg, 1.77 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water (30 mL) and exacted with EtOAc (30 mL x 2). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried overNa2SO4, filtered and concentrated. The mixture was purified by column chromatography on silica gel (Pet.ether: EtOAc=10: 1 - 5: 1) to afford tert-butyl (6-(l-tosyl-lH-pyrrolo[2,3- b]pyridin-3-yl)bicyclo[4.1.0]heptan-3-yl)carbamate (700 mg, 82%) as a white solid, which was then purified further by chiral -HPLC (Analytical Data: Column: Daicel AS-3 (100mm x 3mm x 3um): Mobile Phase A: Liquid CO2, Mobile Phase B: ethanol; Flow rate: 1 mL / rnin; Gradient: 80% A to 80% A; Wave Length: 214 mn; RTl(min) 5.2; RT2(min): 6.0; RT3(min) 6.9; RT4(min): 7.2; Sample Solvent: Ethanol) to afford tert-butyl (6-(l-tosyl-lH-pyrrolo[2.3-b]pyridin-3-yl)bicyclo[4. 1.0]heptan-3-yl)carbamate eluting fraction 1-4.

[0364] Eluting fraction 1: 90 mg, white solid; LCMS (m / z): 482.2 [M+H]+.

[0365] Eluting fraction 2: 185 mg, white solid; LCMS (m / z): 482.3 [M+H]+.

[0366] Eluting fraction 3: 168 mg, white solid; LCMS (m / z): 482.2 [M+H]+.

[0367] Eluting fraction 4: 76 mg, white solid: LCMS (m / z): 482.2 [M+H]+.

[0368] Step 7. To a solution of tert-butyl (6-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[4.1.0]heptan-3-yl)carbamate eluting fraction 1 (90 mg, 0.186 mmol) in THF (1.5 mL) and MeOH (1.5 mL) was added 4 moL / LNaOH (0.3 mL). The reaction mixture was stirred at 70 °C for 3h. The reaction mixture was diluted with water (10 mL) and exacted with EtOAc (30 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (Pet.ether:EtOAc=l: l) to afford tert-butyl (6-(lH- pyrrolo[2,3-b]pyridin-3-yl)bicyclo[4.1.0]heptan-3-yl)carbamate (38 mg, 62%) as an off-white solid. LCMS (m / z): 328.2 [M+H]+.

[0369] The same procedure was applied to fractions 2-4 from step 6.

[0370] Eluting fraction 2: 57 mg, 76%, off-white solid; LCMS (m / z): 328.3 [M+H]+.

[0371] Eluting fraction 3: 101 mg, 88%, off-white solid; LCMS (m / z): 328.2 [M+H]+.

[0372] Eluting fraction 4: 39 mg, 75%, off-white solid; LCMS (m / z): 328.2 [M+H]+.

[0373] Step 8. To a solution of tert-butyl (6-(lH-pyrrolo[2.3-bJpyridin-3-yl)bicyclo[4.1.0]heptan-3- yl)carbamate eluting fraction 1 from step 7 (38 mg, 0.116 mmol) in DCM (2 mL) was added 4 moL / L HC1 in 1,4-dioxane (5 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the residue was triturated with DCM:Hcxanc (10 mL, 1 / 1) and lyophilized to afford 6- ( lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[4. 1.0]heptan-3-amine hydrochloride (1-59) (25 mg, 81%) as an off-126 410095-002WO (221369)BUSINESS.33570138.1yellow solid. LCMS (m / z): 228.2 [M+H]+. 1H NMR (4OO MHz, DMSO-d6) 5 11.89 (s, 1H), 8.31 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.07 (s, 3H), 7.38 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 7.8, 5.2 Hz, 1H), 3.03 (s, 1H), 2.27 - 2.20 (m, 2H), 2.09-2.00 (m, 1H), 2.00 - 1.91 (m, 1H), 1.74 (d, J = 12.6 Hz, 1H), 1.54 (td, J = 11.8, 6.0 Hz, 1H), 1.38 (dt, J = 10.6, 5.8 Hz, 1H), 1.00 (dd, J = 9.4, 4.6 Hz, 1H), 0.71 (t, J = 5.4 Hz, 1H).

[0374] The same procedure was applied to fractions 2-4 from step 7.

[0375] Eluting fraction 2: (1-60) 66 mg, 80%, off-yellow solid; LCMS (m / z): 228.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) 8 12.04 (s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.32 (dd, J = 5.2, 1.4 Hz, 1H), 8.12 - 8.00 (m, 3H), 7.41 (d, J = 2.4 Hz, 1H), 7.27 (dd, J = 7.8, 5.2 Hz, lH), 3.17 (s, 1H), 2.54 (d, J = 8.6 Hz, 1H), 2.36 - 2.25 (m. 1H), 2.05 (td. J = 13.4, 5.0 Hz, 1H), 1.79 (d, J = 13.0 Hz, 1H), 1.55 (ddd, J = 13.4, 11.4, 1.8 Hz, 1H). 1.36 (td, J = 12.8, 4.4 Hz, 1H). 1.26 (t. J = 8.2 Hz, 1H), 1.07 (dd. J = 9.2. 4.6 Hz. 1H), 0.69 (t, J = 5.0 Hz, 1H).

[0376] Eluting fraction 3: (1-61) 65 mg, 79%, off-yellow solid; LCMS (m / z): 228.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) 8 12.05 (s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.32 (dd, J = 5.2, 1.2 Hz, 1H), 8.05 (d, J = 5.2 Hz, 3H). 7.41 (d, J = 2.4 Hz. 1H), 7.27 (dd, J = 7.8, 5.2 Hz, 1H). 3.17 (s. 1H), 2.54 (d, J = 8.4 Hz, 1H), 2.32 - 2.24 (m, 1H), 2.06 (dt. J = 13.6, 6.8 Hz, 1H), 1.79 (d, J = 13.0 Hz, 1H). 1.55 (t. J = 12.4 Hz, 1H), 1.36 (td, J = 12.8, 4.4 Hz, 1H), 1.25 (dt, J = 9.4, 5.4 Hz, 1H), 1.07 (dd, J = 9.2, 4.6 Hz, 1H), 0.70 (t, J = 5.0 Hz, 1H).

[0377] Eluting fraction 4: (1-62) 25 mg, 79%, off-yellow solid; LCMS (m / z): 228.2 [M+H]+. 1HNMR (400 MHz, DMSO-d6) 8 12.01 (s, 1H), 8.33 (dd. J = 5.2, 1.4 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.12 (s, 3H), 7.40 (d, J = 2.4 Hz, 1H), 7.30 (dd. J = 7.8, 5.2 Hz, 1H), 3.03 (s. 1H), 2.27 - 2.19 (m, 2H), 2.13 - 2.01 (m, 1H), 1.97 (ddd, J = 13.0, 10.6, 5.4 Hz, 1H), 1.75 (d, J = 12.8 Hz, 1H), 1.54 (td, J = 12.0, 6.2 Hz, 1H), 1.38 (dt, J = 10.4, 5.8 Hz, 1H), 1.00 (dd, J = 9.4, 4.6 Hz, 1H), 0.72 (t, J = 5.4 Hz, 1H).127 410095-002WO (221369)BUSINESS.33570138.1

[0378] Example Method 13 (1-64 & T-65)Eluting fraction 1 + 2

[0379] Step 1. To a solution of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- bjpyridine (630 mg. 1.68 mmol ), tert-butyl (3-iodocyclobutyl)carbamate (500 mg, 1.68 mmol ) in DMF (5 mL) was added Zn (328. 1 mg, 5.05 mmol) and XPhos Pd G2 (66.2 mg, 0.08 mmol). The mixture was stirred at 50 °C for overnight under N2. The mixture was diluted with water (80 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine, dried over Na?SO4, filtrated and concentrated. The residue was purified by Pre-TLC (PE / EA = 2: 1) and chiral HPLC (Analytical Data: Column: Daicel AS-3 (100mm x 3mm x 3pm); Mobile Phase A: Liquid CO2. Mobile Phase B: Methanol; Flow rate: 1 mL / mim Gradient: 90% A to 90% A; Wave Length: 214 nm; RTl(min) 3.0; RT2(min) 3.6; Sample Solvent: Ethanol) to afford tert-butyl (3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b | pyridin-3 -y I )cyclobuty I (carbamate eluting fraction 1 and 2.

[0380] Eluting fraction 1: 120 mg, white solid; LCMS (m / z): 418.3 [M+H]+.

[0381] Eluting fraction 2: 70 mg. white solid; LCMS (m / z): 418.3 [M+H]+.

[0382] Step 2. To a solution of tert-butyl (3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)cyclobutyl)carbamate eluting fraction 1 from step 1 (120 mg, 0.29 mmol) in DCM (3 mL) was added TFA (3 mL). Hie mixture was stirred at RT for 2 h. Tire mixture was concentrated under vacuum and the residue was added MeOH (10 mL) and K2CO3 (396.2 mg, 2.87 mmol). The mixture was stirred at RT for overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (35% MeCN in H2O (0.1% HCOOH)) to afford trans-3-(lH-pyrrolo[2,3-b]pyndin-3- yl)cyclobutan-l -amine (1-64) (8 mg, 15.1%) as an off-white solid. LCMS (m / z): 188.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 11.28 (s, 1H), 8.17 (dd, J = 4.6, 1.6 Hz, 1H), 7.83 (dd, J = 7.8, 1.6 Hz, 1H), 7.28 (s, 1H), 6.99 (dd, J = 7.8, 4.6 Hz, 1H), 3.62 - 3.50 (m, 2H), 2.38 - 2.28 (m, 2H), 2.15 - 2.06 (m, 2H).

[0383] The same procedure was applied to eluting fraction 2 from step 1 .

[0384] From eluting fraction 2: cis-3-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutan-l-amine (1-65): 8 mg, 26% as a white solid. LCMS (m / z): 188.1 [M+H]+; 1H NMR (4OO MHz, DMSO-d6) 8 11.26 (s, 1H),128 410095-002WO (221369)BUSINESS.33570138.18.16 (dd, J = 4.6, 1.6 Hz, 1H), 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.20 (s, 1H), 7.00 (dd, J = 7.9, 4.6 Hz,lH), 3.24 - 3.16 (m, 1H), 3.15 - 3.03 (m, 1H), 2.65 - 2.56 (m, 2H), 1.91 - 1.77 (m, 2H).

[0385] Example Method 14 (1-66) i) n-BuLi, THE -78 °C, 0.5h ii 78 °C 1 h

[0386] Step 1. To a stirred solution of 3-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridine (200 mg, 0.53 mmol, 1.0 eq.) in THF (4 mL) was added n-BuLi (0.42 ml, 1.06 mmol, 2.0 eq.,2.5M / L) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 0.5 hour. Then tert-butyl (6- oxospiro[3.3]heptan-2-yl)carbamate (144 mg, 0.64 mmol. 1.2 eq) was added. Tire mixture was stirred at - 78 °C for 1 hour. The reaction mixture was diluted with NH4CI2 aq. (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na3SO4, fdtered and concentrated to crude product. The residue was purified by prep-TLC (DCM:MeOH=50: 1) to give tertbutyl (6-hydroxy-6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)spiro[3.3]heptan- 2-yl)carbamate (63 mg, 24%) as yellow oil. LCMS (m / z): 474.4 [M+H]+.

[0387] Step 2. To a stirred solution of tert-butyl (6-hydroxy-6-(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-3-yl)spiro[3.3]heptan-2-yl)carbamate (260 mg, 0.54 mmol, 1.0 eq.) in DCM (4 mL) was added EbSiH (319 mg, 2.7 mmol, 5.0 eq.) and TFA (187 mg, 1.64 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with NaHCCE aq. (40 mL), extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na3SO4. filtered and concentrated to crude product. The residue was purified by prep-TLC129 410095-002WO (221369)BUSINESS.33570138.1(DCM:MeOH=100: 1) to give tert-butyl (6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)spiro[3.3]hept-5-en-2-yl)carbamate (96 mg, 38%) as yellow oil.

[0388] Step 3. A mixture of tcrt-butyl (6-(l-((2-(trimcthylsilyl)cthoxy)mcthyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)spiro[3.3]hept-5-en-2-yl)carbamate (30 mg, 0.065 mmol, 1.0 eq.) in MeOH (2mL) and Pd / C (5 mg, 10%wt) was stirred at room temperature under H2 for 4 hours. The mixture was filtered and concentrated to give tert-butyl (6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-3- yl)spiro[3.3]heptan-2-yl)carbamate (25 mg, 83%) as a white solid.

[0389] Step 4

[0390] To a stirred solution of tert-butyl (6-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-3-yl)spiro[3.3]heptan-2-yl)carbamate (25 mg. 0.054 mmol, 1.0 eq.) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and to the residue was added K2CO3 (60 mg, 0.54 mmol, 10.0 eq.) and MeOH (2 mL). After stirring at RT overnight the reaction mixture was concentrated and the residue was purified by prep-HPLC to give 6-(lH- pyrrolo[2,3-b]pyridin-3-yl)spiro[3.3]heptan-2-amine (1-66) (5.2 mg, 43%) as a white solid. LCMS (m / z): 228.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 11.27 (s. 1H), 8.16 (dd, J = 4.8, 1.4 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H). 7.20 (dd. J = 6.2. 2.4 Hz. 1H), 6.99 (dd, J = 7.8, 4.6 Hz, 1H). 3.52 (d, J = 9.4 Hz, 1H), 2.47 - 2.42 (m, 2H), 2.34 - 2.20 (m, 2H), 2.15 (dd, J = 13.0, 8.2 Hz, 3H), 1.98 (t, J = 9.4 Hz, 1H), 1.90 - 1.61 (m, 2H).

[0391] Example Method 15 (1-68 & 1-69)HCOONH4,NaBH3CN, MeOHRT, 16h Chiral separation HCOOHRT, 1 hStep 4 Step 5From eluting fraction 1 + 2130 410095-002WO (221369)BUSINESS.33570138.1

[0392] Step l. To a solution oftetrahydropentalene-2,5(lH,3H)-dione (0.5 g, 3.62 mmol) and pyridine (0.3 g, 1.05 mmol) in dry DCM (10 mL) at 0 °C was added Tf2O (1.12 g, 3.98 mmol) drop-wise. The resulting mixture was stirred at room temperature overnight. Tire mixture was evaporated to remove solvent before diluted with water (30 mL) and extracted with EtOAc (2 x 30 mL). Tire combined organic layers were washed with water (30 mL) and brine (30 mL), dried over NajSCL, filtered, and evaporated under reduced pressure. The residue was purified by gel silica column chromatography (gradient: PE / EA =100: 1) to give 5-oxo-l,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate (300 mg, 60 %) as colorless oil.

[0393] Step 2. To a solution of 5-oxo-l,3a,4,5,6,6a-hexahydropentalen-2-yl trifluoromethanesulfonate (1.5 g, 5.55 mmol) and B2Pin2(2.11 g, 8.33 mmol) in 1,4-di oxane (30 mL) was added l.r-Bis(diphenylphosphino)ferrocene-palladium(Il) dichloride (406 mg, 0.56 mmol) and potassium acetate ( 1 .63 g, 16.65 mmol) under nitrogen. The reaction mixture was stirred at 100 °C for 2 hours under N2. The mixture was evaporated to remove most solvent before diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. Hie residue was purified by gel silica column chromatography (gradient: pet.ether: EtOAc=15: l) to give 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,3a.4.6a-tetrahydropentalen-2(lH)-one (0.8 g crude, ~80 %) as an off-white solid.

[0394] Step 3. To a solution of tert-butyl 3-bromo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (500 mg, 1.68 mmol) and 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydropentalen-2(lH)-one (306 mg, 2.52mmol) in dioxane / H2O (10 mL / 2 mL) was added Pd(PPli3)4 (194 mg, 0.618 mmol) and K2CO3 (698 mg, 5.05 mmol). The reaction mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The mixture was evaporated to remove most solvent before diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed wdth water (30 mL), brine (30 mL), dried over Na2SO , filtered and concentrated. The crude was purified by gel silica column (pet.ether / EtOAc=8: 1) to give tert-butyl 3-(5-oxo- 1 ,3a, 4, 5 ,6,6a-hexahydropentalen-2-yl)- lH-pyrrolo[2,3-b]pyridine- 1 - carboxylate (500 mg, 51%) as an off-white solid. LCMS (m / z): 339.3 [M+H]+.

[0395] Step 4. To a solution of tert-butyl 3-(5-oxo-l,3a.4.5.6.6a-hexahydropentalen-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (500 mg, 1.48 mmol) and HCOONH4 (1.71 g, 22.16 mmol) in MeOH (10 mL) was added NaBffCN (186 mg, 2.96 mmol). The mixture was stirred at RT overnight. The mixture was evaporated to remove most solvent before diluted wdth water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude was purified by prep-TLC (DCM / MeOH=10: l) and chiral-HPLC (Analytical method: Column: CHIRALPAK IG-3 (100mm x 3mm x 3pm; Co-Solvent: MeOH (0.4% 7M NH3); Flow rate: 1 mL / min: Wave Length: 254 nm: RTl(min) 2.6; RT2(min): 3.4) to afford tert-butyl 3-131 410095-002WO (221369)BUSINESS.33570138.1(5-amino-L3a,4,5,6,6a-hexahydropentalen-2-yl)-lH-pyrrolo[2,3-b]pyridine-l -carboxylate eluting fraction 1 and 2.

[0396] Eluting fraction 1: 75 mg, orange solid; LCMS (m / z): 340.2 [M+H]+.

[0397] Eluting fraction 2: 45 mg. orange solid; LCMS (m / z): 340.2 [M+H]+.

[0398] Step 5. A solution of tert-butyl 3-(5-amino-l,3a,4,5,6,6a-hexahydropentalen-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate eluting fraction 1 from step 4 (69 mg, 0.2 mmol) in HCOOH (1 mL) was stirred at RT for Ih. The mixture was directly freeze-dried to dryness to give 5-(lH-pyrrolo[2,3- b]pyridin-3-yl)-l,2,3,3a,4,6a-hexahydropentalen-2-amine (1-68) (38 mg, HCOOH salt, 95%) as a brown thick solid. LCMS (m / z): 240.2 [M+H]+. IH NMR (400 MHz, DMSO-d6) 8 11.72 (s, IH), 8.46 (s, IH),8.22 (s, 2H). 7.45 (s. IH), 7.10 (s, IH), 6.01 (m, IH), 3.55 - 3.16 (m, 2H). 3.11 - 2.76 (m, 2H), 2.79 - 2.57 (m, IH), 2.43 - 2.16 (m, IH), 2.00-1.60 (m, 2H), 1.51 - 1.07 (m, IH).

[0399] Tire same procedure was applied to eluting fraction 2 from step 4.

[0400] From eluting fraction 2 (1-69): 32 mg, HCOOH salt. 80% as a brown thick solid. LCMS (m / z): 240.2 [M+H]+; IH NMR (400 MHz. DMSO-d6) 3 11.72 (s, IH). 8.40 (s, 2H), 8.23 (d, J = 6.2 Hz, 2H), 7.46 (s. IH), 7.16 - 7.07 (m, IH), 6.09 (d, J = 2.4 Hz, IH). 3.29 (d, J = 8.8 Hz. 2H), 2.91 (dd, J = 16.2, 8.8 Hz, IH), 2.69 (p, J = 9.4 Hz, IH), 2.56 (s, IH), 2.31 (q, J = 8.5 Hz, IH), 2.22 (dq, J = 11 .6, 6.0 Hz, IH), 1.40 -1.23 (m, 2H).

[0401] Example Method 16 (1-70)

[0402] Step 1. To a solution of tert-butyl 3-bromo-lH-pyrrolo[2.3-bJpyridine-l-carboxylate (500 mg, 1.68 mmol) and tert-butyl 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-azaspiro[3.4]oct-6-ene-2- carboxylate (564.2 mg, 1.68 mmol) in l,4-dioxane / H2O (10 mL / 2 mL) was added Pd(PPh3)4 (194.5 mg, 0.168 mmol) and K2CO3(697.7 mg, 5 ,05mmol) . The reaction mixture was stirred at 120 °C overnight under N2. The mixture was diluted with water (30 mL) and exacted with DCM (50 mL*3). Hie combined organic layers were washed with water (30 mL) and brine (30 mL) and dried over Na2SO4, filtered and concentrated.132 410095-002WO (221369)BUSINESS.33570138.1The mixture was purified by column chromatography on silica gel (Pet.Ether: EtOAc=10: l to Pet.Ether: EtOAc=l: l) to afford tert-butyl 6-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2-azaspiro[3.4]oct-6-ene-2-carboxylate (272 mg, 49%) as an off-white solid. LCMS (m / z): 326.1 [M+H]+.

[0403] Step 2. To a solution of tert-butyl 6-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2-azaspiro[3.4]oct-6-ene- 2-carboxylate (50 mg. 0.153 mmol) in DCM (2 mL) was added TFA (0.5 mL).The reaction mixture was stirred at RT for 0.5 h. The reaction mixture was adjusted pH to 8-9 with NaHCCL aq. solution. The mixture was concentrated and the residue was dissolved with DCM:MeOH =10: 1 (20 mL), filtered and concentrated. The mixture was purified by prep-HPLC to afford 3-(2-azaspiro[3.4]oct-6-en-6-yl)-lH- pyrrolo[2,3-b]pyridine (1-70) (4.1 mg, 12%) as a yellow solid. LCMS (m / z): 226.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 11.83 (s, 1H), 8.27-8.23 (m, 2H), 7.56 (s, 1H), 7.17 (dd, J = 8.0, 4.0 Hz, 1H), 6.34 (s, 1H). 4.08 (d, J = 8.0 Hz. 2H), 3.95 (d, J = 8.0 Hz, 2H), 2.75 (t, J = 8.0 Hz. 2H), 2.29 (t, J = 8.0 Hz, 2H))

[0404] Example Method 17 (1-72 & 1-73)fraction 1 + 2

[0405] Step 1. To a solution of tert-butyl 6-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2-azaspiro[3.4]oct-6-ene-2-carboxylate (Intermediate prepared in example method 16, 232 mg, 0.712 mmol) in MeOH (6 mL) was added Pd / C (10%, 71 mg).The reaction mixture was stirred at RT for 24 h under H2 balloon. Tire reaction mixture was filtered and concentrated. Tire mixture was purified by prep-TLC (Pet.Ether: EtOAc=l : 1) and chiral-HPLC (Analytical Data: Column: Daicel AS-3 (100mm x 3mm x 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: Methanol: Flow rate: 1 mL / min; Gradient: 55% Ato 55% A: Wave Length: 214 nm; RTl(min) 5.6; RT2(min); 6.8; Sample Solvent: Ethanol) to afford tert-butyl 6-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2-azaspiro[3.4]octane-2-carboxylate.

[0406] Eluting fraction 1: 83 mg, yellow oil; LCMS (m / z): 328.2 [M+H]+.

[0407] Eluting fraction 2: 84 mg. yellow oil; LCMS (m / z): 328.2 [M+H]+.

[0408] Step 2. A solution of tert-butyl 6-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2-azaspiro[3.4]octane-2- carboxylate eluting fraction 1 from step 1 (40 mg, 0.122 mmol) in formic acid (1 mL) was stirred at RT for 2 h. Tire reaction mixture was directly freeze-dried to afford 3-(2-azaspiro[3.4]octan-6-yl)-lH-pyrrolo[2,3- b]pyridine fonnate (1-72) (43 mg, 64%) as a yellow solid. LCMS (m / z): 228.0 [M+H]+. 1H NMR (400133 410095-002WO (221369)BUSINESS.33570138.1MHz, DMS0-d6) 5 11.32 (s, 1H), 8.42 (s, 1H), 8.17 (d, J = 4.6 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.01 (dd, J = 7.8, 4.6 Hz, 1H), 3.85 - 3.74 (m, 4H), 3.28 - 3.21 (m, 1H), 2.41 (d, J = 11.8 Hz, 1H), 2.16 - 1.89 (m, 4H), 1.75 - 1.62 (m, 1H).

[0409] The same procedure was applied to eluting fraction 2 from step 1 .

[0410] From eluting fraction 2 (1-73): 48 mg. 71% as a yellow solid. LCMS (m / z): 228.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 11.32 (s, 1H), 8.39 (s, 1H), 8.17 (dd, J = 4.6, 1.4 Hz, 1H), 7.95 (dd, J = 7.8, 1.4 Hz, 1H), 7.22 (s, 1H), 7.01 (dd, J = 7.8, 4.6 Hz, 1H), 3.89 - 3.77 (m, 4H), 3.24 (h, J = 7.6, 7.0 Hz, 1H), 2.42 (dd. J - 12.8. 7.2 Hz. 1H), 2.13 - 1.89 (m, 4H), 1.68 (dq, J = 12.2, 8.8 Hz, 1H).

[0411] Example Method 18 (1-74)Boc Step 1 Boc Step 2

[0412] Step 1. A solution oftert-butyl 3-iodo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (440 mg, 1 .27 mmol), tert-butyl 3 -methyleneazetidine -1 -carboxylate (196 mg, 1.16 mmol), K2CO3 (321 mg, 2.32 mmol), Pd(OAc)2 (26 mg, 0.11 mmol) and TBAB (374 mg, 1.16 mmol) in DMF (2 mL) was stirred at 60 °C for 16 h under N2. The reaction mixture diluted with water (20 mL), and extracted with EA (20 mL*3). The combined organic phases were dried over Na SC>4, filtered and concentrated. Hie residue was purified by column (PE:EA=50: l to 3: 1) to give tert-butyl 3-((l-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (110 mg, 22%) as yellow solid. LCMS (m / z): 386.1 [M+H]+.

[0413] Step 2. A solution of tert-butyl 3-((l-(tert-butoxycarbonyl)azetidin-3-ylidene)methyl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (40 mg, 0.1 mmol) in DCM / TFA (2 mL / 1 mL) was stirred at RT for 1 h. The reaction mixture was concentrated and purified by prep-HPLC to give 3-(azetidin-3- ylidenemethyl)-lH-pyrrolo[2.3-b]pyridine (1-74) (10 mg, 55%) as a brown solid. LCMS (m / z): 186.1 [M+H]+. ’H NMR (400 MHz, DMSO-r / 6) 8 11.82 (s, 1H), 8.25 - 8.21 (m, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.08 (dd, J = 7.8, 4.6 Hz, 1H), 6.47 (s, 1H), 4.46 (m, 4H).134 410095-002WO (221369)BUSINESS.33570138.1

[0414] Example Method 19 (1-76 & 1-77)From eluting fraction 1+2 From eluting fraction 1+2

[0415] Step 1. To a stirred solution of 2-ethoxy-6-fluorobenzonitrile (5.0 g. 30.27 mmol, 1.0 eq.) in n-butanol (50 mL, 10 vol) was added hydrazine hydrate (4.5 g, 90.81 mmol, 3.0 eq.). The reaction mixture was allowed to stir at 80 °C for 16 h. The completion of reaction was monitored by TLC using 40% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (3 X 150 mL). Tire combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude material. The obtained crude material was purified by flash column chromatography on silica gel using 40% ethyl acetate in hexane as an eluent to get 4-ethoxy-lH-indazol-3 -amine (3.3 g, 62%) as off white solid. LCMS (m / z): 178.4 [M+H]+.

[0416] Step 2. To a stirred solution of 4-ethoxy-lH-indazol-3-amine (2.0 g, 11.28 mmol, 1.0 eq.) in acetonitrile (20 mL, 10 vol.) and N, N dimethylformamide (2 111L, 1 vol.) was added tert-butyl nitrite (1.39 g, 13.54 mmol, 1.2 eq.) and copper bromide (0.80 g. 5.64 mmol. 0.5 eq.) at room temperature. The reaction mixture was allowed to stir at 50°C for 30 minutes. The completion of reaction was monitored by TLC using 20% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (2 X 90 mL). Tire combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude material. The obtained crude material was purified by flash column chromatography on silica gel135 410095-002WO (221369)BUSINESS.33570138.1using 13% ethyl acetate in hexane as an eluent to get 3-bromo-4-ethoxy-lH-indazole (0.22 g, 8%) as white solid. LCMS (m / z): 241.0 [M+H]+.

[0417] Step 3. The racemic material of tcrt-butyl (4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2- yl)cyclohex-3-en-l-yl)carbamate (10.0 g) was submitted to chiral prep HPLC purification to separate the enantiomers. Eluting fraction 1: 4.1 g; Eluting fraction 2: 3.9 g. Analytical chiral HPLC: Column CHIRALPAK IG-3 (100x3mm, 3 pm); Solvent: 0.1% methanolic ammonia in MeOH:ACN (50:50); Injection volume: 2 pL; Wavelength: 230 nm; Eluting fraction 1 : retention time 0.858 min. Eluting fraction 2: retention time 0.953 min.

[0418] To a stirred solution of 3-bromo-4-ethoxy-lH-indazole (0.1 g, 0.41 mmol, 1.0 eq.) and tertbutyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (eluting fraction 1, 0.16 g, 0.49 mmol, 1.2 eq.) in 1, 4 dioxane (5 mL, 50 vol) and water (0.1 mL. 1 vol) was added tri-potassium phosphate (K3PO4) (0.13 g, 0.62 mmol, 1 .5 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.06 g, 0.08 mmol, 0.2 eq.) was added at room temperature. The reaction mixture was allowed to stir at 120 °C under microwave irradiation for 1 h. Tire completion of reaction was monitored by TLC using 40% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to get crude. The obtained crude material was purified by flash column chromatography on silica gel using 25% ethyl acetate in hexane as eluent to get tert-butyl (4-(4-ethoxy-lH-indazol-3-yl) cyclohex-3- cn-l-yl) carbamate (Qty: 0.070 g, 47%) as off white solid. LCMS (m / z): 358.2 [M+H]+.

[0419] The same procedure was applied to eluting fraction 2 of tert-butyl (4-(4,4,5.5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate.

[0420] From eluting fraction 2: 0.065 g, 44%, off-white solid. LCMS (m / z): 359.3 [M+H]+.

[0421] Step 4. To a stirred solution of tcrt-butyl (4-(4-cthoxy-lH-indazol-3-yl) cyclohcx-3-cn-l-yl) carbamate (from fraction 1, step 3, 0.07 g, 0.19 mmol, 1.0 eq.) in dichloromethane (3.5 mL, 50 vol) was added 4M hydrochloric acid in 1, 4 dioxane (0.5 mL) at 0 °C. The resulting reaction mixture was allowed to stir at room temperature for 2 h. The completion of reaction was monitored by TLC using 90% ethyl acetate in hexane and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduce pressure. The isolated solid material was further triturated with diethyl ether (2 X 20 mL) to get 4-(4-cthoxy-lH-indazol-3-yl) cyclohcx-3-cn-l -amine hydrochloride (1-76) (Qty: 0.082 g, Yield: quantitative) as off white solid. LCMS (m / z): 258.1 [M+H]+. 1H NMR (4OO MHz, DMSO-d6) 5 12.96 (s, 1H). 8.17 (s, 3H), 7.22 (t, J = 8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H). 6.39-6.38 (m, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.37-3.34 (m, 1H), 2.84-2.79 (m, 1H), 2.61-2.55 (m, 2H), 2.33-2.26 (m, 1H), 2.13-2.10 (m, 1H), 1.82-1.73 (m, 1H), 1.41 (t, J = 6.8 Hz, 3H).136 410095-002WO (221369)BUSINESS.33570138.1

[0422] The same procedure was applied to fraction 2 of tert-butyl (4-(4-ethoxy-lH-indazol-3-yl) cyclohex-3 -en-l-yl) carbamate prepared in step 3.

[0423] From eluting fraction 2 (1-77): 0.065 g, 44%, off-white solid. LCMS (m / z): 258.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.22 (s, 3H), 7.22 (t, J = 8 Hz, 1H). 7.02 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.39-6.38 (m, 1H). 4.12 (q, J = 6.8 Hz, 2H). 3.34 (s. 1H), 2.84-2.79 (m. 1H), 2.61-2.57 (m, 2H), 2.33-2.27 (m, 1H), 2.14-2.10 (m, 1H), 1.82-1.74 (m, 1H), 1.41 (t, J = 6.8 Hz, 3H).

[0424] Example Method 20 (1-40 & 1-41)BocFrom eluting fraction 1+2

[0425] Step 1. To a solution of tert-butyl (l-methyl-4-oxocyclohexyl)carbamate (200 mg, 0.88 mmol) in THF (4 mL) at -78 °C was added LiHMDS (1 M in THF, 1.7 mL, 1.76 mmol) under N2. After addition, the reaction mixture was stirred at -78 °C for 0.5 h, a solution of 1,1.1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (376 mg, 1.06 mmol) in THF (2 mL) was added. The reaction mixture was stirred at 0 °C for 2 h. The mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography on silica (PE / EtOAc=10: l) to give 4-((tert-butoxycarbonyl)amino)-4-methylcyclohex-l- en-l-yl trifluoromethanesulfonate (60 mg. 19.1%) as an oil.

[0426] Step 2. To a solution of 4-((tert-butoxycarbonyl)amino)-4-methylcyclohex-l -en-l-yl trifluorom ethanesulfonate (220 mg, 0.61 mmol) in dioxane / H2O (2 mL / 1 mL) was added tert-butyl 3-410095-002WO (221369)BUSINESS.33570138.1(4,4,5 ,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (210 mg, 0.61 mmol), K2CO3 (254 mg, 1.80 mmol) and Pd(dppf)C12 (44 mg, 0.06 mmol). The mixture was stirred at 80 °C overnight under N2. The mixture was diluted with water (30 mL), extracted with EtOAc (30 mL x 3). Hie combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was dissolved in McOH / lLO (ImL / lmL), NaOH (23 mg, 0.59 mmol) was added. The mixture was stirred at RT for 3 h. The mixture was diluted with water (20 mL). extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum purified by prep-TLC (PE / EtOAc=2 / l) and chiral-HPLC (Analytical Data: Column: Daicel AS-3 (100mm x 3mm - 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: Methanol; Flow rate: 1 mL / min; Gradient: 60% A to 60% A; Wave Length: 214 mn; RTl(min) 5.4; RT2(min); 5.9: Sample Solvent: Ethanol) to afford tert-butyl 6-(lH-pyrrolo[2,3-b]pyridin-3-yl)-2-azaspiro[3.4]octane-2-carboxylate.

[0427] Eluting fraction 1: 35 mg, white solid; LCMS (m / z): 328.1 [M+H]+.

[0428] Eluting fraction 2: 25 mg, white solid; LCMS (m / z): 328.1 [M+H]+.

[0429] Step 3. To a solution of tert-butyl (l-methyl-4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en- l-yl)carbamate eluting fraction 1 from step 2 (35 mg. 0.11 mmol) in DCM (1.5 mL) was added HCl / dioxane (4M, 1.5 mL). The mixture was stirred at room temperature for 1 h. Tire mixture was concentrated in vacuum and triturated with Et20 to afford l-methyl-4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l- amine (1-40) (HC1 salt, 14.3 mg, 50.1%) as a yellow solid. LCMS (m / z): 228.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 12.08 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 4.0 Hz, 1H), 8.20 (s, 3H), 7.61 (d, J = 2.4 Hz, 1H), 7.28 - 7.14 (m, 1H), 6.14 (s, 1H), 2.68 - 2.51 (m, 3H), 2.42 - 2.31 (m, 1H), 2.01 - 1.90 (m, 1H). 1.89 - 1.81 (m. 1H), 1.32 (s, 3H).

[0430] The same procedure was applied to eluting fraction 2 from step 2.

[0431] From eluting fraction 2 (1-41): 10.3 mg, 51.3% as a yellow solid. LCMS (m / z): 228.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 12.13 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 4.8 Hz, 1H), 8.22 (s, 3H), 7.62 (d, J = 2.4 Hz. 1H), 7.31 - 7.17 (m, 1H), 6.14 (s, 1H), 2.68 - 2.51 (m. 3H), 2.42 - 2.30 (m, 1H), 2.00 - 1.90 (m, 1H). 1.90 - 1.81 (m. 1H), 1.32 (s, 3H).

[0432] Example Method 21138 410095-002WO (221369)BUSINESS.33570138.1

[0433] Step 1. A solution of tert-butyl 3-bromo-lH-pyrrolo[2,3-b]pyridine-l -carboxylate (80 mg, 0.27 mmol), tert -butyl 6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3-azabicyclo[3. 1 ,0]hexane-3- carboxylatc (100 mg, 0.32 mmol), cataCxiumn A Pd G3 (19.6 mg, 0.027 mmol) and CS2CO3 (263 mg, 0.81 mmol) in TAA / H2O (1 mL / 0.25 mL) was stirred at 100 °C for 1 .5 h under microwave. The reaction mixture diluted with water (20 mL), extracted with EA (20 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (PE:EA= 3: 1) to give tert-butyl 3-(3-(tert- butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)-lH-pyrrolo[2,3-b]pyridine-l -carboxylate (15 mg, 14%) as a white solid. LCMS (m / z): 400.2 [M+H]+.

[0434] Step 2. A solution of tert-butyl 3-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexan-6-yl)- lH-pyrrolo[2,3-b]pyridine-l-carboxylate (15 mg) in 4M HCl / dioxane (1 mL), and MeOH (1 mL) was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated to give 3-(3- azabicyclo[3.1.0]hexan-6-yl)-lH-pyrrolo[2,3-b]pyridine HC1 as brown solid. LCMS (m / z): 200.1 [M+H]+: 1H NMR (400 MHz, DMSO-d6) 8 12.13 (s, 1H), 9.65 (s, 1H), 9.47 (s, 1H), 8.33 (dd, J = 17.0, 6.4 Hz, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.31 (t, J = 6.4 Hz, 1H), 3.51 (dd, J = 11.4, 6.0 Hz, 2H), 3.36 (q, J = 9.0, 8.2 Hz, 2H), 2.42 (s. 1H), 2.08 (d, J = 3.2 Hz, 2H).

[0435] Example Method 22 (1-5 & 1-6)

[0436] Step 1: A mixture of 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.0 g, 0.50 mmol), tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (2.4 g, 0.74 mmol), K2CO3 (1.7 g, 1.3 mmol) and Pd(dppf)C12 (366 mg, 0.500 mmol) in 1,4-dioxane / water (20 mL / 5mL) was stirred at 70 °C under N2 overnight. Hie reaction mixture was diluted with water (180 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over Na2SC>4, filtered and concentrated. The mixture was purified by column chromatography (PE / EtOAc=10: 1~6: 1) to afford tert-butyl (4-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-yl)carbamate (1.8 g, 78 %) as a yellow oil. LCMS (m / z): 467.2 [M+H]+.139 410095-002WO (221369)BUSINESS.33570138.1

[0437] Step 2: A mixture of tert-butyl (4-(l -tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l - yl)carbamate (1.6 g, 3.4 mmol) and 4N NaOH (2 mL, 9 mmol) in THF / MeOH (6 mL / 6mL) was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3 x 60 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over NazSCL, filtered and concentrated. The racemic mixture of tert-butyl(4-(lH-pyrrolo[2.3-b]pyridin-3-yl)cyclohex-3-en-l- yl)carbamate (670 mg) was purified by chiral HPLC to separate the enantiomers. (Column: Daicel OD (20 mm x 250mm, 10pm); Mobile Phase A: Liquid CO;, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 80% A for 6 mins; Wavelength: 214 nm; Sample Solvent: MeOH (65mL), Injection volume: 1.0 mL). Analytical chiral HPLC (Column: Daicel OD-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 80 % A for 5 mins; Wavelength: 214 nm; RT1 = 2.186 min, RT2 = 4.245 min). Eluting fraction 1: 250 mg. 23.3 %, off-white solid; LCMS (m / z): 314.2 [M+H]+. Eluting fraction 2: 230 mg, 21.5 %, off-white solid; LCMS (m / z): 314.2 [M+H]+.

[0438] Step 3: A mixture of tert-butyl(4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l- yl)carbamate eluting fraction 1 from step 2 (239 mg, 0.763 mmol) in 4M HCl / dioxane (8mL) / DCM (8 mL) was stirred at room temperature for 2 hours. Hie mixture was directly concentrated and triturated with DCM / hexane (lmL / 2mL) to afford 4-(lH-pyrrolo[2.3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-6, 151.4 mg. 83 %) as a yellow solid. LCMS (m / z): 214.2 [M+H]+; 'H NMR (400 MHz, DMSO-ds) 5 12.55 (s, 1H), 8.63 (d, J = 8.0 Hz, 1H), 8.42 - 8.27 (m, 4H), 7.68 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 8.0, 5.2 Hz, 1H), 6.19 (s, 1H), 3.32 (s, 1H), 2.70-2.60 (m, 2H), 2.58-2.52 (m, 1H), 2.38-2.28 (m 1H), 2.17-2.08 (m, 1H), 1.81 (qd, J = 11.4, 5.8 Hz, 1H).

[0439] The same procedure was applied to eluting fraction 2 (215 mg, 0.686 mmol) from step 2. From eluting fraction 2: 4-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-5. 152.9 mg, 93%) as a yellow solid. LCMS (m / z): 214.2 [M+H]+; 1HNMR (4OO MHz, DMSO-d6) 8 12.43 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.41 - 8.29 (m, 4H), 7.65 (s, 1H), 7.36-7.30 (m, 1H), 6.18 (s, 1H), 3.33 (br s, 1H), 2.68- 2.57 (m, 2H), 2.58-2.51 (m, 1H), 2.39-2.28 (m, 1H), 2.16-2.08 (m, 1H), 1.86-1.72 (m, 1H).140 410095-002WO (221369)BUSINESS.33570138.1

[0440] Example Method 23 (1-91 & T-92)From eluting fraction 1+2

[0441] Step 1: To a stirred solution of 2-fluoro-6-(trifluoromethoxy) (1.0 g, 4.9 mmol) in n-butanol (20 mL, 20 vol) was added hydrazine hydrate (0.73 g, 15 mmol). The reaction mixture was allowed to stir at 80 °C for 16 h. The completion of reaction was monitored by TLC using 40 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude material. The crude material was purified by flash column chromatography on silica gel using 38 % ethyl acetate in hexane as an eluent to afford 4-(trifhioromethoxy)-lH-indazol-3-amine (0.85 g, yield: 80 %) as off white solid. LCMS (m / z): 218.0 [M+H]+.

[0442] Step 2: To a stirred solution of 4-(trifluoromethoxy)-lH-indazol-3-amine (0.85 g, 3.9 mmol) in acetonitrile (17 mL, 20 vol.) and N.N -dimethylformamide (0.1 mL, cat.) was added tert-butyl nitrite (0.48 g, 4.7 mmol) and copper bromide (0.28 g, 2.0 mmol) at room temperature. The reaction mixture was allowed to stir at 50 °C for 30 minutes. The completion of the reaction was monitored by TLC using 40 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (70 mL) and extracted with ethyl acetate (2 X 60 mL). The combined organic layers were dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain the crude material. The crude material was purified by flash column chromatography on silica gel using 18 % ethyl acetate in hexane as an eluent to afford 3-bromo-4-(trifluoromethoxy)-lH-indazole (0.15 g, yield: 14 %) as an off white solid. LCMS (m / z): 280.9 [M+H]+.141 410095-002WO (221369)BUSINESS.33570138.1

[0443] Step 3: To a stirred solution of 3-bromo-4-(trifluoromethoxy)-lH-indazole (0.08 g, 0.3 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate eluting fraction 1 from example method 19 (0.11 g, 0.34 mmol) in 1,4-dioxanc (1.6 mL, 20 vol) and water (0.1 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.09 g, 0.4 mmol). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12.DCM complex (0.046 g. 0.057 mmol) was added at room temperature. The reaction mixture was allowed to stir at 120 °C under microwave irradiation for 1 h. The completion of the reaction was monitored by TLC using 40 % ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude material. The crude material was purified by flash column chromatography on silica gel using 32 % ethyl acetate in hexane as eluent to afford tert-butyl (4-(4- (trifluoromethoxy)-lH-indazol-3-yl) cyclohex-3 -en-l-yl) carbamate (0.045 g, 40 %) as off white solid. LCMS (m / z): 342.0 [M-55]+.

[0444] Tire same procedure was applied using eluting fraction 2 of tert-butyl (4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate from example method 19 (0.09 g, 0.29 mmol). From eluting fraction 2: 0.040 g, 40% off-white solid. LCMS (m / z): 342.0 [M-55]+.

[0445] Step 4: To a stirred solution of tert-butyl (4-(4-(trifluoromethoxy)-lH-indazol-3-yl) cyclohex- 3-en-l-yl) carbamate prepared from eluting fraction 1 in step 3 (0.045 g, 0.11 mmol) in dichloromethane (0.9 mL, 20 vol) was added trifluoro acetic acid (0.45 mL, 10 vol) at 0 °C. Tire resulting reaction mixture was allowed to stir at room temperature for 2 h. Tire completion of reaction was monitored by TLC using 15 % methanol in di chloromethane and LCMS analysis. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The isolated solid material was further triturated with diethyl ether (3 X 10 mL) to afford 4-(4-(trifluoromethoxy)-lH-indazol-3-yl) cyclohex-3-en-l -amine, 2,2,2- trifluoroacetate salt (1-92, 0.0076 g, yield: 21 %) as off white solid. LCMS (m / z): 298.2 [M+H]+; 'H NMR (400 MHz, DMSO-de) 5 13.44 (s, 1H), 7.93 (bs, 3H), 7.55 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.07 (d. J = 7.6 Hz, 1H), 6.07-6.06 (m, 1H), 3.40-3.35 (m. 1H obscured by water peak), 2.74-2.66 (m, 1H), 2.59- 2.55 (m. 2H), 2.32-2.26 (m, 1H), 2.12-2.08 (m, 1H). 1.77-1.67 (m, 1H).

[0446] The same procedure was applied to eluting fraction 2 (0.040 g, 0.10 mmol) from step 3. From eluting fraction 2: 4-(4-(trifluoromethoxy)-lH-indazol-3-yl) cyclohex-3 -en-1 -amine 2,2,2-trifluoroacetate salt (1-91, 0.014 g, 47%) as off white solid. LCMS (m / z): 298.2 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 13.44 (s, 1H), 7.95 (bs, 3H), 7.55 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.07-6.06 (m, 1H), 3.40-3.30 (m, 1H, obscured by water peak), 2.80-2.65 (m, 1H), 2.62-2.53 (m, 2H), 2.28- 2.22 (m. 1H), 2.12-2.09 (m, 1H), 1.75-1.71 (m, 1H).142 410095-002WO (221369)BUSINESS.33570138.1

[0447] Example Method 24 (1-87, T-88, 1-89, & T-90)i) CH3COONH34 M HCI / 1 ,4-dioxane, DCM,Chiral resolution RT, 1 hStep 11dioxane,hStep 10 using eluting fraction 2 Step 12From eluting fraction 1 & 2, step 10 products

[0448] Step 1: To a stirred solution of 3-iodo-lH-pyrrolo[2,3-b]pyridine (1 g, 4 mmol) in THF (10 mL) at 0 °C was added NaH (60%, 196 mg, 4.90 mmol) slowly. The reaction mixture was stirred at 0 °C for 0.5 hour. TsCI (1.17 g, 6.14 mmol) was added. The mixture was stirred at room temperature for 1 hour.143 410095-002WO (221369)BUSINESS.33570138.1The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. Tire residue was purified by column chromatography (DCM:MeOH=50: 1—20: 1) to give 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (1.57 g, yield: 98 %) as a white solid. LCMS (m / z): 399.0 [M+H]+.

[0449] Step 2: To a stirred solution of 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (20 g, 50 mmol), Pd(PPh3)2Cl2(881 mg, 1.25 mmol), Cui (478 mg, 2.51 mmol) and TEA (15.2 g, 150 mmol) in THF (100 mL) was added a solution of prop-2-yn-l-ol (5.6 g, 100 mmol) in TEIF (10 mL) at room temperature under N2. The reaction mixture was stirred at 70 °C for 4 hours under N2. The mixture was diluted with water (800 mL) and extracted with EtOAc (3 x 200 mL). Tire combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography (Pet.Ether: EtOAc=10: l - 1:3) to afford 3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)prop-2-yn-l-ol (14.9 g. 91 %) as a yellow solid. LCMS (m / z): 327.1 [M+H]+.

[0450] Step 3: To a stirred solution of 3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)prop-2-yn-l-ol (14.9 g, 45.7 mmol) in DCM (450 mL) at 0 °C was added Dess-Martin periodinane (29 g, 68 mmol). Tire reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with NaHCOs aq. solution (600 mL) and extracted with DCM (3 x 400 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography (Pet.Ether: EtOAc=8: l- 2: 1) to afford 3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)propiolaldehyde (12.9 g, 87 %) as a yellow solid. LCMS (m / z): 325.1 [M+H]+.

[0451] Step 4: To a stirred solution of 3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)propiolaldehyde (7.9 g, 24 mmol) in THF (73 mL) at -10 °C was added allylmagnesium bromide (36 mL, 36 mmol). The reaction mixture was stirred at -10 °C for 2 hours. The mixture was quenched with NELC1 aq. solution (400 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography (Pet.Ether: EtOAc=5: 1 - 2: 1) to afford l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)hex-5-en-l-yn-3-ol (5.2 g, 36 %) as yellow oil. LCMS (m / z): 367.1 [M+H]+.

[0452] Step 5: A mixture of l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)hex-5-en-l-yn-3-ol (5.2 g, 14 mmol) and PtCl2(313 mg, 1.15 mmol) in toluene (20 mL) was stirred at 80 °C overnight under N2in a sealed tube. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (Pet.Ether: EtOAc=8: l - 3: 1) to afford l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-one (3.8 g, 72 %) as a yellow solid. LCMS (m / z): 367.2 [M+H]+.

[0453] Step 6: A mixture of l-(l-tosyl-lH-pyrrolo[2.3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-one (3.8 g, 10 mmol) and CH3COONH3 (40 g, 520 mmol) in MeOH / DCE (375 mL / 125 mL) was stirred at room temperature for 2 hours. NaBH3CN (5.2 g, 83 mmol) was added, and the mixture was stirred at 40 °C for 2144 410095-002WO (221369)BUSINESS.33570138.1hours. The mixture was diluted with water (800 mL) and extracted with DCM (3 x 300 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The mixture was purified by column chromatography (DCM / MeOH=l:0 - 8: 1) to afford l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-amine (1.49 g, 39 %) as a yellow oil. LCMS (m / z): 368.2 [M+H]+.

[0454] Step 7: A mixture of l-(l-tosyl-lH-pyrrolo[2.3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine (1.49 g, 4.05 mmol), BOC2O (1.3 g, 6.1 mmol) and TEA (1.23 g, 12.1 mmol) in DCM (20 mL) was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated to afford crude tert-butyl (l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate (1.87 g, 99 %) as a yellow oil. LCMS (m / z): 468.2 [M+H]+.

[0455] Step 8: A mixture oftert-butyl (l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan- 3-yl)carbamate (1 g, 2 mmol) and NaOH (4M, 1 .3 mL, 5.3 mmol) in THF / MeOH (8 mL / 8 mL) was stirred at 70 °C for 3 hours. The mixture was diluted with water (80 mL) and extracted with DCM (3 x 30 mL). Tire combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (DCM / MeOH=20: 1) to afford tert-butyl (l-(lH-pyrrolo[2.3-b]pyridin-3- yl)bicyclo[3. 1 ,0]hexan-3-yl)carbamate (520 mg. 77 %) as a white solid. The racemic material (920 mg from parallel batches) was purified by prep-HPLC (30% MeCN in H2O (0.1% TFA)). A mixture of tert-butyl ((lR,3S,5R)-l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate and tert-butyl ((lS,3R,5S)-l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate were obtained in a single fraction (210 mg, peak 1). LCMS (m / z): 314.2 [M+H]+. A mixture of tert-butyl ((1S,3S,5S)-1-(1H- pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate and tert-butyl ((1R,3R,5R)-1-(1H- pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate were obtained in a second fraction (168 mg, peak 2) as a white solid. LCMS (m / z): 314.2 [M+H]+. NOEs were used to confirm the relative configuration of the components of each fraction.

[0456] Step 9: Fraction 1 obtained in step 8 (210 mg) was further purified by chiral-HPLC to separate the enantiomers. (Column: Daicel AD (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 65% A for 8 mins; Wavelength: 214 nm; Sample Solvent: MeOH (10 mL), Injection volume: 0.8 mL). Analytical chiral HPLC (Column: Daicel AD-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 65 % A for 3 mins; Wavelength: 214 nm; RT1 = 1.444 min, RT2 = 2.193 min). Eluting fraction 1: 100 mg, white solid; LCMS (m / z): 314.2 [M+H]+. Eluting fraction 2: 80 mg, white solid; LCMS (m / z): 314.2 [M+H]+.

[0457] Step 10: Fraction 2 obtained in step 8 was further purified by chiral-HPLC to separate the enantiomers. (Column: Daicel OJ (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CO2, Mobile Phase145 410095-002WO (221369)BUSINESS.33570138.1B: MeOH; Flow rate: 55 mL / min; Gradient: 80% A for 4 mins; Wavelength: 214 nm; Sample Solvent: MeOH (40 mL), Injection volume: 0.9 mL). Analytical chiral HPLC (Column: Daicel OJ-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 80 % A for 3 mins; Wavelength: 214 nm; RT1 = 1.581 min, RT2 = 1.956 min). Eluting fraction 1: 100 mg, white solid; LCMS (m / z): 314.2 [M+H]+. Eluting fraction 2: 70 mg, white solid; LCMS (m / z): 314.2 [M+H]+.

[0458] Step 11: To a solution of tert-butyl l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3- yl)carbamate eluting fraction 1 from step 9 (100 mg, 0.3 mmol) in DCM (4 mL) was added 4M HC1 in 1,4- dioxane (4 mL). Tire reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and triturated with DCM / liexane (2 / 1) to afford l-(lH-pyrrolo[2.3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-amine hydrochloride from eluting fraction 1 from step 9 (1-87, 45.3 mg, 56.8%) as a yellow solid. LCMS (m / z): 214.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 12.15 (s, 1H), 8.37 - 8.30 (m, 2H), 8.14 (s, 3H), 7.43 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 7.8, 5.2 Hz, 1H), 4.01 (tt, J = 9.8, 4.4 Hz, 1H), 2.68 - 2.55 (m, 2H), 2.16 (dd, J = 14.2, 4.8 Hz, 1H), 1.80 (dd, J = 14.2, 4.4 Hz, 1H), 1.67 (dt, J = 9.2, 5.0 Hz, 1H), 1.28 - 1.21 (m, 1H), 1.08 (t, J = 4.8 Hz, 1H).

[0459] The same procedure was applied to eluting fraction 2 from step 9 to obtain l-(lH-pyrrolo[2,3- b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine hydrochloride (1-89, 53.8 mg. 84.4%) as ayellow solid. LCMS (m / z): 214.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 12.23 (s, 1H), 8.40 - 8.33 (m, 2H), 8.17 (s, 3H), 7.45 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 7.8, 5.4 Hz, 1H), 4.02 (tt, J = 9.8, 4.6 Hz, 1H), 2.68-2.56 (m, 2H), 2.16 (dd, J = 14.2, 4.6 Hz, 1H), 1.80 (dd, J = 14.2, 4.4 Hz, 1H), 1.68 (dt, J = 9.4, 5.0 Hz, 1H), 1.28 - 1.21 (m, 1H). 1.09 (t, J = 4.8 Hz, 1H).

[0460] Step 12: To a solution of tert-butyl l-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3- yl)carbamate eluting fraction 1 from step 10 (80 mg, 0.2 mmol) in DCM (4 mL) was added 4M HO in 1,4- dioxane (8 mL). Tire reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and triturated with DCM / hexane (1 / 10) to afford l-(lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-amine hydrochloride from fraction 1 step 10 (1-88, 41.2 mg, 52%) as a yellow solid. LCMS (m / z): 214.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 12.12 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H). 8.34 (d, J = 4.8 Hz. 1H). 8.30 (s. 3H), 7.42 (d, J = 2.2 Hz, 1H), 7.28 (dd. J = 7.8, 5.2 Hz, 1H). 3.43 - 3.28 (m, 1H), 2.42 (dd, J = 12.2, 7.4 Hz, 1H), 2.31 - 2.26 (m, 1H), 2.23-2.18 (m, 2H), 1.61 (dt, J = 8.2, 3.8 Hz, 1H), 0.97 - 0.88 (m, 2H).

[0461] Tire same procedure was applied to eluting fraction 2 from step 10 to obtain l-(lH-pyrrolo[2,3- b]pyridin-3-yl)bicyclo[3. 1.0]hexan-3-amine hydrochloride (1-90, 46.8 mg, 83.9%) as ayellow solid. LCMS (m / z): 214.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 12.06 (s. 1H), 8.49 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 4.4 Hz, 1H), 8.27 (s, 3H), 7.41 (d, J = 2.4 Hz, 1H), 7.26 (dd, J = 7.8, 5.2 Hz, 1H), 3.41 - 3.30 (m, 1H),146 410095-002WO (221369)BUSINESS.33570138.12.42 (dd, J = 12.2, 7.4 Hz, 1H), 2.30 - 2.25 (m, 1H), 2.23-2.17 (m, 2H), 1.61 (dt, J = 8.2, 4.2 Hz, 1H), 0.98- 0.86 (m, 2H).

[0462] Example Method 25 (1-101 & 1-102)

[0463] Step 1: A solution of 3 -((tert-butoxycarbonyl)amino)cyclobutane-l -carboxylic acid (3.6 g, 17 mmol) and CDI (3.25 g, 20.1 mmol) in dry THF (54 mL) was stirred at 0 °C for 1 h. A solution of N,O- dimethylhydroxylamine hydrochloride (1.96 g, 20.1 mmol) and TEA (2.03 g. 20.1 mmol) in dry THF (18 mL) was added and the mixture was stirred at room temperature for 16 h. The reaction was diluted with water (400 mL) and extracted with EtOAc (3 x 200mL). The combined organic phases were washed with water (200 mL) and brine (200 mL), dried over Na2SO4 and concentrated under vacuum to afford tert-butyl (3-(methoxy(methyl)carbamoyl)cyclobutyl)carbamate (4.3 g, 99 % yield) as an off-white solid. LCMS (m / z): 259.2 [M+H]+.

[0464] Step 2: To a solution of 1 -chloro-2-fluorobenzene (1.4 g, 11 mmol) in fresh THF (28 mL) at - 75 °C was added n-BuLi (4.29 mL, 10.7 mmol). After stirring at -75 °C for 0.5 h, a solution of tert-butyl (3-(methoxy(methyl)carbamoyl)cyclobutyl)carbamate (2.2 g, 8.6 mmol) in fresh THF (14 mL) was added and the mixture was stirred at -75 °C to 0 °C for 3 h. The mixture was quenched with NELC1 solution (aq., 200 mL) and extracted with EtOAc (3 x 200mL). Hie combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na?SO4 and concentrated under vacuum. The residue was purified by column chromatography (Pet. ether / EtOAc=10 / l) to afford tert-butyl (3-(3-chloro-2- fluorobenzoyl)cyclobutyl)carbamate (1.35 g, 38 % yield) as a white solid. LCMS (m / z): 271.9 [M-55]+.

[0465] Step 3: A solution of tert-butyl (3-(3-chloro-2-fluorobcnzoyl)cyclobut l)carbamatc (300 mg, 0.91 mmol), NH2NH2.H2O (137 mg, 2.75 mmol) and AcOH (54 mg, 0.91 mmol) in 1-butanol (12 mL) was147 410095-002WO (221369)BUSINESS.33570138.1stirred at 130 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (120 mL) and extracted with EtOAc (3 x 50mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried overNa2SO4 and concentrated under vacuum. Tire residue was purified by prep-TLC (Pet.ether / EtOAc=2 / l) to afford tert-butyl (3-(7-chloro-lH-indazol-3-yl)cyclobutyl)carbamate (110 mg) as an off-white solid. The mixture of isomers was resolved by chiral HPLC. (Column: Daicel IC (20 mm x 250mm. 10pm): Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 65% A for 3.2 mins; Wavelength: 214 nm; Sample Solvent: MeOH (20 mL), Injection volume: 1 .25 mL). Analytical chiral HPLC (Column: Daicel IC (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 65 % A for 6 mins; Wavelength: 214 nm; RT1 = 3.350 mm, RT2 = 4.108 mm).

[0466] Eluting fraction 1: 36 mg, 12 % yield, off-white solid; LCMS (m / z): 322.1 [M+H]1. NOE analysis confirmed the absolute stereochemistry of this eluting fraction, identifying the product as tert-butyl ((ls,3s)-3-(7-chloro-lH-indazol-3-yl)cyclobutyl)carbamate. Eluting fraction 2: 51 mg, 17 % yield off-white solid; LCMS (m / z): 266.0 [M-55]+. NOE analysis confirmed the absolute stereochemistry of this eluting fraction, identifying the product as tert-butyl ((lr,3r)-3-(7-chloro-lH-indazol-3-yl)cyclobutyl)carbamate.

[0467] Step 4: Asolution oftert-butyl ((ls,3s)-3-(7-chloro-lH-indazol-3-yl)cyclobutyl)carbamate (36 mg, 110 pmol) in HCl / dioxane (2 mL) and DCM (1 mL) was stirred at room temperature for 2 h. The reaction was concentrated under vacuum and the residue was purified by trituration (ether) to afford ( 1 s,3 s)- 3-(7-chloro-lH-indazol-3-yl)cyclobutan-l-amine hydrochloride (1-102, 25 mg, 86 % yield) as a yellow solid. LCMS (m / z): 222.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 8.36 (brs, 3H), 7.85 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 3.82 - 3.72 (m, 1H), 3.71 - 3.61 (m, 1H), 2.75 - 2.66 (m, 2H). 2.57 - 2.51 (m. 2H).

[0468] The same procedure was applied to tert-butyl ((lr,3r)-3-(7-chloro-lH-indazol-3- yl)cyclobutyl)carbamate (51 mg, 160 pmol) from step 3 to afford (lr,3r)-3-(7-chloro-lH-indazol-3- yl)cyclobutan-l -amine hydrochloride (1-101, 36 mg, 87 % yield) as an off-white solid. LCMS (m / z): 220.0 [M+H]+; ’H NMR (400 MHz, DMSO-dg) 8 8.34 (brs, 3H), 7.67 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.4 Hz, 1H). 7.10 (m, J = 8.0 Hz, 1H). 4.10 - 4.01 (m. 1H), 3.95 - 3.86 (m, 1H), 2.68 - 2.60 (m, 4H).148 410095-002WO (221369)BUSINESS.33570138.1

[0469] ExpEluting fraction 1 + Eluting fraction 2From elutingFrom eluting fraction 1 + fraction 1 + fraction 2 fraction 2

[0470] Step 1: To a solution of 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.0 g, 5.0 mmol) in dry THF (28 mL) at -78 °C was added LDA (3.7 mL,7.5 mmol) under N2. The mixture was stirred at -78 °C for 1 hour, then a solution of PhSCFCl ( 1. 1 g, 6.2 mmol) in THF (2 mL) was added. Tire mixture was stirred at room temperature overnight. The reaction mixture was diluted with NFLC1 (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with dried over NajSCL, filtered and concentrated. Tire mixture was purified by column chromatography (Pet. ether / EtOAc=10: 1-3: 1) to afford tert-butyl (4-2-chloro-3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.4 g, 78 %) as an off-white solid. LCMS (m / z): 432.9 [M+H]+.[00471J Step 2: A mixture of 2-chloro-3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.5 g, 5.5 mmol) and tert-butyl (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (2.8 g, 8.3 mmol) Pd(dppf)C12(420 mg, 0.58 mmol) and K3PO4 (2.45 g, 11.5 mmol) in l,4-dioxane / H2O (30 mL / 6 mL) was stirred at 60 °C for 2 hours under N2. Tire reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). Hie combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography (pet. ether / EtOAc = 10: 1 - 8: 1 - 6: 1 - DCM / MeOH = 1:0-20: 1) to afford tert-butyl (4-(2-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l- yl)carbamate (3 g, 99%) as a yellow solid. The racemic mixture was purified by chiral HPLC to separate149 410095-002WO (221369)BUSINESS.33570138.1the enantiomers. Analytical chiral HPLC (Column: Daicel AS-3 (3 mm x 100mm, 3 pm); Co-solvent: 0.4% 7M NHs in IPA; Flow rate: 1 mL / min; Run time: 3.5 mins; Wavelength: 214 nm; RT1 = 1.891 min, RT2 = 2.123 min). Eluting fraction 1: 220 mg, off-white solid; LCMS (m / z): 502.2 [M+H]+. Eluting fraction 2: 250 mg, off-white solid; LCMS (m / z): 502.2 [M+H]+.

[0472] Step 3: A mixture of tert-butyl (4-(2-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex- 3-en-l-yl)carbamate eluting fraction 1 from step 2 (170 mg, 0.34 mmol) and 4 M NaOH (5 mL) in THF / MeOH (6 mL / 6 mL) was stirred at 70 °C for 2 hours. The reaction mixture was diluted with water (40 mL) and extracted with DCM (3 x 20 mL). Tire combined organic layers were dried over Na2SC>4, filtered and concentrated. The mixture was purified by prep-TLC (DCM / MeOH=20: l) to afford tert-butyl (4-(2- chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-yl)carbamate from eluting fraction 1 (80 mg, 68 % yield) as a yellow solid. LCMS (m / z): 348. 1 [M+H]1. The same procedure was applied to eluting fraction 2 (200 mg) from step 2. From eluting fraction 2: tert-butyl (4-(2 -chloro- lH-pyrrolo[2,3-b]pyridin-3- yl)cyclohex-3-en-l-yl)carbamate (40 mg, 28 %) as a yellow solid. LCMS (m / z): 348.2 [M+H]+.

[0473] Step 4: A mixture of tert-butyl (4-(2-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l- yl)carbamate from eluting fraction 1 in step 3 (150 mg) in 4M HCl / dioxane (8 mL) / DCM (8 mL) was stirred at room temperature for 2 hours. Tire mixture was directly concentrated, and the residue was triturated with DCM / hexane (lmL / 2mL) to afford 4-(2-chloro-lH-pyrrolo[2.3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-107, 103.8 mg) as a yellow solid. LCMS (m / z): 248.1 [M+H]+. ’H NMR (400 MHz, DMSO-ds) 8 8.29 (s, 3H), 8.26 - 8.22 (m, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.15 (dd, J = 8.0, 4.8 Hz, 1H), 5.86 (s, 1H), 3.43-3.29 (m, 1H), 2.65 - 2.53 (m, 3H), 2.39 - 2.29 (m, 1H), 2.11 (d, J = 12.2 Hz, 1H), 1.80 (qd, J = 11.2, 5.6 Hz, 1H).

[0474] The same procedure was applied to tert-butyl (4-(2 -chloro- lH-pyrrolo[2.3-b]pyridin-3- yl)cyclohex-3-en-l-yl)carbamate prepared from eluting fraction 2 in step 3 (200 mg). From eluting fraction 2: 4-(2-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-108, 100 mg) as a yellow solid. LCMS (m / z): 248.1 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 8 8.27 (s, 3H), 8.25 - 8.22 (m, 1H), 8.07-8.01 (m. 1H) 7.16-7.11 (m, lH), 5.86 (s, 1H), 3.45-3.30 (m, 1H), 2.68 - 2.53 (m, 3H), 2.38 - 2.25 (m, 1H). 2.11 (d, J = 12.4 Hz, 1H), 1.85-1.73 (m, 1H).150 410095-002WO (221369)BUSINESS.33570138.1

[0475] Example Method 27 (1-93)

[0476] Step 1: To a solution of 3-((tert-butoxycarbonyl)amino)bicyclo[l.l.l]pentane-l-carboxylic acid (3 g, 13 mmol) in DCM (50 mL) at 0 °C was added DMAP (322.5 mg, 2.614 mmol), 2- hydroxyisoindoline-1.3-dione (2.37 g, 14.5 mmol) and EDCI (3.78 g, 19.8 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction solution was diluted with water (500 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with: PE: EA = 5: 1, v / v) to afford l.3-dioxoisoindolin-2-yl 3-((tert- butoxycarbonyl)amino)bicyclo[l. l.l]pentane-l-carboxylate (2.3 g, 63 % yield) as a white solid. ’H NMR (400 MHz, DMSO-de) 5 7.99 - 7.93 (m. 4H), 2.39 (s, 6H), 1.39 (s, 9H).

[0477] Step 2: To a solution of 3-iodo-lH-pyrrolo[2,3-b]pyridine (25 g, 0.102 mol) in THF (250 mL) at 0 °C was added NaH (60%, 4.92 g, 0.123 mol) under N2. After stirring at 0 °C for 0.5 h, TsCl (29.2 g, 0.153 mol) was added. Tire mixture was stirred at room temperature for 2 h. Hie reaction solution was diluted with water (1 L) and extracted with DCM (2 x 250 mL). The combined oiganic layers were washed with brine (800 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with: PE: EA = 50 / 1- 0 / 1, v / v) to410095-002WO (221369)BUSINESS.33570138.1afford 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (34 g, 83% yield) as a yellow solid. LCMS (m / z): 399.0 [M+H]+.

[0478] Step 3: To a solution of t-BubpyCAMCN (93.9 mg, 0.280 mmol) and NiBr2(dmc) (86.4 mg, 0.280 mmol) in DMAc (3 mL) was added 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (556 mg, 1.40 mmol), l,3-dioxoisoindolin-2-yl 3-((tert-butoxycarbonyl)amino)bicyclo[l . 1. l]pentane-l-carboxylate (782 mg, 2.10 mmol) and Zn (dust) (182 mg, 2.78 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h under N2. The reaction solution was diluted with water (50 mL) and filtered, and the aqueous phase was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. Tire residue obtained was purified by column chromatography on silica gel (eluting with: PE: EA = 20: 1—5:1, v / v) to afford tertbutyl (3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[l.l.l]pentan-l-yl)carbamate (60 mg. 9.4 % yield) as a white solid. LCMS (m / z): 454.2 [M+H]+.

[0479] Step 4: To a solution of tert-butyl (3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[l. l.l]pentan-l-yl)carbamate in THF (1 mL) and MeOH (1 mL) was added 4 M NaOH (0.2 mL). The reaction mixture was stirred at 70 °C for 3 h. The reaction solution was diluted w ith water (20 mL) and extracted with EtOAc (2 x 10 mL). Tire combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% HCOOH-ACN, 55% ACN) to afford tert-butyl (3-(lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[l. l.l]pentan-l-yl)carbamate (15 mg, 34 % yield) as a light-yellow solid. LCMS (m / z): 300.1 [M+H]+.

[0480] Step 5: To a solution of tert-butyl (3-(lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[l.l.l]pentan-l- yl)carbamate (15 mg, 0.050 mmol) in DCM (0.5 mL) was added 4 M HC1 in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was triturated with DCM (5 mL). The solid was collected by filtration to afford 3-(lH-pyrrolo[2,3- b]pyridin-3-yl)bicyclo[l. l.l]pentan-l-amine hydrochloride (1-93, 4.7 mg, 40 % yield) as a yellow solid. LCMS (m / z): 200.0 [M+H]+. H NMR (400 MHz, DMSO-de) 8 12.29 (s, 1H), 9.05 (brs, 3H), 8.39 - 8.33 (m, 2H). 7.49 (d, J = 2.2 Hz. 1H), 7.32 - 7.26 (m, 1H), 2.38 (s, 6H).152 410095-002WO (221369)BUSINESS.33570138.1

[0481] Example Method 28 (1-95 & T-96)

[0482] Step 1: To a stirred solution of tert-butyl (3-hydroxycyclobutyl)carbamate (1.00 g, 5.34 mmol) in tetraliydrofuran (20 mL, 20 vol) were added carbon tetrabromide (3.50 g, 10.7 mmol) and triphenylphosphine (2.80 g, 10.7 mmol) portion-wise at room temperature. Tire reaction mixture was allowed to stir at room temperature for 20 h. The completion of the reaction was monitored by TLC using 10% ethyl acetate in hexane (KMnO4staining reagent). After completion of the reaction, the reaction mixture was poured into water (125 mL) and extracted with ethyl acetate (2 X 75 mL). The combined organic layers were dried over anhydrous Na SCL and concentrated under reduced pressure to afford the crude material. Tire crude residue was purified by flash column chromatography on silica gel using 8% ethyl acetate in hexane as eluent to obtain tert-butyl (3-bromocyclobutyl)carbamate (0.40 g, 30%) as white solid. ’HNMR (400 MHz. DMSO-ok) 37.33 (m, 1H), 4.59-4.55 (m, 1H), 4.36-4.30 (m, 1H), 2.61-2.47 (m, 4H). 1.36 (s. 9H).

[0483] Step 2: Preparation of solution-A: In a 30 mL glass vial a solution of 3-bromo-4-methoxy- IH-indazole (0.25 g, 1.1 mmol), tert-butyl (3-bromocyclobutyl)carbamate (0.550 g, 2.20 mmol, from multiple batches prepared as in step 1), tris(trimethylsilyl)silane (0.273 g, 1.10 mmol), [4,4'-Bis(l,l- dimethylethyl)-2,2'-bipyridine-Nl,N 1 ']bis[3,5-difluoro-2-[5-(trifluoro methyl) -2-pyridinyl-N]phenyl- C]Iridium(III)hexafluorophosphate (0.025 g, 0.022 mmol), sodium carbonate (0.231 g, 2.20 mmol) in dimethoxy ethane (DME) (5 mL, 20 vol) was prepared. The vial was sealed and placed under argon.

[0484] Preparation of pre-catalysed solution: In a separate vial, a solution of nickel (II) chloride ethylene glycol dimethyl ether complex (0.005 g, 0.02 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (0.006 g, 0.02 mmol) in dimethoxy ethane (DME) (5 mL, 20 vol) was sonicated for 10 min. Solution A (sonicated for 10 min before addition) was then added. The reaction mixture was degassed with argon and irradiated with a blue LED light (427 nm, Kessil Blue LED) at room temperature for 16 h. The completion of the410095-002WO (221369)BUSINESS.33570138.1reaction was monitored by TLC using 40% ethyl acetate: n-hexane as mobile phase. After completion of the reaction, parallel batches were combined, poured into saturated sodium bicarbonate (NaHCCh) solution (50 mL) and extracted with ethyl acetate (2 X 25 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. Tire obtained crude material was purified by flash column chromatography on silica gel using 20% ethyl acetate in hexane and concentrated under vacuum. The isolated material was further purified by reverse phase flash column chromatography using neat water as eluent. The isolated fractions were lyophilized to afford tert-butyl (3-(4-methoxy-lH-indazol- 3-yl)cyclobutyl)carbamate (Qty: 0.07 g, 10%) as a white solid. LCMS (m / z): 300.1 [M+H]+.

[0485] Step 3: To a stirred solution of tcrt-butyl (3-(4-mcthoxy-lH-indazol-3- yl)cyclobutyl)carbamate (0.035 g, 0.11 mmol) in dichloromethane (0.35 mL, 10 vol) was added 4M hydrochloric acid in 1,4-dioxane (0.17 mL, 5 vol) at 0 °C under an inert atmosphere of nitrogen gas. The resulting mixture was stirred at room temperature for 5 h. The completion of the reaction was monitored by TLC using 5% methanol in di chloromethane. After completion of the reaction, parallel batches were combined and concentrated under reduced pressure. The isolated material was resuspended in DCM (10 mL) then solvent removed by distillation in order to remove trapped volatile impurities. This was repeated with a second portion of DCM (10 mL) to obtain solid material which was further triturated with diethyl ether (4 X 10 mL) and dried well under high vacuum to afford 3-(4-methoxy-lH-indazol-3-yl)cyclobutan- 1-amine hydrochloride (0.040 g, 71%) as off-white semi solid. This mixture of isomers was submitted to reverse phase preparative HPLC purification to isolate both isomers individually. (Column: Waters Sunfire C18 OBD (250 mm x 19 mm x 5pm); Mobile Phase A: 0.05% Formic acid in water, Mobile Phase B: Acetonitrile:water (80:20); Flow rate: 12 mL / min; Gradient: 95 %A for 2 mins, 88% A for 22 mins, 0% A for 3 mins, 95% A for 3 mins; Wavelength: 210 mn; Sample Solvent: MeOH:water; Loading: 6 mg; Number of injections: 6; RT1 = 11.220 mins. RT2 = 13.069 mins).

[0486] Eluting fraction 1 (1-95): 6.31 mg, 15%, off-white semi-solid; LCMS (m / z): 218.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 12.64 (s, 1H), 8.38 (s, 1H), 7.22-7.18 (t, J = 8.0 Hz, 1H), 6.99-6.98 (d, J = 8.0 Hz, 1H), 6.46-6.44 (d, J = 7.6 Hz, 1H), 4.03-4.01 (m, 1H), 3.86 (s, 3H), 3.73-3.70 (m, 1H), 2.59-2.55 (m, 2H). 2.38-2.33 (m, 2H). NOE analysis of this fraction was used to confinn the stereochemistry, and the identity of this fraction was confirmed to be as (lr,3r)-3-(4-methoxy-lH-indazol-3-yl)cyclobutan-l-amine formate.

[0487] Eluting fraction 2 (1-96): 4.96 mg, 12%, off-white semi-solid; LCMS (m / z): 218.1 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 8 12.65 (s, 1H), 8.37 (s, 1H), 7.21-7.17 (t, J = 8.4 Hz, 1H), 6.99-6.97 (d, J = 8.4 Hz, 1H). 6.46-6.44 (d, J = 7.6 Hz, 1H), 3.87 (s. 3H), 3.63-3.44 (m, 2H), 2.60-2.56 (m, 2H). 2.26-2.24 (m, 2H). NOE analysis of fraction 1 was used to confirm the stereochemistry, therefore the identity of this fraction was deduced to be ( Is, 3s)-3-(4-methoxy-lH-indazol-3-yl)cyclobutan-l -amine formate.154 410095-002WO (221369)BUSINESS.33570138.1

[0488] Example Method 29 (1-98 & 1-99)BOC20

[0489] Step 1: To a solution of 3-iodo-lH-pyrazolo[3,4-b]pyridine (5 g, 20 mmol) in toluene (50 mL) was added 3,4-dihydro-2H-pyran (13.73 g, 163.3 mmol) and TFA (465 mg, 4.08 mmol). The mixture was stirred at 100 °C overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL). dried over Na2SO4. filtrated and concentrated. Purification by column chromatography (PE / EtOAc=10 / l) afforded 3-iodo-l -(tetrahydro- 2H-pyran-2-yl)-lH-pyrazolo[3,4-b]pyridine (7 g, 93 %) as a yellow7solid. LCMS (m / z): 330.0 [M+H]+.

[0490] Step 2: A solution of 3-iodo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-b]pyridine (2.0 g, 6.1 mmol), tert-butyl (3-iodocyclobutyl)carbamate (2.29 g, 7.90 mmol ), Zn ( 1.19 g, 18.2 mmol) and XPhos Pd G2 (238.74 mg, 303.82 pmol) in DMF (10 mL) was stirred at 50 °C overnight under N2 in sealed tube. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried overNa2SO4, filtrated and concentrated. Purification by column chromatography (PE / EA=2 / 1) afforded tert-butyl (3-(l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazolo[3,4-b]pyridin-3-yl)cyclobutyl)carbamate (1.22 g. 53 %) as an off-white solid. LCMS (m / z): 373.3 [M+H]+.

[0491] Step 3: A solution of tert-butyl (3-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[3,4-b]pyridin- 3-yl)cyclobutyl)carbamate (1.22 g, 3.28 mmol) in 4 M HCl / 1.4-dioxane (15 mL) was stirred at 50 °C overnight under N2. Tire mixture was concentrated directly. The residue w as re-dissolved in MeOH (10 mL) and K2CO3 (10 eq.) was added. After stirring at room temperature for 30 min, the mixture was filtered and the filtrate w as concentrated to give the crude product (600 mg), which was used directly in the next step. LCMS (m / z): 189.1 [M+H]+.410095-002WO (221369)BUSINESS.33570138.1

[0492] Step 4: To a solution of 3-(lH-pyrazolo[3,4-b]pyridin-3-yl)cyclobutan- l-amine (600 mg, 3.19 mmol) in DCM (6 mL) was added BOC2O (695.7 mg, 3.187 mmol) and DIEA (824.0 mg, 6.375 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (100 mL) and washed with water (50 mL x 2). The organic phases were dried over Na2SO4. filtered and concentrated. Purification by column chromatography (DCM / MeOH=10 / l) and prep-TLC (DCM / MeOH=10 / l) afforded tert-butyl (3-(lH-pyrazolo[3,4-b]pyridin-3-yl)cyclobutyl)carbamate (300 mg, 32 %) as an off-white solid.

[0493] Tire mixture of isomers was separated by chiral-HPLC. (Column: Daicel AS (30 mm x 250mm, 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 80% A for 5 mins; Wavelength: 214 nm; Sample Solvent: MeOH (6 mL), Injection volume: 1.0 mL). Analytical chiral HPLC (Column: Daicel AS-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2. Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 80 % A for 5 mins; Wavelength: 214 nm; RT1 = 2.686 min. RT2 = 3.220 min). The stereochemistry of each fraction was confirmed by NOE analysis. Eluting fraction 1 : Tertbutyl ((ls,3s)-3-(lH-pyrazolo[3,4-b]pyridin-3-yl)cyclobutyl)carbamate (110 mg, 11 %) as an off white solid. LCMS (m / z): 289.1 | M+H| . Eluting fraction 2: Tert-butyl ((lr,3r)-3-(lH-pyrazolo[3,4-b]pyridin-3- yl)cyclobutyl)carbamate (85 mg, 9 %) as an off-white solid. LCMS (m / z): 289.1 [M+H]+.

[0494] Step 5: To a solution of tert-butyl ((ls.3s)-3-(lH-pyrazolo[3.4-b]pyridin-3- yl)cyclobutyl)carbamate (100 mg, 0.34 mmol) in DCM (2 mL) was added 4M HCl / 1.4-dioxane (2 mL). The mixture was stirred at room temperature for 2h. Tire mixture was concentrated, and tire residue was triturated to afford (ls,3s)-3-(lH-pyrazolo[3,4-b]pyridin-3-yl)cyclobutan-l-amine (1-99, 44 mg, HC1 salt, 66 %) as a white solid. LCMS (m / z): 189.0 [M+H]+. 'H NMR (400 MHz, DMSO-de) 5 13.33 (brs, 1H), 8.49 (d, J = 4.6 Hz, 1H), 8.37 (d, J = 8.2 Hz, 1H), 7.70 (brs, 2H). 7.16 (dd, J = 8.0, 4.6 Hz, 1H), 3.79 - 3.55 (m, 2H). 2.74 - 2.63 (m. 2H), 2.47 - 2.39 (m, 2H).

[0495] The same procedure was applied to tert-butyl ((lr,3r)-3-(lH-pyrazolo[3,4-b]pyridin-3- yl)cyclobutyl)carbamate from step 4 (80 mg, 0.27 mmol) to afford (lr,3r)-3-(lH-pyrazolo[3,4-b]pyridin-3- yl)cyclobutan-l -amine (1-98, 46 mg, HC1 salt, 88 %) as a yellow solid. LCMS (m / z): 189.0 [M+H]+. 'l l NMR (400 MHz, DMSO-d6) 5 13.37 (brs. 1H), 8.50 (d, J = 4.6 Hz, 1H), 8.30 - 8.17 (m, 4H), 7.19 - 7.12 (m, 1H). 4.04-4.01 (m, 1H), 3.96 - 3.89 (m, 1H), 2.68 - 2.60 (m, 4H).156 410095-002WO (221369)BUSINESS.33570138.1

[0496] Example Method 30 (1-104 & 1-105)

[0497] Step 1: To a solution of tert-butyl ((3-hydroxycyclobutyl)methyl)carbamate (10.0 g, 49.7 mmol) in DCM (100 mb) was added L (15.1 g, 59.6 mmol), PPh, (4.06 g, 59.6 mmol) and imidazole (15.6 g, 59.6 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was filtered and diluted with water (500 mL), extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over NazSO^ filtered and concentrated under vacuum. The residue was purified by column chromatography (PE / EA= 100 / 1-40 / 1) to afford tert-butyl ((3- iodocyclobutyl)methyl)carbamate (7.0 g, yield: 45%) as a white solid. LCMS (m / z): 255.9 [M-55]+.

[0498] Step 2: To a solution of 3-iodo-l-tosyl-lH-pyrrolo[2,3-b]pyridine (2.0 g, 5.0 mmol), tert-butyl ((3-iodocyclobutyl)methyl)carbamate (1.88 g, 6.03 mmol) in DMF (10 mL) was added Zn (979.4 mg, 15.07 mmol) and XPhos Pd G2 (197.3 mg, 0.2508 mmol). The mixture was stirred at 50 °C overnight under Nz in a sealed tube. After filtration, the filtrate was diluted with water (300 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed by brine (100 mL), dried over NazSO^ filtrated and concentrated. Purification by column chromatography (PE / EA= 100 / 1-40 / 1) gave tert-butyl ((3-(l-tosyl- lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl) methyl) carbamate (700 mg, 30.6 %) as a white solid. LCMS (m / z): 456.3 [M+H]+.

[0499] Step 3: To a solution of tert-butyl ((3-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl) cyclobutyl)methyl)carbamate (700 mg, 1.54 mmol) in THF / MeOH (5 / 5 mL) was added NaOH (aq.) (4N, 1.15 mL). The mixture was stirred at 70 °C for 3 h. The mixture was diluted with water (150 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NazSOz. filtered and concentrated. Purification by prep-TLC (DCM / MeOH=20 / l) afforded tert-butyl ((3-410095-002WO (221369)BUSINESS.33570138.1(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl) methyl) carbamate (300 mg) as a white solid. The mixture of isomers was separated by chiral HPLC (Column: Daicel OD (250 mm x 30 mm x 10pm); Mobile Phase A: Liquid CCL, Mobile Phase B: MeOH; Flow7rate: 55 mL / min; Gradient: 85 % A for 12 mins; Wavelength: 214 nm; Sample Solvent: MeOH (15 mL); Injection volume: 1.0 mL. Analytical chiral HPLC (Column: Daicel OD-3 (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 85 % A for 6 mins; Wavelength: 214 nm; RT1 = 2.268 min. RT2 = 3.099 min) to give tert-butyl (((ls,3s)-3-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl)methyl)carbamate (eluting fraction 1, 80 mg) as a white solid and tert-butyl (((lr,3r)-3-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl)methyl)carbamate (eluting fraction 2, 170 mg) as a white solid. The stereochemistry of each product was confinned by NOE analysis. LCMS (m / z): 302.2 [M+H]+for both fractions.

[0500] Step 4: To a solution of tert-butyl ((ls,3s)-3-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl)carbamate eluting fraction 1 from step 3 (80 mg,0.27 mmol) in DCM (3 mL) was added HCl / l,4-dioxane (4M, 3 mL). After stirring at room temperature for 4h, the mixture was concentrated under vacuum and the residue was triturated with DCM / Et2O=l / 10 (3 mL) to afford ((1 s,3s)- 3-(lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl)methanamine (1-104, 50 mg, 93%) as a yellowish solid. LCMS (m / z): 202.0 [M+H]+. ’HNMR (400 MHz, DMSO-de) 5 12.33 (s, 1H), 8.42 (d, J = 7.8 Hz, 1H), 8.36 (d. J = 5.2 Hz. 1H), 8.15 - 8.01 (m. 3H), 7.52 - 7.48 (m, 1H), 7.33 (dd, J = 7.8, 5.4 Hz, 1H). 3.58 (p, J = 8.8 Hz, 1H), 2.94 - 2.84 (m, 2H), 2.66 - 2.52 (m, 2H), 2.49 - 2.47 (m, 1H), 2.06 - 1.88 (m, 2H).

[0501] Tire same procedure was applied to tert-butyl ((lr,3r)-3-(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-pyrrolo[2,3-b]pyridin-3-yl)cyclobutyl)carbamatc eluting fraction 2 in step 3 (170 mg, 0.56 mmol) to afford ((lr,3r)-3-(lH-pyrrolo[2.3-b]pyridin-3-yl)cyclobutyl)methanamine (1-105, 110 mg, 96%) as a yellowish solid. LCMS (m / z): 202.0 | M+H| . 'H NMR (400 MHz, DMSO-de) 8 12.42 (s, 1H), 8.45 - 8.32 (m, 2H), 8.26 - 8.01 (m, 3H), 7.61 - 7.56 (m, 1H), 7.36 (dd, J = 7.6, 5.4 Hz, 1H), 3.82 (p, J = 8.0 Hz, 1H), 3.08 - 3.00 (m, 2H), 2.70 - 2.59 (m, 1H), 2.35 - 2.26 (m, 4H).158 410095-002WO (221369)BUSINESS.33570138.1

[0502] Example Method 31 (1-79 & T-80)From elutingEluting fraction 1 + fraction 1 + Eluting fraction 2 fraction 2

[0503] Step 1: To a solution of 3-bromo-2-metlryl-lH-pyrrolo[2,3-b]pyridine (400 mg, 1.90 mmol) in dry DMF (20 mL) at 0 °C was added NaH (91 mg, 2.3 mmol). The reaction was stirred at 0 °C for 0.5 h, then TsCl (397 mg, 2.08 mmol) was added, and the mixture was stirred room temperature for 2 h. Hie reaction mixture was quenched with ice water (20 mL), diluted with water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (pet. ether / EtOAc= 10 / 1) to afford 3-bromo-2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine (435 mg, 62.8 %) as a white solid. LCMS (m / z): 366.5 [M+H]+.

[0504] Step 2: To a solution of 3-bromo-2-methyl-l -tosyl- lH-pyrrolo[2,3-b]pyridine (435 mg, 1.19 mmol) in dioxanc / FLO (4.8 mL / 1.2 mL) at room temperature was added tert-butyl (4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)carbamate (577 mg, 1.79 mmol), K2CO3 (411 mg, 2.98 mmol) and Pd(dppf)CL (87 mg, 120 pmol). The reaction was stirred at 70 °C for 16 h under N2 in a sealed tube. Tire reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed water (30 mL) and brine (30 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Pet. Ether: EtOAc=10 / l -5 / 1-3 / 1) to afford tert-butyl (4-(2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l- yl)carbamate (530 mg, 92 %) as a white solid. LCMS (m / z): 482.2 [M+EI]+.159 410095-002WO (221369)BUSINESS.33570138.1

[0505] Step 3: To a solution of tert-butyl (4-(2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)cyclohex-3-en-l-yl)carbamate (525 mg, 1.09 mmol) in THF / MeOH (8 mL / 8 mL) at room temperature was added 4 M NaOH (1 mL, 3 mmol). The reaction was stirred at 70 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4. filtered and concentrated under vacuum to give the crude residue (340 mg) as an off-white solid. Tire residue was purified by chiral HPLC (Analytical chiral HPLC, Column: Daicel IG-3 (3 mm x 100mm, 3pm); Co-solvent: 0.4% 7M NH3in MeOH; Flow rate: 1 mL / min; Run time: 4.5 mins; Wavelength: 214 nm; RT1 = 2.309 min, RT2 = 2.590 min). Eluting fraction 1: 80 mg, 22 % as a white solid. LCMS (m / z): 328.1 [M+H]+. Eluting fraction 2: 85 mg, 24 % as a yellow solid. LCMS (m / z): 328.2 [M+H]L

[0506] Step 4: To a solution of tert-butyl (4-(2-methyl-lH-pyrrolo[2.3-b]pyridin-3-yl)cyclohex-3-en- l-yl)carbamate eluting fraction 1 from step 3 (75 mg, 0.23 mmol) in DCM (1 mL) at room temperature was added 4M HCl / dioxane (2 mL). Tire mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified by trituration (ether) to afford 4-(2-methyl- lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-79, 60.9 mg, 98% yield) as a yellow solid. LCMS (m / z): 228.1 [M+H]+.1HNMR(400 MHz, DMSO-de) 5 12.56 (s, 1H), 8.38 - 8.29 (m, 4H). 8.28 - 8.24 (m, 1H). 7.33 - 7.28 (m. 1H), 5.71 - 5.65 (m. 1H), 3.45 - 3.32 (m, 1H). 2.68 - 2.51 (m, 3H), 2.46 (s, 3H), 2.39 - 2.28 (m, 1H), 2.14 - 2.06 (m, 1H), 1 .90 - 1.78 (m, 1H).

[0507] The same procedure was applied to eluting fraction 2 (80 mg, 0.24 mmol) from step 3. From eluting fraction 2: 4-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)cyclohex-3-en-l-amine hydrochloride (1-80, 58.3 mg, 90% yield) as a yellow solid. LCMS (m / z): 228.1 [M+H]+. ’H NMR (400 MHz, DMSO-de) 5 12.47 (s. 1H), 8.38 - 8.19 (m, 5H), 7.31 - 7.24 (m, 1H). 5.71 - 5.65 (m. 1H), 3.39 (s, 1H), 2.69 - 2.51 (m,3H), 2.45 (s, 3H), 2.38 - 2.27 (m, 1H), 2.15 - 2.05 (m, 1H), 1.89 - 1.77 (m, 1H).

[0508] Example Method 32 (1-110, 1-111, 1-112, & 1-113)160 410095-002WO (221369)BUSINESS.33570138.1i) CH3COONH3From eluting fraction 1-4

[0509] Step 1: To a solution of l-(trimethylsilyl)hex-5-en-l-yn-3-ol (8 g, 48 mmol) in DMSO (50 mL) at room temperature was added KF (5.52 g, 95.1 mmol). Hie reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL). dried over Na2SO4. filtered and concentrated under vacuum to afford hex-5-en-l-yn-3-ol (4 g, yield: 87.5%) as yellow oil. 'H NMR (400 MHz, DMSO-ds) 8 5.87 - 5.74 (m, 1H), 5.43 (d, J = 5.6 Hz, 1H), 5.15 - 5.02 (m, 2H), 4.25 - 4.17 (m, 1H), 3.26 (d, J = 2.0 Hz, 1H), 2.36 - 2.25 (m, 2H).

[0510] Step 2: To a solution of 2-methyl-lH-pyrrolo[2,3-b]pyridine (9.5 g, 0.072 mol) and KOH (10. 1 g, 0.180 mol) in DMF (100 mL) was added a solution of L (18.5 g, 0.0730 mol) in DMF (20 mL) dropwise. The reaction mixture was stirred at room temperature for Ih. The mixture was poured into cold-water (IL, contained 1 % ammonia and 0.2 % NaHSOs). The solid was precipitated, collected by filtration and washed with waterto afford 3-iodo-2-methyl-lH-pyrrolo[2,3-b]pyridine (17 g, 92 %) as agrey solid. LCMS (m / z): 259.0 [M+H]+.

[0511] Step 3: To a solution of 3-iodo-2-methyl-lH-pyrrolo[2.3-b]pyridine (17 g, 0.066 mol) in THF (200 mL) at 0 °C was added NaH (3.16 g, 0.0790 mol, 60 %) under N;. The reaction mixture was stirred at 0 °C for 0.5 hour. TsCl (18.9 g, 0.0990 mol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (1 L) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated.161 410095-002WO (221369)BUSINESS.33570138.1The residue was purified by silica-gel column (Pet.Ether: EtOAc=20: 1-100% EtOAc) to afford 3-iodo-2- methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine (24 g, yield: 88 %) as a yellow solid. LCMS (m / z): 413.0 [M+H]+.

[0512] Step 4: To a solution of 3-iodo-2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridine (5 g, 12 mmol) in TEIF (50 mL) at room temperature was added TEA (2.5 g, 24 mmol), Cui (116 mg, 0.609 mmol), PdCk(PPh3)2 (213 mg, 0.303 mmol) and hex-5-en-l-yn-3-ol (3.5 g, 36 mmol). The reaction mixture was stirred at 70 °C overnight under a N2 atmosphere. The mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO.i, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: Pet.Ether: EtOAc=20: 1-5: 1) to afford l-(2-methyl-l-tosyl-lH- pyrrolo[2,3-b]pyridin-3-yl)hex-5-en-l-yn-3-ol (4 g, yield: 72.4 %) as yellow oil. LCMS (m / z): 381.2 [M+H]+.

[0513] Step 5: To a solution of l-(2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)hex-5-en-l-yn-3- ol (4 g, 10 mmol) in toluene (40 mL) at room temperature was added PtCL (140 mg, 0.53 mmol). The mixture was stirred at 80 °C overnight under a N2 atmosphere in a sealed tube. The mixture was filtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: Pet.Ether: EtOAc=20: 1-5: 1) to afford l-(2-methyl-l-tosyl-lH-pyrrolo[2.3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-one (3.1 g, yield: 78 %) as ayellow solid. LCMS (m / z): 381.1 [M+H]+.

[0514] Step 6: To a solution of l-(2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-one (3.1 g, 8.2 mmol) in MeOH / DCE (30 / 30 mL) at room temperature was added CH3COONH3 (31.4 g, 407 mmol) and AcOH (1 mL). The mixture was stirred at 60 °C overnight. Then NaBFLCN (4.1 g, 65 mmol) was added at room temperature. The mixture was stirred at 60 °C for 2 hours. The mixture was diluted with water (600 mL) and extracted with DCM (200 mLx 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluent: DCM: MeOH=30: 1-7.5: 1) to afford l-(2-methyl-l-tosyl-lH-pyrrolo[2.3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine (2.7 g, yield: 87%) as a yellow solid. LCMS (m / z): 382.2 [M+H]+.

[0515] Step 7: To a solution of l-(2-methyl-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-amine (2.7 g, 7.1 mmol) in DCM (30 mL) at room temperature was added TEA (2.15 g, 21.2 mmol) and BOC2O (1.7 g, 7.8 mmol). The mixture was stirred at room temperature overnight. Tire mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL). dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: Pet. Ether: EtOAc162 410095-002WO (221369)BUSINESS.33570138.1=20: 1-5: 1) to afford tert-butyl (l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3- yl)carbamate (2.4 g, yield: 70 %) as a white solid. LCMS (m / z): 482.2 [M+H]+.

[0516] Step 8: To a solution of tert-butyl (l-(l-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-yl)carbamate (2 g, 4 mmol) in THF / MeOH (15 mL / 15 mL) at room temperature was added 4M NaOH (2.6 mL, 10 mmol). The mixture was stirred at 70 °C for 3 hours. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SCL, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: Pet. Ether: EtOAc =5: 1-1: 1). The mixture of diastereomers (800 mg) was further separated by chiral-HPLC (Column: Daicel IG (250 mm x 20 mm x 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 65 % A for 13.5 mins; Wavelength: 214 nm; Sample Solvent: MeOH (60 mL); Injection volume: 0.65 mL. Analytical chiral HPLC (Column: Daicel IG (3 mm x 100mm, 3 pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 65 % A for 14 mins; Wavelength: 214 nm; RT1 = 5.369, RT2 = 5.982 min, RT3 = 7.940 min, RT4 = 11.801) to obtain three isolates. Isolate 1 was a mixture of eluting fraction 1 and 2, isolate 2 was eluting fraction 3, and isolate 3 was eluting fraction 4. The isolate containing a mixture of products from eluting fraction 1 and 2 (380 mg) was further separated by chiral- HPLC Column: Daicel OJ (250 mm x 20 mm x 10pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 85 % A for 19.0 mins; Wavelength: 214 nm; Sample Solvent: MeOH (40 mL); Injection volume: 0.85 mL. Analytical chiral HPLC (Column: Daicel OJ (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 85 % A for 5 mins; Wavelength: 214 nm; RT1 = 1.589 min, RT2 = 2.179 min, RT3 = 3.518) to obtain three eluting fractions (A-C in order of elution). Each fraction was analyzed using the first chiral HPLC method so that identical products could be combined. Eluting fraction A of the second separation was consistent with eluting fraction 2 of the first separation. Eluting fraction B was consistent with eluting fraction 4. Eluting fraction C was consistent with eluting fraction 1. Identical products were combined, and each was further purified by prep-HPLC (35% MeCN / l%o TFA in water). NOE analysis was used to assign the relative stereochemistry of each fraction. Products 1 and 4 were assigned as tert-butyl ((lR,3R,5R)-l-(2-methyl- lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3. 1.0]hexan-3-yl)carbamate or tert-butyl ((lS.3S,5S)-l-(2-methyl- lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate. Products 2 and 3 were assigned as tertbutyl ((lS,3R,5S)-l-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate or tertbutyl (( 1 R,3 S,5R)- 1 -(2-methyl- lH-pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-yl)carbamate .

[0517] Product 1 : Eluting fraction 1 of first chiral HPLC separation, 160 mg, white solid. LCMS (m / z): 328.3 [M+H]+. Product 2: Eluting fraction 2 of first chiral HPLC separation. 50 mg, white solid. LCMS (m / z): 328.2 [M+H]+. Product 3: Eluting fraction 3 of first chiral HPLC separation, 60 mg. white solid.163 410095-002WO (221369)BUSINESS.33570138.1LCMS (m / z): 328.2 [M+H]+. Product 4: Eluting fraction 4 of first chiral HPLC separation, 190 mg, white solid. LCMS (m / z): 328.4 [M+H]+.

[0518] Step 9: To a solution of tcrt-butyl (l-(2-mcthyl-lH-pyrrolo[2,3-b]pyridin-3- yl)bicyclo[3.1.0]hexan-3-yl)carbamate product 1 from step 8 (160 mg, 0.49 mmol) in DCM (8 mL) was added 4 M HC1 in 1,4-dioxane (4 mL). Tire reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was triturated with Et;O to afford 1 -(2 -methyl- 1H- pyrrolo[2,3-b]pyridin-3-yl)bicyclo[3.1.0]hexan-3-amine hydrochloride product 1 (1-110) 98.2 mg, 76.1%) as a red solid. LCMS (m / z): 228.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 12.30 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.30 - 8.16 (m, 4H), 7.31 (dd, J = 7.8, 5.4 Hz, 1H), 3.30 (s, 1H), 2.46 (s, 3H), 2.38 - 2.23 (m, 3H). 2.03 - 1.95 (m. 1H), 1.52 - 1.46 (m, 1H), 0.97 (t, J = 4.6 Hz, 1H), 0.72 (dd, J = 8.4, 5.2 Hz, 1H).

[0519] The same procedure was applied to products 2-4 from step 8.

[0520] Product 2 (1-111): 39.7 mg, 99.2%, hydrochloride salt as a yellow solid. LCMS (m / z): 228.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 12.18 (s, 1H), 8.25 - 8.17 (m, 2H), 8.05 (s, 3H), 7.27 (dd, J = 7.8, 5.4 Hz, 1H), 3.97 (s, 1H), 2.81 - 2.70 (m, 1H), 2.44 (s, 3H), 2.34 - 2.25 (m, 1H), 2.11 (dd, J = 14.2, 4.2 Hz, 1H). 1.85 (dd, J = 14.2, 3.8 Hz, 1H), 1.59 - 1.50 (m, 1H), 1.14 (t, J = 4.8 Hz, 1H), 1.05 - 1.00 (m, 1H).

[0521] Product 3 (1-112): 32.2 mg, 89.4% hydrochloride salt as a yellow solid. LCMS (m / z): 228.2 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 5 12.34 (s, 1H), 8.29 - 8.22 (m, 2H), 8.11 (s, 3H), 7.31 (dd, J = 7.6, 5.4 Hz, 1H), 3.97 (s, 1H), 2.79 - 2.70 (m, 1H), 2.45 (s. 3H), 2.34 - 2.23 (m, 1H), 2.13 (dd, J = 14.2, 4.2 Hz, 1H). 1.86 (dd, J = 14.2, 3.8 Hz, 1H), 1.58 - 1.52 (m, 1H), 1.17 (t, J = 4.8 Hz, 1H), 1.05 - 0.99 (m, 1H).

[0522] Product 4 (1-113): 86.7 mg, 63.3% hydrochloride salt as a red solid. LCMS (m / z): 228.1 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 8 12.48 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.33 (s, 3H), 8.29 - 8.24 (m, 1H), 7.35 (dd, J = 7.8, 5.4 Hz, 1H), 3.30 (s, 1H), 2.47 (s, 3H), 2.38 - 2.29 (m, 2H), 2.28 - 2.20 (m, 1H), 2.06 - 1.97 (m, 1H), 1.53 - 1.45 (m. 1H), 0.98 (t, J = 4.6 Hz, 1H), 0.73 (dd, J = 8.2, 5.2 Hz, 1H).164 410095-002WO (221369)BUSINESS.33570138.1

[0523] Example Method 33 (1-81)

[0524] Step 1: A solution of tert-butyl 3-(5-amino-l, 3a, 4,5,6, 6a-hexahydropentalen-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (160 mg, 0.47 mmol), HCOONH4 (892 mg, 14.1 mmol) and Pd / C (10 %. 160 mg) in MeOH (10 mL) was stirred at room temperature for 2 h under H2 balloon. After filtration, the filtrate was concentrated to afford the crude tert-butyl 3-(5-aminooctahydropentalen-2-yl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (140 mg, 88%) as an off-white solid, which was used directly. LCMS (m / z): 342.2 [M+H]+.

[0525] Step 2: To a solution of tert-butyl 3-(5-aminooctahydropentalen-2-yl)-lH-pyrrolo[2,3- b]pyridine-l -carboxylate (140 mg. 0.41 mmol) in EtOH (5 mL) was added BOC2O (94 mg, 0.43 mmol). Hie mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness and the residue was purified by gel silica column chromatography (gradient: PE / EtOAc =2: 1, v / v) to give tert-butyl 3-(5- ((tert-butoxycarbonyl)amino)octahydropentalen-2-yl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (60 mg, 36 %) as an off-white solid. LCMS (m / z): 442.3 [M+H]+.

[0526] Step 3: To a solution of tert-butyl 3-(5-((tert-butoxycarbonyl)amino)octahydropentalen-2-yl)- lH-pyrrolo[2,3-b]pyridine-l-carboxylate (40 mg, 0.091 mmol) in MeOH (2 mL) was added a solution of NaOH (19 mg, 0.45 mmol) in water (1 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (gradient: DCM / MeOH=10: 1) to give tertbutyl (5-(lH-pyrrolo[2,3-b]pyridin-3-yl)octahydropentalen-2-yl)carbamate (38 mg, 79 %) as a colourless thick solid. LCMS (m / z): 342.2 [M+H]+.410095-002WO (221369)BUSINESS.33570138.1

[0527] Step 4: To a solution of tert-butyl (5-( lH-pyrrolo[2,3-b]pyridin-3-yl)octahydropentalen-2- yl)carbamate (38 mg, 0.11 mmol) in DCM (2 mL) was added 4M HCl / dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness and freeze-dried to give 5- (lH-pyrrolo[2,3-b]pyridin-3-yl)octahydropentalen-2-amine HC1 salt (1-81, 32 mg, 95 % yield) as an off- white solid. LCMS (m / z): 242.2 [M+H]1; 'H NMR (400 MHz. DMSO-de) 8 12.0 (s, 1H). 8.34-8.30 (m, 2H), 8.10 (s, 3H), 7.41-7.38 (m, 1H), 7.26-7.22 (m, 1H), 3.71 - 3.65 (m, 1H), 3.47-3.45 (m, 1H), 3.35-3.30 (m, 1H), 3.12-3.08 (m, 1H), 2.71-2.66 (m, 1H), 2.52-2.50 (m, 1H), 2.42-2.38 (m, 1H), 2.28-2.22 (m, 1H), 2.00-1.78 (m, 2H), 1.53-1.41 (m, 2H).

[0528] Example 34: h5-HT2A Receptor Calcium Assay

[0529] HEK cells over expressing human 5-HT2A receptor were trypsinized, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialyzed serum. Next day, media was removed from the cell plates and 30 pl assay buffer (20 mM HEPES: HBSS, pH 7.4) was added. 10 pl Calcium 5 dye solution (Molecular Devices: R8186) was added to the wells and incubated at 37 °C for 40 minutes. Dye solution was made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) were performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates were placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls were added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds were screened in duplicate using a 9 point half-log dose -response curve.

[0530] Data analysis was performed using Dotmatics. Briefly, data was normalized to low (DMSO) and high controls (5-HT Emax)). Assay Z’ should be greater than 0.5, and on-plate control 5-HT should be within 0.25 log of average.

[0531] 115-HT2A Receptor Calcium Assay results are shown in Table 2. The letter codes for pECso include: A (>6); B (>5 - 6); and C (<5). The letter codes for Emax% include: A (>90%); B (90 - >70%); C (70 - >50%); and D (<50%).Table 2. h5-HT2A Receptor Calcium Assay Results166 410095-002WO (221369)BUSINESS.33570138.1167 410095-002WO (221369)BUSINESS.33570138.1

[0532] Example 35: h5-HT2A Receptor NanoBiT I -Arrestin Assay

[0533] HEK cells expressing LgBiT tagged 5-HT2A and smBiT [3- Arrestin are trypsinizcd. counted, and seeded in white 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialyzed serum. Tire following day 25 pL ofNanoGlo live cell substrate (Promega N2012) is added to each well and the cells incubated for 25 minutes. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. 20 pL of 5X compound solution is added to the cells. Cells are incubated for 90 minutes at 37 °C and luminescence measured using the Envision plate reader. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 34.168 410095-002WO (221369)BUSINESS.33570138.1

[0534] Example 36: 5-HT2B Receptor Calcium Assay

[0535] HEK cells over expressing human 5-HT2B receptor are trypsinized, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pl assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pl Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37°C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 34.

[0536] Example 37: h5-HT2C Receptor Calcium Assay

[0537] HEK cells over expressing human 5-HT2C receptor are trypsinised, counted and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pl assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pl Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37°C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at cx / cm: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 34.

[0538] Example 38: m5-HT2A Receptor Calcium Assay

[0539] HEK cells over expressing mouse 5-HT2A receptor are trypsinized, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pL assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pl Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37°C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to169 410095-002WO (221369)BUSINESS.33570138.1the cell plate. The plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 34.

[0540] Example 39: Head Twitch Response and Locomotor Activity in mice.

[0541] Tire aim of this study is to determine the effect of provided compounds to elicit the head twitch response and the effect on locomotor activity. The Head Twitch Response (HTR; also called ‘‘wet-dog shakes”) is a widely used behavioral assay in mice and rats respectively to test for activation of the serotonin 5-HT2A receptor. The response is a rapid, side-to-side movement of the head and neck. Halberstadt, A. L., Geyer. M. A. Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacology (Berl). 2013; 227(4):727- 739; Halberstadt, A. L., Geyer, M. A.. Effect of Hallucinogens on Unconditioned Behavior. Curr Top Behov Neurosci. 2018; 36: 159-199. While not a direct correlation, HTR serves as an indicator of potential psychedelic effect in humans. Halberstadt, A. L., Chatha, M., Klein, A. K., Wallach J., Brandt. S. D. Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology. 2020; 167: 107933. Whole brain and plasma samples are collected for drug metabolism and pharmacokinetics (DMPK).

[0542] Sixty (60) male C57BL / 6J mice (8-9 w eeks of age, 20-25 g upon arrival) are obtained. Mice are dosed with either vehicle (p.o or i.p) or compound (p.o or i.p) at time “0” and placed in the arenas. Dosing is to a timed scheduled. Mice are weighed prior to dosing and body weight recorded. A reference (e.g., lysergic acid diethylamide (LSD) or 2.5-dimethoxy-4-iodoamphetamine (DOI)) may be used.

[0543] The number of head twitches are counted by a trained observer w ho is blind to treatment, and sessions are recorded using video capture equipment (Etho vision vl7) for a period of time post dosing. The locomotor activity of all groups is measured using the Ethovision system. Other behaviours of note are also scored. At the conclusion of the observation period (T=30) each mouse will be humanely euthanized using CO2 and a cardiac puncture performed prior to confirming death via cervical dislocation. The mice are utilized for brain and blood sampling / DMPK.

[0544] Terminal plasma', following confirmation of death, as much blood as possible is removed from the animal to individual K3EDTA tubes, which arc then held on wet ice for a maximum of 30 minutes prior to centrifugation. Blood samples are spun at 2000 g for 10 minutes at 4 °C and as much plasma as possible is extracted and transferred to individual 0.5mL screwcap microtubes, frozen over dry ice and stored at - 80°C for subsequent analysis of compound levels.170 410095-002WO (221369)BUSINESS.33570138.1

[0545] Brain', following confirmation of death, the brain is removed from each mouse, rinsed in purified water, blotted dry, weighed, and snap frozen in individual 7 mL precellys tubes, samples to be stored at -80 °C for subsequent analysis of compound levels.

[0546] Data'. A square root transformation is used for the number of head twitches. If there is evidence that square root transformed data are not normally distributed, the log(x+l) transformation and no transformation is also considered. The primary analysis is the total number of twitches over the 30-minute observation period. Analysis is by three-way analysis of variance with treatment, day and observer as factors. If an appropriate transformation cannot be found, robust regression may be used. Non-parametric methods (exact Wilcoxon rank sum test) may be used if there are no twitches for many of the animals. Locomotor activity analysis is by two-way AN OVA on square-root transformed data with treatment and day as factors.

[0547] Example 40: Forced Swim Test in mice.

[0548] Tire experiment is designed to utilize the forced swim test (FST), a method with predictive capabilities for evaluating the efficacy of antidepressant medications. Petit-Demouliere, B , Chenu, F., Bourin, M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl). 2005, 177(3), 245-255; Malikowska-Racia, N., Salat, K., Nowaczyk, A., Fijalkowski, L., Popik, P. Dopamine D2 / D3 receptor agonists attenuate PTSD-like symptoms in mice exposed to single prolonged stress. Neuropharmacology 2019, 155, 1-9; McDonnell, C. W., Dunphy-Doherty, F., Rouine, J., et al. The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression. Front Psychiatry 2021, 11, 599588.

[0549] FST is a utilized behavioral model in preclinical screening, which is based on observing a rodent's response to a threat. Passive behavior, drifting, and lack of movement to attempt escape are interpreted as susceptibility to depressed mood. This test involves placing the animal in a container of water with no means of escape and inducing short-term stress due to the necessity to stay afloat. Hie assay can provide reproducible results and detect various antidepressants. Cryan J. F., “Depression” Encyclopedia of Behavioral Neuroscience 2010, 382-386. Exposure of animals to the FST has been demonstrated to elicit neurochemical changes in the brain consistent with a depressive phenotype, such as transient reductions in serotonin and norepinephrine levels in cortical and limbic structures. Matthews, K.., Stewart, C., “Depression Models” Encyclopedia of Stress (Second Edition) 2007, 760-766.

[0550] Naive C57BL6 / J mice are used for this study, and a reference (e.g., psilocybin) may be administered. The animals undergo a 7-day acclimatization period to their new environment and are weighed prior to compound administration. To evaluate the efficacy of the tested compounds, the mice are subjected to drug therapy with the vehicle, the tested compounds, and a reference (e.g., psilocybin) at the171 410095-002WO (221369)BUSINESS.33570138.1minimum effective dose (e.g., 5mg / kg psilocybin). Subsequently, a forced swim test is conducted at certain time points following drug administration (e.g., at 0.5-2.0 hrs and at 24 hours).

[0551] Tire mouse is carefully placed in a glass cylindrical tank (approximately 30cm x 14cm) filled with water at a temperature of 26-28 °C, ensuring that the water level is high enough to prevent the mouse from touching the bottom with its paws or tail, thus preventing escape. The animal is observed and recorded for a duration of 6 minutes after placement in the tank. After recording, the mouse is delicately dried with a soft paper towel and placed back in its cage under a heat lamp for an additional 6 minutes to warm up. Using ANY-maze software, the active swim time, drift time, and attempts to climb the cylinder wall are analyzed based on the last 4 minutes of the recording. A decrease in active swimming time and lack of attempts to escape the cylinder are indicative of depressive-like symptoms.

[0552] Example 41: Chronic Social Defeat Methodology.

[0553] In the first part of the CSD study, CD-I male mice undergo aggression screening (mild) in order to score aggressive behaviour toward C57BL / 6J mice to ensure the defeat of the intruder during chronic social defeat (CSD) procedure. The C57BL / 6J male mice are subjected to 10 days of CSD procedure (moderate) followed by the 1st social preference test.

[0554] 1st social preference test (SP: mild) (day 11) is performed to assess CSD effect on social avoidance, which is the primary behavioural endpoint in the CSD model. The SP test consists of 2 x 2.5 mini sessions. During the habituation session, mice explore the apparatus containing an empty perforated cylinder (“no target”) placed in one side of the chamber. Prior to the test session, an unfamiliar CD-I mouse is placed in the perforated cylinder (“target present”). The “interaction zone” is defined as the area surrounding the perforated cylinder. Tire social preference score is calculated by dividing the time spent in the “interaction zone” when the target is present by the time spent in tire “interaction zone” when the target is absent. The test assesses the level of social aversion in the mice based on the interaction time of the test mice with the other individual additional parameters: time spent in the comer and total distance travelled is analysed. Based on the results from the first SP test, mice are divided into either exhibiting a stress-resilient (SP score above 100) or a stress- susceptible phenotype (SP score under 100).Subsequently susceptible mice are assigned to experimental groups ensuring that overall average SP scores of each group were at similar level. Following baseline SP recordings mice undergo drug administration with either a reference (e.g., psilocybin), vehicle or test compound (TC) on Day 14. At the next step, all groups are submitted to the 2nd SP test (mild) 24 hr post-administration on Day 15 to assess drug effect on social avoidance. Then, all groups are submitted to the 3rd SP test (mild) to assess the long-term drug effect on social avoidance on Day 21 or 28. Body weight and animal welfare are monitored daily.172 410095-002WO (221369)BUSINESS.33570138.1

Claims

1. CLAIMS1. A compound of formula I ' ' :or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X3is N or CR3;X7is N or CR7; each of R1, R2, R3, R4, or R7is independently selected from hydrogen, halogen, -CN, -OR’, -NR2, -C(O)R, -C(O)NRj, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1-6 aliphatic, a 3 - to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or each R5is independently hydrogen or an optionally substituted group selected from Cue aliphatic or 3-to 8- membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;Rbis hydrogen or optionally substituted C1-6 aliphatic;R8is:Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl, or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl;Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom or a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom;Ring C is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl;173 410095-002WO (221369)BUSINESS.33570138.1Ring D is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having a single nitrogen heteroatom; each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; or two R9groups on the same or different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiro, fused, or bridged carbocyclyl or spiro, fused, or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R9and an R13group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R10is independently selected from halogen. -CN, -OR, -NRe, or an optionally substituted Ci-e aliphatic;R11is hydrogen, halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; each R12is independently hydrogen or optionally substituted Ci-s aliphatic; each R13is independently hydrogen or optionally substituted Ci-e aliphatic; each R is independently hydrogen or optionally substituted Ci-e aliphatic;L1is a covalent bond or an optionally substituted bivalent C1-3 saturated or unsaturated, straight or branched, hydrocarbon chain; m is 0, 1, or 2; and77 is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound of claim 1, wherein L1is a bivalent C1.3 saturated straight hydrocarbon chain.

3. The compound of claim 1 or 2, wherein the compound is of formula I':or a pharmaceutically acceptable salt thereof, wherein:R8is:174 410095-002WO (221369)BUSINESS.33570138.

14. Tire compound of any one of claims 1-3, wherein X3is N.

5. The compound of any one of claims 1-3, wherein X3is CR3.(R9)n6. The compound of any one of claims 1-5, wherein R8is7. The compound of any one of claims 1-5, whereinThe compound of any one of claims 1-5, wherein9. The compound of any one of claims 1-5, whereinThe compound of any one of claims 1-5, wherein175 410095-002WO (221369)BUSINESS.33570138.

111. The compound of any one of claims 1-9, wherein the compound is of formulae Xll-a, XH-b, XII- c, Xll-d, or Xll-e:or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-9, wherein the compound is of formulae XHI-a, XHI-b, XIII-c, XIILd, XlV-a, XlV-b, XIV-c, XlV-d, XV-a, XV-b, XV-c, XV-d, XVI-a, XVI-b, XVI-c, XVLd XVII-a, XVII-b, XVII-c, XVII-d, or XVII-e176 410095-002WO (221369)BUSINESS.33570138.1XIV-C410095-002WO (221369)177BUSINESS.33570138 1178 410095-002WO (221369)BUSINESS.33570138.1XVII-e or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1-6 or 11-12, wherein Ring A is a saturated or partially unsaturated 4- to 6-membered monocyclic carbocyclyl.179 410095-002WO (221369)BUSINESS.33570138.

115. The compound of any one of claims 1-6 or 11-12, wherein Ring A is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic carbocyclyl.

16. The compound of claim 15, wherein Ring A is17. The compound of any one of claims 1-6 or 11-12, wherein Ring A is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic carbocyclyl180 410095-002WO (221369)BUSINESS.33570138.

118. The compound of claim 17. wherein RingThe compound of claim 17, wherein Ring181 410095-002WO (221369)BUSINESS.33570138.

120. The compound of claim 17, wherein Ring21. The compound of any one of claims 1-5. 7, or 11-12, wherein Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic heterocyclyl having a single nitrogen heteroatom.

23. The compound of any one of claims 1-5, 7, or 11-12, wherein Ring B is a saturated or partially unsaturated 4- to 9-membered fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom.410095-002WO (221369)BUSINESS.33570138.1The compound of claim 23, wherein Ring25. The compound of any one of claims 1-5, 8, or 11-12, wherein RingThe compound of any one of claims 1-5, 9, or 11-12, wherein Ring D is27. The compound of any one of claims 1-9 or 11-12, wherein183 410095-002WO (221369)BUSINESS.33570138.

128. The compound of any one of claims 1-3, wherein the compound is of formula I:184 410095-002WO (221369)BUSINESS.33570138.1I or a pharmaceutically acceptable salt thereof, wherein:R8is:

29. The compound of claim 26, wherein the compound is of formulae I-a. I-a-1, 1-a-2, 1-b, I-b-1, 1-b-2, 1-c, I-c-1, or I-c-2:185 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1I-c-1 I-c-2 or a pharmaceutically acceptable salt thereof.

30. Tire compound of claim 26 or T1 , wherein the compound is of formulae Il-a, II-a-1, II-a-2, Il-b,II-b-1, II-b-2, III-a. III-a-1, III-a-2, Ill-b, III-b-1, or III-b-2:187 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1-3, wherein the compound is of formulae I-d, I-d-1. 1-d-2. 1- e, I-e-1, 1-e-2, 1-e-3, or I-e-4:189 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 1-11 or 13-30, wherein X1is N.

33. The compound of any one of claims 1-11 or 13-30, wherein X1is CR1.

34. The compound of any one of claims 1-11 or 13-33, wherein X7is N.

35. The compound of any one of claims 1-11 or 13-33, wherein X7is CR7.

36. The compound of any one of claims 28-30, wherein the compound is of formulae IV-a, IV-a-1, IV- a-2, IV-b, IV-b-1, IV-b-2, IV-c, IV-c-1, or IV-c-2190 410095-002WO (221369)BUSINESS.33570138.1IV-b191 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 28-30, wherein the compound is of formulae V-a, V-a-1, V-a-2, V-b, V-b-1. V-b-2, V-c. V-c-1, or V-c-2:192 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

38. The compound of any one of claims 28-30, wherein the compound is of fonnulae Vl-a. VI-a-1,VI-a-2, Vl-b, VI-b-1. VI-b-2. VI-c. VI-c-1, or VI-c-2:194 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

39. The compound of any one of claims 28-30, wherein the compound is of formulae Vll-a, VII-a-1,VII-a-2, Vll-b, VII-b-1, VII-b-2, VII-c, VII-c-1, or VII-c-2:196 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

40. The compound of any one of claims 1-3, wherein the compound is of formulae IV-d, IV-d-1, IV- d-2, IV-e, IV-e-1, IV-e-2, IV-e-3, or IV-e-4:198 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

41. The compound of any one of claims 1-3, wherein the compound is of formulae V-d. V-d-1, V-d-2,V-e. V-e-1, V-e-2, V-e-3, or V-e-4:199 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 1-3, wherein the compound is of formulae Vl-d. VI-d-1. VI- d-2, Vl-e, VT-e-1, VI-e-2, VI-e-3, or VI-e-4:200 410095-002WO (221369)BUSINESS.33570138.1VI-e-3 VI-e-4 or a pharmaceutically acceptable salt thereof.

43. The compound of any one of claims 1-3, wherein the compound is of formulae Vll-d, VII-d-1,VII-d-2, VH-e, VII-e-1, VII-e-2, VII-e-3, or VII-e-4:or a pharmaceutically acceptable salt thereof.201 410095-002WO (221369)BUSINESS.33570138.

144. The compound of any one of claim 1-31, 33-37, or 40, wherein R1is hydrogen.

45. Tire compound of any one of claims 1-31, 33-37, or 40, wherein R1is fluoro, chloro, or bromo.

46. The compound of any one of claims 1-31, 33-37, or 40, wherein R1is -CN.

47. The compound of any one of claims 1-31, 33-37, or 40, wherein R1is -OR5.

48. Tire compound of claim 47, wherein R5is hydrogen or an optionally substituted Ci-e aliphatic.

49. The compound of any one of claims 1-31. 33-37, or 40, wherein R1is -NR2.

50. The compound of any one of claims 1-31, 33-37, or 40, wherein R1is -C(O)NR2, -C(O)OR, - NRC(O)R, or -OC(O)R.

51. The compound of any one of claims 1-31, 33-37, or 40, wherein R1is optionally substituted C1-6 aliphatic.

52. The compound of claim 51, wherein R1is C1.6 aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or C1-6 aliphatic.

53. The compound of any one of claims 1-31, 33-37, or 40, wherein R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered heteroaryl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

54. Tire compound of any one of claims 1-31, 33-37, or 40, wherein R1is hydrogen, fluoro, chloro, - OCH3. -OCH2CH3, -OCF3, or phenyl.

55. The compound of any one of claim 1-33, 35-36.

38.

40.

42. or 44-54, wherein R7is hydrogen.

56. The compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is fluoro, chloro, or bromo.202 410095-002WO (221369)BUSINESS.33570138.

157. The compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is -CN.

58. Tire compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is -OR5.

59. The compound of claim 58, wherein R5is hydrogen or an optionally substituted Ci-6 aliphatic.

60. The compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is -NR2.

61. Tire compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is -C(O)NRz, -C(O)OR, -NRC(O)R, or -OC(O)R.

62. The compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is optionally substituted C1.6 aliphatic.

63. Tire compound of claim 62, wherein R7is Ci-e aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or C1-6 aliphatic.

64. The compound of any one of claims 1-33. 35-36, 38, 40, 42, or 44-54, wherein R7is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

65. The compound of any one of claims 1-33, 35-36, 38, 40, 42, or 44-54, wherein R7is hydrogen, fluoro, chloro. -OCH3. -OCH2CH3, -OCF3, or phenyl.

66. The compound of any one of claim 1-65, wherein R2is hydrogen.

67. The compound of any one of claims 1-65, wherein R2is fluoro, chloro, or bromo.

68. The compound of any one of claims 1-65. w herein R2is -CN.

69. The compound of any one of claims 1-65, wherein R2is -OR5.

70. The compound of claim 69, wherein R5is hydrogen or an optionally substituted C1-6 aliphatic.203 410095-002WO (221369)BUSINESS.33570138.

171. The compound of any one of claims 1-65, wherein R2is -NR2.

72. Tire compound of any one of claims 1-65, wherein R2is -C(0)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

73. The compound of any one of claims 1-65, wherein R2is optionally substituted Cue aliphatic.

74. Tire compound of claim 73, wherein R2is Ci-e aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Cue aliphatic.

75. The compound of any one of claims 1-65, wherein R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

76. The compound of any one of claims 1-65, wherein R2is hydrogen, fluoro, chloro. -OCHs, - OCH2CH3, -OCF3, or phenyl.

77. The compound of any one of claims 1-3 or 5-76, wherein R3is hydrogen.

78. The compound of any one of claims 1-3 or 5-76, wherein R3is fluoro, chloro, or bromo.

79. The compound of any one of claims 1-3 or 5-76, wherein R3is -CN.

80. The compound of any one of claims 1-3 or 5-76, wherein R3is -OR3.

81. The compound of claim 80, wherein R5is hydrogen or an optionally substituted C1-6 aliphatic.

82. The compound of any one of claims 1-3 or 5-76, wherein R3is -NR2.

83. The compound of any one of claims 1-3 or 5-76, wherein R3is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.204 410095-002WO (221369)BUSINESS.33570138.

184. The compound of any one of claims 1-3 or 5-76, wherein R3is optionally substituted Cue aliphatic.

85. The compound of claim 84, wherein R3is Ci-e aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Ci-6 aliphatic.

86. The compound of any one of claims 1-3 or 5-76. wherein R3is an optionally substituted 3- to 8- membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered hctcroaryl having 1- 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

87. The compound of any one of claims 1-3 or 5-76, wherein R3is hydrogen, fluoro, chloro, -OCH3, - OCH2CH3, -OCF3, or phenyl.

88. The compound of any one of claim 1-87, wherein R4is hydrogen.

89. The compound of any one of claims 1-87, wherein R4is fluoro, chloro, or bromo.

90. The compound of any one of claims 1-87. wherein R4is -CN.

91. The compound of any one of claims 1-87, wherein R4is -OR5.

92. The compound of claim 91, wherein R5is hydrogen or an optionally substituted C1-6 aliphatic.

93. The compound of any one of claims 1-87. wherein R4is -NR2.

94. The compound of any one of claims 1-87, wherein R4is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

95. The compound of any one of claims 1-87. wherein R4is optionally substituted Ci-6 aliphatic.

96. The compound of claim 95, wherein R4is C1-6 aliphatic, optionally substituted with halogen or - OR°, wherein R° is hydrogen or Ci-e aliphatic.205 410095-002WO (221369)BUSINESS.33570138.

197. The compound of any one of claims 1-87, wherein R4is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or 5- to 6-membered hctcroar l having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

98. The compound of any one of claims 1-87, wherein R4is hydrogen, fluoro, chloro. -OCH3, - OCH2CH3, -OCF3, or phenyl.

99. Tire compound of any one of claims 1-98, wherein each R6is hydrogen.

100. The compound of any one of claims 1-98. wherein each R6is optionally substituted C1-6 aliphatic.

101. The compound of any one of claims 1-98, wherein each R is hydrogen or methyl.

102. Tire compound of any one of claims 1-101, wherein m is 0.

103. The compound of any one of claims 1-101, wherein n is 0.

104. The compound of any one of claims 28-101, wherein the compound is of formulae VIII-a, VIII- a-1, VIII-a-2, Vlll-b, VIII-b-1, or VIII-b-2:VIII-a206 410095-002WO (221369)BUSINESS.33570138.1VIII-b-1 VIII-b-2 or a pharmaceutically acceptable salt thereof.

105. The compound of any one of claims 28-101, wherein the compound is of formulae IX-a, IX-a-1,IX-a-2, IX-b, IX-b-1, or IX-b-2:207 410095-002WO (221369)BUSINESS.33570138.1BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

106. The compound of any one of claims 28-101, wherein the compound is of formulae X-a, X-a-1, X- a-2, X-b, X-b-1. or X-b-2:X-b209 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

107. The compound of any one of claims 28-101, wherein the compound is of formulae Xl-a, XI-a-1,XI-a-2, Xl-b, XI-b-1, or XLb-2:210 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

108. The compound of any one of claims 31-101, wherein the compound is of fonnulae VIII-d, VIII- d-1, VIII-d-2, Vlll-e, VIII-e-1, VIII-e-2, VIII-e-3, or VIII-e-4:VIII-d VIII-d- 1 VIII-d-2211 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

109. The compound of any one of claims 31-101, wherein the compound is of formulae IX-d. IX-d-1,IX-d-2, IX-e, IX-e-1, IX-e-2, IX-e-3, or IX-e-4IX-e IX-e-1 IX-e-2212 410095-002WO (221369)BUSINESS.33570138.1or a pharmaceutically acceptable salt thereof.

110. The compound of any one of claims 31-101 , wherein the compound is of formulae X-d, X-d-1 , X- d-2, X-e, X-e-1, X-e-2, X-e-3, orX-e-4.or a pharmaceutically acceptable salt thereof.213 410095-002WO (221369)BUSINESS.33570138.1111. The compound of any one of claims 31-101, wherein the compound is of formulae Xl-d, XI-d-1, XI-d-2, Xl-e, XI-e-1, XI-e-2, XI-e-3, or XI-e-4:XI-e-3 XI-e-4 or a pharmaceutically acceptable salt thereof.

112. The compound of any one of claims 1-111. wherein each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1.6 aliphatic.

113. Tire compound of any one of claims 1-111, wherein two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused or bridged carbocyclyl or fused or bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.214 410095-002WO (221369)BUSINESS.33570138.1114. The compound of any one of claims 1-111, wherein two R9groups on different atoms may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated fused carbocyclyl.

115. The compound of any one of claims 1-1 11, wherein R8and R9form116. The compound of any one of claims 1-115, wherein R11is optionally substituted Cue aliphatic.

117. The compound of claim 1, wherein the compound is of Table 1, or a pharmaceutically acceptable salt thereof.

118. A pharmaceutical composition comprising a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

119. A method of activating 5-HT2AR, or a mutant thereof, in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 118.

120. A method of selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 118.

121. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a p-arrestin signaling pathway associated with 5-HT2AR in a biological sample, comprising administering to the biological sample a compound of any one of claims 1-117, or a phanuaceutically acceptable salt thereof, or a pharmaceutical composition of claim 118.

122. A method of activating 5-HT2AR, or a mutant thereof, in a patient comprising administering a compound of any one of claims 1-117, or a phanuaceutically acceptable salt thereof, or a pharmaceutical composition of claim 118.215 410095-002WO (221369)BUSINESS.33570138.1123. A method of selectively activating 5-HT2AR, or a mutant thereof, (e.g., over the 5-HT2B and / or 5-HT2C receptors, or mutants thereof) in a patient comprising administering a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 118.

124. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a P-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 118.

125. A method for treating a 5-HT2AR-mediated disorder comprising administering to a patient a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 118.

126. A method for treating a neurological disease, disorder, or condition comprising administering to a patient a compound of any one of claims 1-117, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 118.

127. The method of claim 126, wherein neurological disease, disorder, or condition is depression, anxiety, substance abuse, and headaches.

128. The method of any one of claims 122-127, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.216 410095-002WO (221369)BUSINESS.33570138.1