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

Abstract

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

Description

TETRAHYDROPYRIDINYL-6,6-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 / 703.388, filed October 4, 2024: U.S. Provisional Application No. 63 / 749,996. filed January 27, 2025; U.S. Provisional Application No. 63 / 758,426, filed February 14, 2025; and U.S. Provisional Application No. 63 / 879,174, 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” :1410095-004WQ (221364)BUSINESS.33570224 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; tire 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”:I” or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

[0011] In another aspect, the present disclosure provides methods of treating and / or preventing a neurological disease, disorder, or condition in a patient in need thereof, comprising administering to 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 2410095-004WQ (221364)BUSINESS.33570224 1patient 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 45- 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 pharmacally 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- hydroxytryptannne 2A receptor (5-HT2AR) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmacally acceptable salt thereof, or a pharmaceutically acceptable composition thereof, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.2. Compounds and Definitions:

[0016] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of 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 term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (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, aliphatic3410095-004WO (221364)BUSINESS.33570224 1groups 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 Chydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In some embodiments, a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring. A carbocyclic ring may include one or more oxo (=0) or thioxo (=S) substituent. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0018] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:410095-004WO (221364)BUSINESS.33570224 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.” or5410095-004WO (221364)BUSINESS.33570224 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 mav be N (as in 3.4-dihydro-2 / / pvrrolyl). NH (as in pyrrolidinyl), or+NR (as in 6410095-004WO (221364)BUSINESS.33570224 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 term “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 arc not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery; purification, and use for one or7410095-004WO (221364)BUSINESS.33570224 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 -(CI h),,4OR°: -0(CH2)o 4R°, -O-(CH2)CMC(O)OR°; - (CH2)OMCH(OR°)2; -(CH;)„ 4SR0; -(CHfr, 4 Ph. which may be substituted with R°; -(CH2)N40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)OMO(CH2)01- pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)0MN(R°)2; -(CH2)0MN(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)0 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(0)(CH2)OMS 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(CH2)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. -(CH2)o 2R*. -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* -(CIM straight or branched alkylene)C(O)OR*, or - SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CIM aliphatic. -CH2PI1. -0(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, 8410095-004WO (221364)BUSINESS.33570224 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 2O-. 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 and9410095-004WO (221364)BUSINESS.33570224 1N (Ci 4alkyl) salts. In some embodiments, the provided compounds are purified in salt form for convenience and / or ease of purification, e.g., using an acidic or basic mobile phase during chromatography. Salts forms of the provided compounds formed during chromatographic 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 fonns 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] By way of example, structures depicted herein are meant to include all tautomeric forms, including mixtures thereof, such as:

[0043] 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:

[0044] In some embodiments, the present invention provides a compound of formula I”:I” or a pharmaceutically acceptable salt thereof, wherein:10410095-004WQ (221364)BUSINESS.33570224 1each independently is a single or double bond as allowed by valency:X1is N, NR, CR1, or C=O;X2is N, NR, or CR2;X3is N, NR, or CR3;X4is N, NR, CR4, or C=O;X5is N or CR5;X6is N or CR6;X7is N or CR7; wherein at least one of X1and X2is N or NR; each of R1, R2, R3, R4, R5, R6, and R7is independently selected from hydrogen, halogen, -CN, -ORA. -NR2, -C(O)R. -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered 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;RAis hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rsis hydrogen or optionally substituted Ci-6 aliphatic, each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1.6 aliphatic: or an R8and an R9group 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two 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:R10is:, wherein:11410095-004WO (221364)BUSINESS.33570224 1Ring 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 4- to 6-membered monocyclic heterocyclyl having one or two nitrogen heteroatoms, 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;X8is N, C, CH, or C-Ci-e aliphatic;L1is a covalent bond or an optionally substituted bivalent C1-3 saturated or unsaturated, straight or branched, hydrocarbon chain; n is 0. 1. 2, 3, 4. 5. 6, or 7; and each R is independently hydrogen or optionally substituted Cue aliphatic.

[0045] In some embodiments, the present invention provides a compound of formula I’:or a pharmaceutically acceptable salt thereof, wherein: each independently is a single or double bond as allowed by valency;X1is N, NR, CR1, or C=O;X2is N, NR, or CR2;X3is N, NR, or CR3;X4is N, NR, CR4, or C=O;Xsis N or CR5;X6is N or CR6;X7is N or CR7; wherein at least one of X1and X2is N or NR; each of R1, R2, R3, R4, R\ R6, and R7is independently selected from hydrogen, halogen, -CN, -ORA, -NR2, -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 having12410095-004WO (221364)BUSINESS.33570224 11-3 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;RAis hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R8is hydrogen or optionally substituted Ci-6 aliphatic. each R9is independently selected from halogen, -CN, -OR, -NR:, or an optionally substituted Cue aliphatic: or an R8and an R9group 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two 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: n is 0. 1. 2, 3, 4. 5. 6, or 7: and each R is independently hydrogen or optionally substituted Ci.6 aliphatic.

[0046] In some embodiments, the present invention provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4;X5is N or CR5;X6is N or CR6;410095-004WO (221364)BUSINESS.33570224 1X7is N or CR7; wherein at least one of X1and X2is N; each of R1, R2, R3, R4, R5, R6, and R7is independently selected from hydrogen, halogen, -CN, -ORA, -NR2, -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;RAis 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;R8is hydrogen or optionally substituted C1-6 aliphatic, each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Cue aliphatic; or an R8and an R9group 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two 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; n is 0, 1. 2, 3, 4, 5. 6, or 7; and each R is independently hydrogen or optionally substituted Ci-6 aliphatic.

[0047] As defined above and described herein, R10is:some embodiments. R10is. In some embodiments, Rluisembodiments, R10isIn some embodiments,.14410095-004WO (221364)BUSINESS.33570224 1

[0048] 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.

[0049] 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, Ringinsome embodiments, Ring. In some embodiments, Ringembodiments, Ringsome embodiments, Ring A is cyclopentyl. In some embodiments. Ringsome embodiments. Ring A is. gsome embodiments, Ring. In some embodiments, RingIn some embodiments. Ring A is. In some embodiments, RingIn some embodiments, Ring. insome embodiments, Ring A is cyclopentenyl. In some embodiments, Ring A is cyclohexyl. In some410095-004WO (221364)BUSINESS.33570224 1(R9)n embodiments, Ring A is cyclohexenyl. In some embodiments, Ring A isIn some embodiments, Ring A isIn some embodiments, Ring A isIn some embodiments, Ring A isIn some embodiments, Ring A isIn some embodiments, Ring A is. In some embodiments, Ring A is

[0050] 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 isIn 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.

[0051] It will be understood that,. wherein n occurrence of R9may be attached to the structure within brackets, i.e.,410095-004WO (221364)BUSINESS.33570224 1

[0052] 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.

[0053] 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.

[0054] In some embodiments, Ringsome embodiments, Ring^R9)n^R9)n

[0055] In some embodiments, Ring A is N(R )2 orN(R )2

[0056] In some embodiments, Ring A is a saturated or partially unsaturated 6- to 9-membered fused or bridged bicyclic carbocyclyl.

[0057] 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. In410095-004WO (221364)BUSINESS.33570224 1some embodiments, Ring lnsome embodiments, Ringembodiments. RingIn some embodiments. Ringembodiments, Ring, embodiments, Ringsome embodiments, Ring

[0058] 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. In some embodiments, Ringsome embodiments, Ring. In some embodiments, Ring. In some embodiments, Ring. In some embodiments. Ring

[0059] 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- mcmbcrcd bridged bicyclic carbocyclyl. In some embodiments, Ring A is a saturated or partially unsaturated 8-membered fused bicyclic carbocyclyl. In some embodiments, Ringsome embodiments, RingIn some19410095-004WO (221364)BUSINESS.33570224 1embodiments, Ring

[0060] 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.

[0061] 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.

[0062] As defined above and described herein, Ring B is a saturated or partially unsaturated 4- to 6- membered monocyclic heterocyclyl having one or two nitrogen heteroatoms, 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.

[0063] In some embodiments, Ring B is a saturated or partially unsaturated 4- to 6-membered monocyclic heterocyclyl having one or two nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having one nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having two nitrogen heteroatoms. In some embodiments, Ring B is piperazinyl. In some embodiments,Ring B is piperidinyl. In some embodiments, Ring B is selected from410095-004WO (221364)BUSINESS.33570224 1Ringsome embodiments, Ringsome embodiments, Ring B,

[0064] 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 isIn some embodiments, RingIn some embodiments, Ring B isIn some embodiments. Ring

[0065] 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.

[0066] In some embodiments. Ring B is a saturated or partially unsaturated 5-membered 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 nitrogen410095-004WO (221364)BUSINESS.33570224 1heteroatom. In some embodiments. Ring B is a saturated or partially unsaturated 5 -membered fused bicyclic heterocyclyl having a single nitrogen heteroatom.

[0067] In some embodiments, Ring B is a saturated or partially unsaturated 6-mcmbcrcd fused or bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered bridged bicyclic heterocyclyl having a single nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered fused bicyclic heterocyclyl having a single nitrogen heteroatom.

[0068] In some embodiments, Ring B is 3-azabicyclo[3.1.0]hexanyl. In some embodiments, Ring B is some embodiments, Ringsome embodiments, Ring B issome embodiments, Ring

[0069] 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 some embodiments, RingIn some embodiments, RingIn some embodiments, Ring

[0070] As defined above and described herein, X1is N, NR, CR1, or C=O. In some embodiments, X1is N or CR1. In some embodiments, X1is NR. In some embodiments, X1is NH. In some embodiments, X1410095-004WO (221364)BUSINESS.33570224 1is NR, wherein the R of X1is Ci-e aliphatic. In some embodiments, X1is N-CH3. In some embodiments, X1is N-CH2CH3. In some embodiments, X1is N-(CH2)2CH3. In some embodiments, X1is N-(CH)(CH3)2. In some embodiments, X1is N. In some embodiments, X1is CR1. In some embodiments, X1is C=O.

[0071] As defined above and described herein, X2is N, NR, or CR2. In some embodiments, X2is N or CR2. In some embodiments. X2is NR. In some embodiments. X2is NH. In some embodiments. X2is NR, wherein the R of X2is C1-6 aliphatic. In some embodiments, X2is N-CH3. In some embodiments, X2is N- CH2CH3. In some embodiments, X2is N-(CH2)2CH3. In some embodiments, X2is N-(CH)(CH3)2. In some embodiments, X2is N. In some embodiments, X2is CR2.

[0072] As defined above and described herein, X3is N, NR, or CR3. In some embodiments, X3is N or CR3. In some embodiments. X3is NR. In some embodiments. X3is NH. In some embodiments. X3is NR, wherein the R of X3is C1-6 aliphatic. In some embodiments. X3is N-CH3. In some embodiments. X3is N- CH2CH3. In some embodiments, X3is N-(CH2)2CH3. In some embodiments, X3is N-(CH)(CH3)2. In some embodiments, X3is N. In some embodiments, X3is CR3.

[0073] As defined above and described herein, X4is N, NR, CR4, or C=O. In some embodiments, X4is N or CR4. In some embodiments, X4is NR. In some embodiments, X4is NH. In some embodiments, X4is NR, wherein the R of X4is Ci-6 aliphatic. In some embodiments, X4is N-CH3. In some embodiments, X4is N-CH2CH3. In some embodiments, X is N-(CH2)2CH3. In some embodiments, X4is N-(CH)(CH3)2. In some embodiments, X4is N. In some embodiments, X4is CR4. In some embodiments, X4is C=O.

[0074] As defined above and described herein, X5is N or CR5. In some embodiments, X5is N. In some embodiments, X5is CR5.

[0075] As defined above and described herein, X'1is N or CR6. In some embodiments. X6is N. In some embodiments, X6is CR6.

[0076] As defined above and described herein, X7is N or CR7. In some embodiments, X7is N. In some embodiments, X7is CR7.

[0077] In some embodiments, X1is N and X2is CR2. In some embodiments, X2is N and X1is CR1. In some embodiments, X1is N and X2is N. In some embodiments, X1is N and X3is N. In some embodiments, X2is N and X3is N. In some embodiments, X1is N, X2is N, and X6is N. In some embodiments, X1is N, X2is N, and X5is N.

[0078] As defined above and described herein, each independently is a single or double bond. In some embodiments. = is a single bond. In some embodiments, = is a double bond.

[0079] In some embodiments, X1is C=O, X4is C=O and the bonds between X1and X2, X2and X3, and X3and X4are single bonds. In some embodiments, X4is C=O, X1is N, and the bonds between X1and X2, and X3and X4are single bonds and the bond between X2and X3is a double bond.23410095-004WO (221364)BUSINESS.33570224 1

[0080] As defined above and described herein, X8is N, C, CH, or C-Ci.e aliphatic. In some embodiments, X8is CH or C-Ci-e aliphatic. In some embodiments, X8is N or CH. In some embodiments, X8is N. In some embodiments, X8is C. In some embodiments, X8is CH. In some embodiments, X8is C- Ci-6 aliphatic.

[0081] As defined above and described herein, each of R1, R2, R3, R4, R5. R6. and R7is independently selected from hydrogen, halogen, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0082] In some embodiments, each of R1, R2, R3, R4, R5, R6, and R7is independently selected from hydrogen, halogen, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or optionally substituted Ci.g aliphatic.

[0083] In some embodiments, R1is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA. -NR2, -C(O)R. -C(O)NR2, -C(O)OR. -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered 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.

[0084] In some embodiments, R1is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2. -C(O)R, - C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered 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, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, -NRC(O)R, -OC(O)R, 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.

[0085] In some embodiments, R1is selected from hydrogen, bromo, chloro, fluoro. -CN, -ORA. -NR2, -C(O)R. -C(O)NR2. -C(O)OR, -NRC(O)R. -OC(O)R, or optionally substituted Ci-6 aliphatic. In some embodiments, R1is an optionally substituted group selected from 3- to 8-membered saturated or partially24410095-004WO (221364)BUSINESS.33570224 1unsaturated 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.

[0086] In some embodiments, R1is hydrogen. In some embodiments, R1is halogen. In some embodiments, R1is fluoro or chloro. In some embodiments. R1is fluoro. In some embodiments, R1is chloro. In some embodiments, R1is bromo. In some embodiments, R1is -CN.

[0087] In some embodiments, R1is -ORA. In some embodiments, R1is -OH. In some embodiments, R1is -OCH3. In some embodiments, R1is -OCH2CH3. In some embodiments, R1is -OCH2F. In some embodiments, R1is -OCHF2. In some embodiments. R1is -OCF3. In some embodiments, R1is.

[0088] In some embodiments, R1is -NR;. In some embodiments, R1is -NH2. In some embodiments, R1is -NR2, wherein each R is independently Ci-6 aliphatic.

[0089] 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.

[0090] 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 6 aliphatic.

[0091] In some embodiments, R1is -NRC(O)R. In some embodiments, R1is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R1is -NRC(O)H, wherein Ris C1-6 aliphatic. In some embodiments, R1is -NRC(O)R, wherein each R is independently C1-6 aliphatic.

[0092] In some embodiments, R1is -OC(O)R. In some embodiments, R1is -OC(O)H. In some embodiments, R1is -OC(O)R, wherein R is Ci-e aliphatic.

[0093] In some embodiments, R1is optionally substituted Ci-e aliphatic. In some embodiments, R1is Ci-6 aliphatic. In some embodiments, R1is methyl. In some embodiments. R1is ethyl. In some embodiments. R1is n-propyl. In some embodiments, R1is isopropyl. In some embodiments, R1is n-butyl. In some embodiments, R1is s-butyl. In some embodiments, R1is t-butyl.

[0094] 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 -CHF2. In some embodiments. R1is -CF3. In some embodiments, R1is -CH2CF3. In some embodiments, R1is Ci-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Cue aliphatic. In some embodiments, R1is -CH2OH.

[0095] In some embodiments, R1is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3410095-004WO (221364)BUSINESS.33570224 1heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0096] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or hctcrocyclyl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, 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.

[0097] 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.

[0098] 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.

[0099] In some embodiments, R1is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R1is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, and.In some embodiments, R1is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0100] In some embodiments, R2is selected from hydrogen, bromo, chloro, fluoro. -CN, -ORA. -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci.e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0101] In some embodiments, R2is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, - C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms 26410095-004WO (221364)BUSINESS.33570224 1independently 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, bromo, chloro, fluoro, -CN, -ORA, -NRz, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. R2is selected from bromo, chloro, fluoro, -CN. -ORA, -NR2. -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, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0102] In some embodiments, R2is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA. -NR2, -C(O)R. -C(O)NR2. -C(O)OR, -NRC(O)R. -OC(O)R, or optionally substituted C1-6 aliphatic. In some embodiments, R2is an optionally substituted group selected from 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.

[0103] In some embodiments. R2is hydrogen. In some embodiments, R2is halogen. In some embodiments. R2is fluoro or chloro. In some embodiments, R2is fluoro. In some embodiments, R2is chloro. In some embodiments, R2is bromo. In some embodiments, R2is -CN.

[0104] In some embodiments, R2is -ORA. In some embodiments, R2is -OH. In some embodiments, R2is -OCH3. In some embodiments, R2is -OCH2CH3. In some embodiments, R2is -OCH2F. In some embodiments, R2is -OCHF2. In some embodiments. R2is -OCF3. In some embodiments, R2is.

[0105] In some embodiments, R2is -NR2. In some embodiments, R2is -NH2. In some embodiments, R2is -NR2, wherein each R is independently Ci-e aliphatic.

[0106] In some embodiments, R2is -C(O)NR2. In some embodiments, R2is -C(O)NH2. In some embodiments. R2is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0107] In some embodiments, R2is -C(O)OR. In some embodiments, R2is -C(O)OH. In some embodiments, R2is -C(O)OR, wherein R is C1-6 aliphatic.

[0108] In some embodiments, R2is -NRC(O)R. In some embodiments, R2is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R2is -NRC(O)H, wherein R is C1-6 aliphatic. In some embodiments, R2is -NRC(O)R, wherein each R is independently Ci-6 aliphatic.

[0109] In some embodiments, R2is -OC(O)R. In some embodiments, R2is -OC(O)H. In some embodiments, R2is -OC(O)R, wherein R is Ci-e aliphatic.27410095-004WO (221364)BUSINESS.33570224 1

[0110] In some embodiments, R2is optionally substituted Cue aliphatic. In some embodiments, R2is Cue 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.

[0111] In some embodiments. R2is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Cue aliphatic. In some embodiments, R2is Ci.e aliphatic, optionally substituted with halogen. In some embodiments, R2is -CHF2. In some embodiments, R2is -CF3. In some embodiments, R2is -CH2CF3. In some embodiments, R2is Cue aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R2is -CH2OH.

[0112] In some embodiments, R2is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0113] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R2is an optionally substituted cyclopropyl. In some embodiments, R2is an optionally substituted cyclobutyl. In some embodiments, R2is an optionally substituted cyclopentyl. In some embodiments, R2is an optionally substituted cyclohexyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is cyclobutyl. In some embodiments, R2is cyclopentyl. In some embodiments, R2is cyclohexyl.

[0114] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 hctcroatoms 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.

[0115] 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.

[0116] In some embodiments, R2is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3,-OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R2is selected from hydrogen,28410095-004WO (221364)BUSINESS.33570224 1fluoro, chloro, -CN, -OH, -OCHg, -OCH2CH3, methyl, ethyl, and. In some embodiments, R2is selected from hy drogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0117] In some embodiments, R3is selected from hydrogen, bromo, chloro, fluoro. -CN. -ORA. -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci.e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0118] In some embodiments, R3is selected from bromo, chloro, fluoro, -CN, -ORA. -NR2, -C(O)R, - C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, 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, R3is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA. -NR2, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, 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, R3is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, - C(O)OR, -NRC(O)R, -OC(O)R, 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.

[0119] In some embodiments, R3is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or optionally substituted Cue aliphatic. In some embodiments, R3is an optionally substituted group selected from 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.

[0120] In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is fluoro or chloro. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is -CN.

[0121] In some embodiments, R3is -ORA. In some embodiments, R3is -OH. In some embodiments, R3is -OCH3. In some embodiments. R3is -OCH2CH3. In some embodiments. R3is -OCH2F. In some29410095-004WO (221364)BUSINESS.33570224 1embodiments, R3is -OCHF2. In some embodiments, R3is -OCF3. In some embodiments, R3is '' .

[0122] In some embodiments, R3is -NR2. In some embodiments, R3is -NH2. In some embodiments, R3is -NR2, wherein each R is independently C1-6 aliphatic.[00123J In some embodiments, R3is -C(O)NR2. In some embodiments, R3is -C(O)NH2. In some embodiments, R3is -C(O)NR2, wherein each R is independently Ci-e aliphatic.

[0124] In some embodiments, R3is -C(O)OR. In some embodiments, R3is -C(O)OH. In some embodiments, R3is -C(O)OR, wherein R is C1-6 aliphatic.

[0125] In some embodiments, R3is -NRC(O)R. In some embodiments, R3is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R3is -NRC(O)H, wherein R is C1-6 aliphatic. In some embodiments, R3is -NRC(O)R, wherein each R is independently Ci-e aliphatic.

[0126] In some embodiments, R3is -OC(O)R. In some embodiments, R3is -OC(O)H. In some embodiments, R3is -OC(O)R, wherein R is C1-6 aliphatic.

[0127] In some embodiments, R3is optionally substituted C1-6 aliphatic. In some embodiments, R3is Ci-6 aliphatic. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is n-propyl. In some embodiments, R3is isopropyl. In some embodiments, R3is n -butyl. In some embodiments, R3is s-butyl. In some embodiments, R3is t-butyl.

[0128] In some embodiments, R3is C1-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R3is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R3is -CHF2. In some embodiments, R3is -CF3. In some embodiments, R3is -CH2CF3. In some embodiments, R3is Ci-e aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R3is -CH2OH.

[0129] In some embodiments, R3is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0130] In some embodiments, R3is an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, 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.30410095-004WO (221364)BUSINESS.33570224 1In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0131] In some embodiments, R3is 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, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0132] 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.

[0133] In some embodiments, R3is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3,-OCH2CH3, -OCR, methyl, ethyl, CF3, and. In some embodiments, R3is selected from hydrogen, fluoro, chloro. -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, and. In some embodiments, R3is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0134] In some embodiments, R4is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, 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.

[0135] In some embodiments, R4is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -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. In some embodiments, R4is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, 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, R4is selected from bromo, chloro, fluoro, -CN. -ORA, -NR2, -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, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or31410095-004WO (221364)BUSINESS.33570224 1sulfur.

[0136] In some embodiments, R4is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or optionally substituted Ci-e aliphatic. In some embodiments, R4is an optionally substituted group selected from 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.

[0137] In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments, R4is fluoro or chloro. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is bromo. In some embodiments. R4is -CN.

[0138] In some embodiments, R4is -ORA. In some embodiments, R4is -OH. In some embodiments, R4is -OCH3. In some embodiments, R4is -OCH2CH3. In some embodiments, R4is -OCH2F. In some embodiments, R4is -OCHF2. In some embodiments, R4is -OCF3. In some embodiments, R4is.

[0139] In some embodiments, R4is -NR2. In some embodiments, R4is -NH2. In some embodiments, R4is -NR2, wherein each R is independently C1.6 aliphatic.

[0140] 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 C1-6 aliphatic.

[0141] In some embodiments, R4is -C(O)OR. In some embodiments, R is -C(O)OH. In some embodiments, R4is -C(O)OR, wherein R is Ci-6 aliphatic.

[0142] In some embodiments, R4is -NRC(O)R. In some embodiments, R4is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R4is -NRC(O)H, wherein R is Ci-e aliphatic. In some embodiments, R4is -NRC(O)R, wherein each R is independently C1-6 aliphatic.

[0143] In some embodiments, R4is -OC(O)R. In some embodiments, R4is -OC(O)H. In some embodiments, R is -OC(O)R, wherein R is C1.6 aliphatic.

[0144] In some embodiments, R4is optionally substituted Ci-e aliphatic. In some embodiments, R4is C1-6 aliphatic. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is n-propyl. In some embodiments, R4is isopropyl. In some embodiments, R4is n-butyl. In some embodiments, R4is s-butyl. In some embodiments. R4is t-butyl.

[0145] In some embodiments, R4is C1.6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R4is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R4is -CHF2. In some embodiments, R4is -CF3. In some embodiments, R4is -CH2CF3. In some embodiments, R4is Ci-e aliphatic, optionally substituted with -OR°, 32410095-004WO (221364)BUSINESS.33570224 1wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R4is -CH2OH.

[0146] In some embodiments, R4is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or hctcrocyclyl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] In some embodiments, R4is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R4is selected from hydrogen, fluoro, chloro. -CN. -OH. -OCH3. -OCH2CH3, methyl, ethyl, and. In some embodiments, R is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0151] In some embodiments, R5is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA. -NR2, -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 33410095-004WO (221364)BUSINESS.33570224 1heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0152] In some embodiments, R5is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, - C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R5is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, 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, R5is selected from bromo, chloro, fluoro, -CN. -ORA, -NR2, -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, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0153] In some embodiments, R5is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or optionally substituted C1-6 aliphatic. In some embodiments, R5is an optionally substituted group selected from 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 hcteroar l having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0154] In some embodiments, Rsis hydrogen. In some embodiments, R5is halogen. In some embodiments, R5is fluoro or chloro. In some embodiments, R5is fluoro. In some embodiments, R5is chloro. In some embodiments, R3is bromo. In some embodiments. R5is -CN.

[0155] In some embodiments, R5is -ORA. In some embodiments, R3is -OH. In some embodiments, R5is -OCH3. In some embodiments, R5is -OCH2CH3. In some embodiments, R5is -OCH2F. In some embodiments, R5is -OCHF2. In some embodiments, R5is -OCF3. In some embodiments, R5is.

[0156] In some embodiments, R5is -NR2. In some embodiments, R5is -NH2. In some embodiments, R5is -NR2, wherein each R is independently C1-6 aliphatic.

[0157] In some embodiments, R3is -C(O)NR2. In some embodiments, R5is -C(O)NH2. In some embodiments, R5is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0158] In some embodiments. R5is -C(O)OR. In some embodiments, R3is -C(O)OH. In some embodiments, R3is -C(O)OR, wherein R is C1.6 aliphatic.

[0159] In some embodiments, R5is -NRC(O)R. In some embodiments, R5is -NHC(O)R, wherein R34410095-004WO (221364)BUSINESS.33570224 1is Ci-6 aliphatic. In some embodiments, R5is -NRC(O)H, wherein R is Ci-6 aliphatic. In some embodiments, R5is -NRC(O)R, wherein each R is independently Ci-e aliphatic.

[0160] In some embodiments, R5is -OC(O)R. In some embodiments, R5is -OC(O)H. In some embodiments, R5is -OC(O)R, wherein R is Ci-6 aliphatic.

[0161] In some embodiments, R is optionally substituted Ci-6 aliphatic. In some embodiments, R is Ci-6 aliphatic. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R’ is n-propyl. In some embodiments, R5is isopropyl. In some embodiments, R5is n -butyl. In some embodiments, R5is s-butyl. In some embodiments, R5is t-butyl.

[0162] In some embodiments, R5is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R5is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R5is -CHF2. In some embodiments, R5is -CF3. In some embodiments, R’ is -CH2CF3. In some embodiments, R5is Ci-e aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R5is -CH2OH.

[0163] In some embodiments, R5is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0164] 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-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R5is an optionally substituted cyclopropyl. In some embodiments, R5is an optionally substituted cyclobutyl . In some embodiments, R5is an optionally substituted cyclopcntyl. In some embodiments, R is an optionally substituted cyclohcxyl. In some embodiments, R5is cyclopropyl. In some embodiments, R5is cyclobutyl. In some embodiments, R5is cyclopentyl. In some embodiments, R’ is cyclohexyl.

[0165] In some embodiments, R5is 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, R5is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0166] In some embodiments, R5is an optionally substituted phenyl. In some embodiments. R5is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.35410095-004WO (221364)BUSINESS.33570224 1

[0167] In some embodiments, R5is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCHs,-OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R5is selected from hydrogen, fluoro, chloro. -CN. -OH. -OCH3. -OCH2CH3, methyl, ethyl, and. In some embodiments, R5is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0168] In some embodiments, R6is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA. -NR2, -C(O)R. -C(O)NR2, -C(O)OK -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.

[0169] In some embodiments, R6is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -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. In some embodiments, R6is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -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, phenyl, or a 5- to 6- membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments. R6is selected from bromo, chloro, fluoro, -CN. -ORA, -NR2. -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, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0170] In some embodiments, R6is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA. -NR2, -C(O)R. -C(O)NR2. -C(O)OR, -NRC(O)R. -OC(O)R, or optionally substituted Cue aliphatic. In some embodiments, R' is an optionally substituted group selected from 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.

[0171] In some embodiments. R6is hydrogen. In some embodiments, Rbis halogen. In some embodiments, R' is fluoro or chloro. In some embodiments, R" is fluoro. In some embodiments, R6is36410095-004WO (221364)BUSINESS.33570224 1chloro. In some embodiments, R6is bromo. In some embodiments, R' is -CN.

[0172] In some embodiments, R6is -ORA. In some embodiments, R6is -OH. In some embodiments, R6is -OCH3. In some embodiments, R6is -OCH2CH3. In some embodiments, R6is -OCH2F. In some embodiments, R6is -OCHF2. In some embodiments. R6is -OCF3. In some embodiments, Rbis.

[0173] In some embodiments, R6is -NR2. In some embodiments, R6is -NH2. In some embodiments, R6is -NR2, wherein each R is independently Ci-e aliphatic.

[0174] In some embodiments, R6is -C(O)NR2. In some embodiments, R6is -C(O)NH2. In some embodiments, R6is -C(O)NR2, wherein each R is independently C1-6 aliphatic.

[0175] In some embodiments, R' is -C(O)OR. In some embodiments, R6is -C(O)OH. In some embodiments, R' is -C(O)OR, wherein R is Ci e aliphatic.

[0176] In some embodiments, R6is -NRC(O)R. In some embodiments, R6is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R6is -NRC(O)H, wherein R is C1-6 aliphatic. In some embodiments, R6is -NRC(O)R, wherein each R is independently C1-6 aliphatic.

[0177] In some embodiments, R6is -OC(O)R. Tn some embodiments, R6is -OC(O)H. In some embodiments, R6is -OC(O)R, wherein R is Ci-e aliphatic.

[0178] 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, Rbis isopropyl. In some embodiments, Rbis n-butyl. In some embodiments, R6is s-butyl. In some embodiments, Rbis t-butyL

[0179] In some embodiments, R6is Ci-e aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R6is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R6is -CHF2. In some embodiments. R6is -CF3. In some embodiments. Rfiis -CH2CF3. In some embodiments, R' is Ci-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R6is -CH2OH.

[0180] In some embodiments, R6is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0181] In some embodiments, R6is 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, R6is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R6is an optionally substituted 3- to 6-membered 37410095-004WO (221364)BUSINESS.33570224 1saturated or partially unsaturated carbocyclyL In some embodiments, R is an optionally substituted cyclopropyl. In some embodiments, R6is an optionally substituted cyclobutyl . In some embodiments, Rbis an optionally substituted cyclopentyl. In some embodiments, Rbis an optionally substituted cyclohexyl. In some embodiments, R6is cyclopropyl. In some embodiments, R6is cyclobutyl. In some embodiments, R6is cyclopentyl. In some embodiments, R6is cyclohexyl.

[0182] In some embodiments, R6is 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, R6is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0183] In some embodiments, R6is an optionally substituted phenyl. In some embodiments. R6is an optionally substituted 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0184] In some embodiments, R6is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3,-OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R6is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, and. In some embodiments, R6is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0185] In some embodiments, R7is selected from hydrogen, bromo, chloro, fluoro. -CN, -ORA. -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci.e aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0186] In some embodiments, R7is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2. -C(O)R, - C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, 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 hctcroar l having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, 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. In38410095-004WO (221364)BUSINESS.33570224 1some embodiments, R7is selected from bromo, chloro, fluoro, -CN, -ORA, -NR2, -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, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0187] In some embodiments, R7is selected from hydrogen, bromo, chloro, fluoro. -CN, -ORA. -NR2, -C(O)R, -C(O)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or optionally substituted Ci-e aliphatic. In some embodiments, R7is an optionally substituted group selected from 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.

[0188] In some embodiments. R7is hydrogen. In some embodiments, R7is halogen. In some embodiments, R7is fluoro or chloro. In some embodiments, R7is fluoro. In some embodiments, R7is chloro. In some embodiments, R7is bromo. In some embodiments, R7is -CN.

[0189] In some embodiments, R7is -ORA. In some embodiments, R7is -OH. In some embodiments, R7is -OCH3. In some embodiments, R7is -OCH2CH3. In some embodiments, R7is -OCH2F. In some embodiments, R7is -OCHF2. In some embodiments, R7is -OCF3. In some embodiments, R7is

[0190] In some embodiments, R7is -NR2. In some embodiments, R7is -NH2. In some embodiments, R7is -NR2, wherein each R is independently C1-6 aliphatic.

[0191] 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.

[0192] In some embodiments, R7is -C(O)OR. In some embodiments, R7is -C(O)OH. In some embodiments, R7is -C(O)OR, wherein R is C1-6 aliphatic.

[0193] In some embodiments, R7is -NRC(O)R. In some embodiments, R7is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R7is -NRC(O)H, wherein R is C1-6 aliphatic. In some embodiments, R7is -NRC(O)R, wherein each R is independently Cue aliphatic.

[0194] In some embodiments, R7is -OC(O)R. In some embodiments, R7is -OC(O)H. In some embodiments, R7is -OC(O)R, wherein R is C1-6 aliphatic.

[0195] In some embodiments, R7is optionally substituted C1-6 aliphatic. In some embodiments, R7is Cue 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.

[0196] In some embodiments, R7is Ci-6 aliphatic, optionally substituted with halogen or -OR°,39410095-004WO (221364)BUSINESS.33570224 1wherein R° is hydrogen or Ci-s aliphatic. In some embodiments, R7is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R7is -CHF2. In some embodiments, R7is -CF3. In some embodiments, R7is -CH2CF3. In some embodiments, R7is Ci-e aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R7is -CH2OH.

[0197] In some embodiments, R7is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0198] 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. In some embodiments, R7is cyclopropyl. In some embodiments, R7is cyclobutyl. In some embodiments, R7is cyclopentyl. In some embodiments. R7is cyclohexyl.

[0199] In some embodiments, R7is 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, R7is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0200] 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.

[0201] In some embodiments, R7is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl. CF3, and. In some embodiments, R7is selected from hydrogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, and. In some embodiments, R7is selected from hy drogen, fluoro, chloro, -CN, -OH, -OCH3, -OCH2CH3, methyl, ethyl, CF3, and.

[0202] As defined above and described herein, RAis hydrogen or an optionally substituted group40410095-004WO (221364)BUSINESS.33570224 1selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0203] In some embodiments, RAis hydrogen or an optionally substituted Ci-e aliphatic. In some embodiments, RAis hydrogen. In some embodiments, RAis optionally substituted Ci-6 aliphatic. In some embodiments, RAis CH2F. In some embodiments. RAis CHF2. In some embodiments, RAis CF3. In some embodiments, RAis C1-6 aliphatic. In some embodiments, RAis methyl. In some embodiments, RAis ethyl. In some embodiments, RAis n-propyl. In some embodiments, RAis isopropyl. In some embodiments, RAis n-butyl. In some embodiments, RAis s-butyl. In some embodiments, RAis t-butyl.

[0204] In some embodiments, RAis 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, RAis an optionally substituted 3-to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, RAis an optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, RAis an optionally substituted cyclopropyl. In some embodiments, RAis an optionally substituted cyclobutyl. In some embodiments, RAis an optionally substituted cyclopentyl. In some embodiments, RAis an optionally substituted cyclohexyl. In some embodiments, RAis cyclopropyl. In some embodiments, RAis cyclobutyl. In some embodiments, RAis cyclopentyl. In some embodiments. RAis cyclohexyl.

[0205] In some embodiments, RAis 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, RAis an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0206] As defined above and described herein, each R8is hydrogen or optionally substituted Ci.e aliphatic; each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci. e aliphatic; or an R8and an R9group 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two 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.

[0207] In some embodiments. R8is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R8is hydrogen. In some embodiments, R8is optionally substituted Ci.e aliphatic. In some41410095-004WO (221364)BUSINESS.33570224 1embodiments, Rsis Ci-6 aliphatic. In some embodiments, R8is methyl. In some embodiments, R8is ethyl. In some embodiments, R8is n-propyl. In some embodiments, R8is isopropyl. In some embodiments, R8is n-butyl. In some embodiments, R8is s-butyl. In some embodiments, R8is t-butyl.

[0208] In some embodiments, R8is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R8is -CH2F. In some embodiments. R8is -CHF2. In some embodiments, R8is -CF3.

[0209] In some embodiments, each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6 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 C1-6 aliphatic. In some embodiments, R9is -NR2. In some embodiments, R9is -NH2. In some embodiments, R9is -NR2. wherein each R is independently C1-6 aliphatic. In some embodiments, R9is an optionally substituted Cue aliphatic. In some embodiments, R9is C1.6 aliphatic. In some embodiments, 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 C1-6 aliphatic, optionally substituted with fluoro. In some embodiments, R9is -CF3.

[0210] In some embodiments, an R8and an R9group 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 R8and an R9group 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 R8and an R9group 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. In some embodiments, an R8and an R9group may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged carbocyclyl. In some embodiments, an R8and an R9group may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated bridged heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, an R8and an R9group may be taken together to fonn an optionally substituted 3- to 8-mcmbcrcd saturated or partially unsaturated fused carbocyclyl. In some embodiments, an R8and an R9group 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.42410095-004WO (221364)BUSINESS.33570224 1

[0211] In some embodiments, two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spirohctcrocyclyl having 1-3 hctcroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl. In some embodiments, two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0212] 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 fomr 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. 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 form an optionally substituted 3- to 8-membered saturated or partially unsaturated bridged heterocyclyl having 1-3 hctcroatoms 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 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.

[0213] 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 or unsaturated, straight or branched, hydrocarbon chain.

[0214] As defined above and described herein, n is 0, 1, 2, 3, 4, 5, 6, or 7. 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 some43410095-004WO (221364)BUSINESS.33570224 1embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0215] As defined above and described herein, each R is independently hydrogen or optionally substituted Cue aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted Ci-6 aliphatic. In some embodiments, R is Cue aliphatic. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is n-propyl. In some embodiments, R is isopropyl. In some embodiments, R is n-butyl. In some embodiments, R is s-butyl. In some embodiments, R is t-butyl.

[0216] In some embodiments, the present invention provides a compound of formula I”-A:or a pharmaceutically acceptable salt thereof, wherein each of Ring A, X1, X2, X3, X4, X5, X6, X7, R8, R9, L1, and n is 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 formula I”-A, embodiments of variables Ring A, X1, X2, X3, X4, X5, X6, X7, R8, R9, L1, and n as defined above and described in classes and subclasses herein, also apply to compounds of formula I”-A, both singly and in combination.

[0218] In some embodiments, the present invention provides a compound of formula I”-B1 or I”-B2:or a pharmaceutically acceptable salt thereof, wherein each of Ring B, X1, X2, X3, X4, X\ Xb, X7, X8, R8, R9, 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 I”-B1 or I”-B2, embodiments of variables Ring B, X1, X2, X3, X4, X’, Xb, X7, X8, R8, R9, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae I”-B1 or I”-B2, both singly and in combination.44410095-004WO (221364)BUSINESS.33570224 1

[0220] In some embodiments, the present disclosure provides a compound of formulae Il-a, Il-b, orII-c:II-c or a pharmaceutically acceptable salt thereof, wherein each of X3, X , X5, X6, X7, R1, R2, R8, R9and 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 Il-a, Il-b, and II-c, embodiments of variables X1, X2, X3, X4, X5, X6, X7, R8, R9and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae Il-a, Il-b, and II-c. both singly and in combination.[00222J In some embodiments, the present disclosure provides a compound of formulae Il-al or Il-bl :Il-al Il-bl or a pharmaceutically acceptable salt thereof, wherein each of X2, X3, X5, X6, X7, R, R8, R9and 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 Il-al and Il-bl, embodiments of variables X2, X3, X5, X6, X7, R R8, R9and n as defined above 45410095-004WO (221364)BUSINESS.33570224 1and described in classes and subclasses herein, also apply to compounds of formulae Il-al and Il-bl, both singly and in combination.

[0224] In some embodiments, the present disclosure provides a compound of formulae Ill-a, Ill-b, orIII-c:or a pharmaceutically acceptable salt thereof, wherein each of X3, X4, X\ Xb, X7, R1, R2, and R8is 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 Ill-a, Ill-b, or III-c, embodiments of variables X1. X2. X3. X4. X5. X6. X7. and R8as defined above and described in classes and subclasses herein, also apply to compounds of formulae Ill-a, Ill-b, orIII-c, both singly and in combination.

[0226] In some embodiments, the present disclosure provides a compound of formulae IV-a, IV-b, orIV-c:410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of X3, X5, X6, X7, R1, R2, R8, R9, RA, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0227] It will be understood that, unless otherw ise specified or prohibited by the foregoing definition of formulae IV-a. IV-b. or IV-c, embodiments of variables X1, X2, X3, X3, Xb, X7, R8, R9, RA, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a, IV-b, or IV-c, both singly and in combination.

[0228] In some embodiments, the present disclosure provides a compound of formulae IV-d, IV-e, IV- f, or IV-g:IV-f IV-g or a pharmaceutically acceptable salt thereof, wherein each ofX Xb, X7, R, R2, R3, R8, R9. 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 formulae IV-d, IV-e, IV-f, or IV-g, embodiments of variables X5, X6, X7, R, R2, R3, R8, R9, and n as410095-004WO (221364)BUSINESS.33570224 1defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-d, IV-e, IV-f, or IV- g, both singly and in combination.

[0230] In some embodiments, the present disclosure provides a compound of formulae V-a, V-b, V-c,V-d, V-e, V-f, or V-g:V-g48410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, Rb, R7, R8, R9, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0231] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae V-a, V-b, V-c, V-d, V-e, V-f, or V-g, embodiments of variables R1, R2, R3, R4, R’, R6, R7, R8, R9, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae V-a, V-b, V-c, V-d, V-e, V-f, or V-g, both singly and in combination.410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, and R8is defined and described in classes and subclasses herein, both singly and in combination.

[0233] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vl-a, Vl-b, VI-c, Vl-d, Vl-e, Vl-f. or Vl-g, embodiments of variables R1, R2, R3, R4, R5, R6, R7, and R8as defined above and described in classes and subclasses herein, also apply to compounds of formulae Vl-a, Vl-b, VI-c, Vl-d, Vl-e, Vl-f, or Vl-g, both singly and in combination.

[0234] In some embodiments, the present disclosure provides a compound of formulae VH-a, Vll-b, VII-c, Vll-d, VH-e, VH-f, or Vll-g:50410095-004WO (221364)BUSINESS.33570224 1Vll-g or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, R6, R7. R8. R9. RAand n is defined and described in classes and subclasses herein, both singly and in combination.

[0235] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VH-a, VH-b, VII-c, VH-d, VH-e, VH-f, or VH-g, embodiments of variables R1, R2, R3, R5, R6, R7, R8, R9, RAand n as defined above and described in classes and subclasses herein, also apply to 51410095-004WO (221364)BUSINESS.33570224 1compounds of formulae Vll-a, VH-b, VII-c, VH-d, Vll-e, VH-f, or Vll-g, both singly and in combination.

[0236] In some embodiments, the present disclosure provides a compound of formulae Vll-al, VII- bl, VII-cl, VH-dl, Vll-el, VH-fl, or VH-gl:VH-gl or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, R6, R7, R8, and RAis defined and described in classes and subclasses herein, both singly and in combination.

[0237] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VTI-al, VH-bl, VII-cl, Vll-dl, Vll-el, VH-fl, or VH-gl, embodiments of variables R1, R2, R3, R5, R6, R7. R8. and RAas defined above and described in classes and subclasses herein, also apply to52410095-004WO (221364)BUSINESS.33570224 1compounds of formulae Vll-al, VH-bl, VII-cl, VH-dl, VH-el, Vll-fl, or VH-gl, both singly and in combination.

[0238] In some embodiments, the present disclosure provides a compound of formulae VII-a2, VII- b2, VII-c2, VII-d2, VII-e2, VII-f2, or VII-g2:410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R\ R . R7, R9, RAand n is defined and described in classes and subclasses herein, both singly and in combination.

[0239] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VII-a2, VII-b2, VII-c2, VII-d2, VII-e2, VII-f2, or VII-g2, embodiments of variables R1, R2, R3, R5, R6. R7. R9, RAand n as defined above and described in classes and subclasses herein, also apply to compounds of formulae VII-a2, VII-b2, VII-c2, VII-d2, VII-e2, VII-f2, or VII-g2, both singly and in combination.

[0240] In some embodiments, the present disclosure provides a compound of formulae VH-h, VH-i,VH-j, VII- k, VII-1, or Vll-m:or a pharmaceutically acceptable salt thereof, wherein each of R, R2, R3, R5, Rfa, R7, R8, R9. and n is defined and described in classes and subclasses herein, both singly and in combination.54410095-004WO (221364)BUSINESS.33570224 1

[0241] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VH-h, VH-i, Vll-j, VH-k, VII-1, or Vll-m, embodiments of R, R2, R3, R’, R6, R7, R8, R9, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae VH-h. VH-i, Vll-j, VH-k, VII-1, or Vll-m, both singly and in combination.

[0242] In some embodiments, the present disclosure provides a compound of formulae VH-hl, VII- il, VH-jl, VH-kl, VII-11, or Vll-ml:or a pharmaceutically acceptable salt thereof, wherein each of R, R2, R3, R5, R6, R7. and R8is defined and described in classes and subclasses herein, both singly and in combination.

[0243] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vll-hl, VH-il, VH-jl, VH-kl, VII-11, or Vll-ml, embodiments of R, R2, R3, R5, R6, R7, and R8as defined above and described in classes and subclasses herein, also apply to compounds of formulae Vll-hl, Vll-il, Vll-jl, Vll-kl, VII-11, or Vll-ml, both singly and in combination.

[0244] In some embodiments, the present disclosure provides a compound of formulae VII-h2, VII- i2, VII-j2, VII-k2, VII-12, or VII-m2:55410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of R. R2. R3, R5, R6, R7, R9. and n is defined and described in classes and subclasses herein, both singly and in combination.

[0245] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of fonnulae VII-h2, VII-i2, VII-j2, VII-k2, VII-12, or VII-m2, embodiments of R, R2, R3, R5, R6, R7, R9, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae VII-h2, VII-i2, VII-j2, VII-k2. VII-12, or VII-m2, both singly and in combination.

[0246] In some embodiments, the present disclosure provides a compound of formulae VII-h3, VII- i3, VII-j3, VII-k3, VII-13, or VII-m3:410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of R, R2, R3, R5, Rb, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0247] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae VII-h3, VII-i3, VII-j3, VII-k3, VII-13, or VII-m3, embodiments of R, R2, R3, R5, R6, and R7as defined above and described in classes and subclasses herein, also apply to compounds of formulae VII- h3, VII-i3, VH-j3, VH-k3, VII-13, or VII-m3, both singly and in combination.

[0248] In some embodiments, the present disclosure provides a compound of fonnulae Vlll-a, VIII- b. VIII-c, Vlll-d. Vlll-e. Vlll-f, or VUI-g:57410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R\ R6, R7, R9, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0249] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Vlll-a, VHI-b. VIII-c, VUI-d, VUI-e, Vlll-f, or Vlll-g, embodiments of variables R1, R2, R3, R4, R5. R6. R7. R9and n as defined above and described in classes and subclasses herein, also apply to58410095-004WO (221364)BUSINESS.33570224 1compounds of formulae VUI-a, Vlll-b, VIII-c, VUI-d, VUI-e, Vlll-f, or VUI-g, both singly and in combination.

[0250] In some embodiments, the present disclosure provides a compound of formulae IX-a, IX-b,IX-g or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0251] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IX-a, IX-b. IX-c. IX-d, IX-e, IX-f. or IX-g, embodiments of variables R1, R2, R3, R4, R3, R6,59410095-004WO (221364)BUSINESS.33570224 1and R7as defined above and described in classes and subclasses herein, also apply to compounds of formulae IX-a, IX-b, IX-c, IX-d, IX-e, IX-f, or IX-g, both singly and in combination.

[0252] In some embodiments, the present disclosure provides a compound of formulae X-a, X-b, X-X-g or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, R6, R7, and RAis defined and described in classes and subclasses herein, both singly and in combination.

[0253] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae X-a, X-b, X-c, X-d. X-e, X-f. or X-g, embodiments of variables R1, R2, R3, R5, Rb, R7, and RA60410095-004WO (221364)BUSINESS.33570224 1as defined above and described in classes and subclasses herein, also apply to compounds of formulae X- a, X-b, X-c, X-d, X-e, X-f, or X-g, both singly and in combination.

[0254] In some embodiments, the present disclosure provides a compound of formulae Xl-a, Xl-b,XI-g or a pharmaceutically acceptable salt thereof, wherein each of R4and R7is defined and described in classes and subclasses herein, both singly and in combination.

[0255] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Xl-a, Xl-b. XI-c, Xl-d, Xl-e, Xl-f, or XI-g, embodiments of variables R4and R7as defined61410095-004WO (221364)BUSINESS.33570224 1above and described in classes and subclasses herein, also apply to compounds of formulae Xl-a, Xl-b, XI- c, Xl-d, Xl-e, Xl-f, or XI- g, both singly and in combination.

[0256] In some embodiments, the present disclosure provides a compound of formulae XH-a, Xll-b,XII-g

[0257] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae XH-a, Xll-b, XII-c, Xll-d, Xll-e, XH-f, or XII-g, embodiments of variables R7and RAas defined above and described in classes and subclasses herein, also apply to compounds of formulae Xll-a, Xll-b. XII-c, Xll-d, Xll-e, XH-f. or XII-g. both singly and in combination.62410095-004WO (221364)BUSINESS.33570224 1

[0258] In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.Table 1.410095-004WO (221364)BUSINESS.33570224 1BUSINESS.33570224 165410095-004WO (221364)BUSINESS.33570224 1410095-004WO (221364)BUSINESS.33570224 1410095-004WO (221364)BUSINESS.33570224 1410095-004WO (221364)BUSINESS.33570224 1

[0259] 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

[0260] According to another embodiment, the invention provides a composition comprising a provided compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate 5-HT2AR, or a mutant thereof, in a biological sample or in a patient. In some embodiments, a composition of this invention is formulated for administration to a patient in need of such composition.

[0261] 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 pharmacally 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 pharmaceutical 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.

[0262] The term ‘'patient” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0263] Tire tcnn “pharmaceutically 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, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.69410095-004WO (221364)BUSINESS.33570224 1

[0264] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic. intralesional and intracranial injection or infusion techniques. Preferably, 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.

[0265] 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.

[0266] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage fonn 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 are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0267] 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 a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.

[0268] 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 readily70410095-004WO (221364)BUSINESS.33570224 1prepared for each of these areas or organs.

[0269] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdcnnal patches may also be used.

[0270] 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

[0271] 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.

[0272] 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.

[0273] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.

[0274] 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.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0275] In some embodiments, provided compounds and compositions are for use in medicine.

[0276] Compounds and compositions described herein are generally useful as agonists of 5-HT2AR.

[0277] 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 provided71410095-004WO (221364)BUSINESS.33570224 1compound, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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 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.

[0282] 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 treating a 5-HT2AR-mediated disorder as described herein. Such disorders are described in detail herein.

[0283] G protein-coupled receptors (GPCRs) signal through numerous pathways, including disease- associated but also non-disease-associated pathways, and as a result modulation of GPCRs can cause undesired side effects. Modulators of GPCRs can bind and preferentially activate specific pathways over others, often referred to as ligand-mediated bias or pathway bias. 5-HT2AR may interact with multiple signaling pathways upon ligand binding, e.g., pathways that engage with G proteins or |3-arrestins. See72410095-004WO (221364)BUSINESS.33570224 1Kossatz, 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 [3-arrestin signaling pathway). In some embodiments, provided methods include administering to a patient a provided compound, or a pharmacally acceptable salt thereof, wherein the compound 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.[00284J 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.

[0285] In some embodiments. G protein signaling pathways are evaluated through detection of calcium, e.g.. as described in Example 14. In some embodiments, P-arrestin signaling pathways are evaluated as described in Example 15.

[0286] 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 14) as compared to p-arrestin signaling pathways (e.g., as measured in Example 15).

[0287] 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 pharmacally 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.

[0288] The activity of a co pound, 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 detennine activation and / or the subsequent functional consequences of73410095-004WO (221364)BUSINESS.33570224 1activated 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] In some embodiments, the present invention provides a method for treating a depressive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the depressive disorder is a major depressive disorder. In other embodiments, the depressive74410095-004WO (221364)BUSINESS.33570224 1disorder includes treatment resistant depressions.

[0295] 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 pharmacally acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the anxiety disorder is generalized anxiety disorder. In other embodiments, tire anxiety disorder is social anxiety disorder.

[0296] 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 pharmacally acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, such a disorder is post-traumatic stress disorder. In other embodiments, such a disorder is an adjustment disorder.

[0297] In some embodiments, the 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 pharmacally acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0298] 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. In some embodiments, the eating disorder is anorexia. In other embodiments, the eating disorder is bulimia.

[0299] 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.

[0300] 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 pharmacally 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.

[0301] In some embodiments, the present invention provides a method for treating a substance-related and / or addictive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or 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 a tobacco use disorder. For example, in some embodiments provided compound, or a pharmaceutically75410095-004WO (221364)BUSINESS.33570224 1acceptable salt thereof, may be useful in facilitating smoking cessation.

[0302] In some embodiments, the present invention provides a method for treating a neurocognitive disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof. In some embodiments, the neurocognitive disorder includes those due to a primary neurodegenerative disease, for example, Alzheimer's disease or Parkinson’s disease.

[0303] In some embodiments, the present invention provides a method for treating a personality disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmacally acceptable composition thereof.

[0304] 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.

[0305] 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, tire bipolar disorder is bipolar I disorder. In some embodiments, the bipolar disorder is bipolar II disorder.

[0306] 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

[0307] As depicted in the Examples below, in certain exemplar} 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.76410095-004WO (221364)BUSINESS.33570224 1

[0308] General Scheme 177410095-004WO (221364)BUSINESS.33570224 1

[0309] General Scheme 2410095-004WO (221364)BUSINESS.33570224 1

[0310] General Scheme 3,Step 1

[0311] Step 1: To a stirred solution of 6-bromo-4-chlorocinnoline (0.10 g, 0.41 mmol) and tert-butyl 5-(4,4A,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.19 g, 0.62 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added tri -potassium phosphate (K3PO4) (0.26 g, 1.23 mmol). The reaction mixture was purged with N2 gas for 10 min and Pd(dppf)C12.DCM complex (0.03 g, 0.04 mmol) was added at RT. The reaction mixture was allowed to stir at 100 °C for 2 h. The completion of the reaction was monitored by TLC using 40% EA in hexane and LCMS analysis. After completion of79410095-004WO (221364)BUSINESS.33570224 1the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EA (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated under a reduced pressure to give crude material. Tire obtained crude material was purified by flash column chromatography on silica gel using 20% EA in hexane as eluent to obtain tert-butyl 5-(4- chlorocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate as yellow solid (0.06 g, 42%). LCMS (m / z): 346.2 [M+H]+.

[0312] Step 2: To a stirred solution oftert-butyl 5-(4-chlorocinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (0.06 g, 0.17 mmol) in DCM (0.6 mL) was added 4 M HC1 in 1,4-dioxane (0.3 mL) at 0 °C. Tire resulting mixture was stirred at RT for 3 h or until the reaction was complete. The completion of the reaction was monitored by TLC using 10% MeOH in DCM and LCMS analysis. The reaction mixture was concentrated under reduced pressure. The obtained crude material was triturated with pentane (2 x 20 mL) and dried to obtain 4-chloro-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnoline dihydrochloride as light grey solid (1-8, 0.04 g, 82%). LCMS (m / z): 246.2 [M+H]+. 1H NMR (400 MHz, DMSO): 8 13.85 (s, 1H), 9.54 (s, 2H), 8.01 (dd, J 8.8, 2.0 Hz, 1H), 7.91 (d, J 1.6 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J 8.8 Hz, 1H), 6.56-6.54 (m, 1H), 4.09-4.05 (m, 2H), 3.24-3.18 (m, 2H).

[0313] Additional exemplary compounds prepared via Example 1 methods:410095-004WO (221364)BUSINESS.33570224 1410095-004WO (221364)BUSINESS.33570224 1Example 2 (1-15)

[0314] Step 1: To astirred solution oftert-butyl 5-(4-chlorocinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (intermediate prepared in Example 1, 70 mg, 0.2 mmol) and Pd(dppf)C12 (16 mg, 0.02 mmol) in fresh THF (2 mL) was added ZnEt2 (2 mL, 2.0 mmol) under N2. The mixture was stirred at 70 °C for 4 h. The reaction mixture was diluted with water (40 mL) and extracted with EA (3 x 20 mL). Tire combined organic layers were washed with brine (2 x ioOmL), dried over Na2SC>4, filtered and concentrated to give crude product. The residue was purified by prep-TLC (PE:EA=1: 1) to give tert-butyl 5-(4-ethylcinnolin-6- yl)-3,6-dihydropyridine-l(2H)-carboxylate (40 mg) as a brown oil. LCMS (m / z): 340.2 [M+H]+.

[0315] Step 2: To a solution of tert-butyl 5-(4-ethylcinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (40 mg, 0.11 mmol) in DCM (1 mL) was added 4 M HO in 1,4-dioxane (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated, triturated and freeze-dried to give 4-ethyl-6- (L2,5,6-tetrahydropyridin-3-yl)cinnoline hydrochloride (1-15, 22 mg, 78%) as abrown solid. LCMS (m / z): 240.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 9.63 (bs, 2H), 9.31 (s, 1H), 8.45 (d, J 9.0 Hz, 1H), 8.18 (dd, J 9.0, 1.8Hz, 1H), 8.08 (s, 1H), 6.83-6.82 (m, 1H), 4.55-4.48 (m, 2H), 3.28-3.19 (m, 4H), 2.62-2.58 (m, 2H). 1.35 (t, J 7.4 Hz, 3H).Example 3 (1-16)

[0316] Step 1: To a solution of 6-bromo-4-chlorocinnoline (100 mg, 0.41 mmol) in MeOH (8 mL) was added 40% ammonium hydroxide (0.5 mL). Hie mixture was stirred at 80 °C overnight in a sealed tube. The mixture was concentrated in vacuum and the residue was purified by prep-TLC (DCM / MeOH=20: 1) to afford 6-bromo-4-methoxycinnoline (15 mg, 31%) as a yellow’ solid. LCMS (m / z): 238.9 [M+H]+.

[0317] Step 2: To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (39 mg. 0.13 mmol) and 6-bromo-4-methoxycinnoline (30 mg, 0.1383410095-004WQ (221364)BUSINESS.33570224 1mmol) in IN-dioxaneTLO (2 mL / 1 mL) was added ICCCL (52 mg, 0.38 mmol) and Pd(dppf)C12 (9 mg, 0.01 mmol). The mixture was stirred at 60 °C overnight under N2. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 2). Tire organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum, and purified by prep-TLC (DCM / MeOH=20: 1) to afford tert-butyl 5- (4-methoxycinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (20 mg, 47%) as yellow solid. LCMS (m / z): 342.1 [M+H]+.

[0318] Step 3: To a solution of tert-butyl 5-(4-methoxycinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (30 mg) in DCM (2 mL) was added HCl / dioxane (4 M, 2 mL). The mixture was stirred at RT for 1 h or until reaction completion. Tire mixture was concentrated in vacuum and triturated by Et2O to afford 4-methoxy-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnoline hydrochloride (1-16, 18.1 mg, 74%) as ared- brown solid. LCMS (m / z): 242.1 [M+H]1; 1H NMR (400 MHz, DMSO-d6) 5 9.67 (bs. 2H), 9.31 (s, 1H), 8.42 (d, J 9.0 Hz, 1H), 8.26 (dd, J 9.2, 2.0 Hz, 1H), 8.04 (d, J 1.8 Hz, 1H), 6.81 (t, J 4.2 Hz, 1H), 4.29 (s, 3H), 4.16-4.14 (m, 2H), 3.28-3.19 (m, 2H), 2.63-2.54 (m, 2H).

[0319] Additional exemplary compounds prepared via Example 3 methods:Example 4 (1-13)100°C, 16h Step 1

[0320] Step 1: To a solution of tert-butyl 5-(4-chlorociimolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (100 mg, 0.28 mmol) in lA-dioxanc / FLO (2 mL / 0.5 mL) was added 2,4,6-trimethyl-84410095-004WO (221364)BUSINESS.33570224 11,3,5,2,4,6-trioxatriborinane (108.9 mg, 0.86 mmol, 3.5 M), Pd(dppf)C12 (21.16 mg, 0.02 mmol) and K2CO3 (119.89 mg, 0.86 mmol). The reaction mixture stirred at 100 °C overnight under N2. The mixture was filtered and concentrated. The mixture was purified by prep-TLC (Gradient: PE / EA=1 / 1) to afford tertbutyl 5-(4-methylcinnolin-6-yl)-3,6-dihydropyridine-l(2EI)-carboxylate (60 mg, 53%) as a yellow oil. LCMS (m / z): 326.3 [M+H]+.

[0321] Step 2: A solution of tert-butyl 5-(4-methylcinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (60 mg, 0.18 mmol) in DCM (1.5 rnL) and 4M HCl / dioxane (1.5 mL) was stirred at RT for 2 h. Tire mixture was concentrated to obtain a crude residue. The residue was purified by trituration (DCM, 20 mL) to afford 4-methyl-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnoline hydrochloride (1-13, 46 mg, 99%) as a brown solid; LCMS (m / z): 226.1 [M+H]+; 1H NMR (400 MHz. DMSO-d6) 5 9.77 (s, 2H). 9.32 (s, 1H). 8.44 (d, J 9.0 Hz, 1H). 8.22 (dd, 1H), 8.05 (d, J 1.8 Hz, 1H), 6.87-6.85 (m, 1H), 4.21 (s, 2H). 3.29- 3.21 (m, 2H), 2.78 (s, 3H), 2.63-2.59 (m, 2H).

[0322] To a solution of tert-butyl 5-(4-chloroquinazolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (intermediate prepared in Example 1, 100 mg. 0.28 mmol) in DCM (3 mL) was added 4 M HCl / dioxane (6 mL). The reaction mixture was stirred at RT for 1 h. The mixture was concentrated, freeze-dried and purified by prep-HPLC to afford 6-(l,2,5,6-tetrahydropyridin-3-yl)quinazolin-4-ol (1-9, 35 mg, 38%) as a white solid. LCMS (m / z): 228.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 8.33 (bs, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.93 (d, J 9.0 Hz, 1H), 7.65 (d, J 8.4 Hz. 1H), 6.48-6.46 (m, 1H), 3.87 (s, 2H), 3.07-3.03 (m, 2H), 2.39- 2.35 (m. 2H).Example 6 (1-6)410095-004WO (221364)BUSINESS.33570224 1

[0323] Step 1: To a solution of 2-aminobenzonitrile (1 g, 8.47 mmol) in THF (10 mL) at 25 °C was added EtMgBr (2 M in THF, 21 mL, 42 mmol) slowly and the mixture was heated to 45 °C overnight. The mixture was cooled to 0 °C, then HCI (6 M, 20 mL, 118.6 mmol) was added dropwise. After the addition, the mixture was stirred at 100 °C for 2 h. Tire reaction mixture was cooled to 25°C and the mixture was adjusted pH 6-7 with NaHCCL (aq.). Tire mixture was extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated under vacuum. The residue was purified by column chromatography (PE / EA= 10: 1) to afford l-(2-aminophenyl)propan-l-one (700 mg, 56%) as a yellow solid. LCMS (m / z): 150.1 [M+H]+.

[0324] Step 2: To a solution of l-(2-aminophenyl)propan-l-one (2 g, 13.4 mmol) in THF (20 mL) was added AC2O (4.1 g, 40.3 mmol), TEA (4.1 g, 40.3 mmol) and DMAP (163 mg. 1.34 mmol). The mixture was stirred at 50 °C overnight under N2. The mixture was diluted with water (50 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (PE / EA= 10: 1) to afford N-(2-propionylphenyl)acetamide (1.7 g, 66%) as yellow solid. LCMS (m / z): 192.1 [M+H]+.

[0325] Step 3: To a solution of N-(2-propionylphenyl)acetamide (1.70 g, 8.9 mmol) in DMF (20 mL) was added NBS (1.9 g, 10.7 mmol). The mixture was stirred at 60 °C overnight. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford crude N-(4-bromo-2- propionylphenyljacetamide (2.2 g), which was used in next step without further purification. LCMS (m / z): 270.0 [M+H]+.

[0326] Step 4: To a solution of crude N-(4-bromo-2-propionylphenyl)acetamide (2.2 g, 8.1 mmol) in THF (30 mL) was added 6 N HCI (4.7mL, 28.6 mmol). The mixture was stirred at 70 °C for 4 h. The mixture was cooled to 0 °C and adjusted to pH 6-7 with NaHCCL (aq.). The mixture was extracted with EA (100 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and86410095-004WO (221364)BUSINESS.33570224 1concentrated under vacuum. The residue was purified by column chromatography (PE / EA=5 / 1) to afford l-(2-amino-5-bromophenyl)propan-l-one (1.0 g, 50%) as a yellow solid. LCMS (m / z): 228.0 [M+H]+.

[0327] Step 5: A solution of l-(2-amino-5-bromophcnyl)propan-l-onc (110 mg, 0.48 mmol) in water (2 mL) and cone. HC1 (2 mL) was cooled to 0 °C and stirred for 15 min until a suspension fonned. Aqueous sodium nitrite (2M, 0.36 mL, 0.73 mmol) was added dropwise. The mixture was stirred at RT for 2 h, and then refluxed for 2 h. The mixture was cooled to RT. The solid was collected by filtering and dried to afford 6-bromo-3-methylcinnolin-4-ol (60 mg, 52%) as a yellow solid. LCMS (m / z): 239.0 [M+H]+.

[0328] Step 6: To a solution of 6-bromo-3-methylcinnolin-4-ol (50 mg, 0.21 mmol) in THF (2 mL) was added POCT (96 mg, 0.63 mmol). Hie mixture was stirred at 80 °C for 1 h. The solution was cooled to 0 °C and quenched by the addition of NaHCCL (aq.), then extracted with EA (30 mL x 2). The combined organic layers were washed with brine and dried over NaiSCL. filtered and concentrated under vacuum. The residue was purified by prep-TLC (PE / EA 1 : 1 ) to afford 6-bromo-4-chloro-3-methylcinnoline (30 mg, 57%) as yellow solid. LCMS (m / z): 256.6 [M+H]~.

[0329] Step 7: To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (149 mg, 0.48 mmol) and 6-bromo-4-chloro-3-methylcinnoline (130 mg, 0.51 mmol) in l,4-dioxane / H2O (3 mL / 1 mL) was added K2CO3 (210 mg, 1.52 mmol) and Pd(dppf)Ch (37 mg, 0.05 mmol). The mixture was stirred at 60 °C overnight under N2. The mixture was diluted with water (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SCL, filtered and concentrated under vacuum. The residue was purified by prep-TLC (DCM / MeOH=15: 1) to afford tert-butyl 5-(4-chloro-3-methylcinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (130 mg, 71%) as yellow solid. LCMS (m / z): 360.1 [M+H]+.

[0330] Step 8: To a solution of tert-butyl 5-(4-chloro-3-methylcinnolin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate (100 mg, 0.28 mmol) in CHCI3 (3 mL) was added 4-methylbenzenesulfonohydrazide (207 mg, 1.11 mmol). The mixture was stirred at 60 °C overnight. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with HC1 (0.5 N) and brine, dried over Na2SCL, filtered and concentrated under vacuum to afford crude tert-butyl 5-(3- methyl-4-(2-tosylhydrazinyl)cinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (150 mg), which was used in the next step without further purification. LCMS (m / z): 510.1 [M+H]+.

[0331] Step 9: To a solution of tert-butyl 5-(3-methyl-4-(2-tosylhydrazinyl)cinnolin-6-yl)-3,6- dihydropyridinc-l(2H) -carboxylate (150 mg, 0.28 mmol) in H2O / l,4-dioxanc (5 mL / 1 mL) was added Na2CC>3 (62 mg, 0.59 mmol). The mixture was stirred at 95 °C for 2 h. Tire mixture was diluted with water (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by prep-TLC (PE / EA=2 / 1)87410095-004WO (221364)BUSINESS.33570224 1to afford tert-butyl 5-(3-methylcinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (50 mg, 56%) as a red solid. LCMS (m / z): 326.2 [M+H]+.

[0332] Step 10: To a solution of tcrt-butyl 5-(3-mcthylcinnolin-6-yl)-3,6-dihydropyridinc-l(2H)- carboxylate (50 mg, 0.15 mmol) in DCM (1 mL) was added HCl / dioxane (4M, 1 mL). The mixture was stirred at RT for 1 h. Tire mixture was concentrated in vacuum. The residue was adjusted to pH to 7~8 with DIEA and purified by prep-TLC (DCM / MeOH=10 / l) to afford 3-methyl-6-(L2,5,6-tetrahydropyridin-3- yljcinnoline (1-6, 11.9 mg, 34%) as a yellow solid. LCMS (m / z): 226.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 8.38 (d, J 9.0 Hz, 1H), 8.07 (dd, J 9.0, 2.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J 1.8 Hz, 1H), 6.76 (t, J 4.2 Hz, 1H), 4.05 (t, J 2.2 Hz, 2H), 3.20 (t, J 6.0 Hz, 2H), 2.86 (s, 3H), 2.54-2.52 (m, 2H).Example 7 (1-17)

[0333] Step 1: A solution of 7-bromophthalazin-l-ol (500 mg, 2.23 mmol) in POCI3 (5 mL) was stirred at 80 °C for 1 hour. The solution was cooled to 0 °C and quenched with NaHCOs (aq.) and then extracted with EA (50 mL x 2). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated under vacuum to afford 7-bromo-l -chlorophthalazinc (400 mg, 74%) as a yellow solid. LCMS (m / z): 242.9 [M+H]+.

[0334] Step 2: To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (160 mg, 0.52 mmol) and 7-bromo-l -chlorophthalazine (140 mg, 0.58 mmol) in l,4-dioxane / H2O (3 mL / 1.5 mL) was added K2CO3 (239 mg, 1.74 mmol) and Pd(dppf)C12 (42 mg, 0.05 mmol). The mixture was stirred at 60 °C overnight under N2. The mixture was diluted with water (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4. filtered, and concentrated under vacuum. The residue was purified by prep-TLC (DCM / MeOH=20: l) to afford tert-butyl 5-(4-chlorophthalazin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (60 mg, 30%) as a yellow solid. LCMS (m / z): 346.1 [M+H]+.

[0335] Step 3: To a solution of tert-butyl 5-(4-chlorophthalazin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (60 mg, 0.17 mmol) in THF / NMP (2.5 mL / 0.25 mL) was added ferric acetylacetonate (6 mg, 88410095-004WO (221364)BUSINESS.33570224 10.017 mmol) and MeMgBr (3 M, 0.17 mL, 0.52 mmol) at RT. The mixture was stirred at RT for 2 h. The reaction was quenched with saturated NH4CI (aq.) and extracted with EA (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous NazSCL, filtered and concentrated under vacuum. The residue was purified by prep-TLC (PE / EA=1 / 1) to afford tert-butyl 5-(4-methylphthalazin-6- yl)-3,6-dihydropyridine-l(2H)-carboxylate (30 mg, 54%) as yellow solid. LCMS (m / z): 326.1 [M+H]+.

[0336] Step 4: To a solution of tert-butyl 5-(4-methylphthalazin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (35 mg, 0.10 mmol) in DCM (1 mL) was added HCl / l,4-dioxane (4 M, 1 mL). The mixture was stirred at RT for 1 h. The mixture was concentrated under vacuum and triturated by MeCN / Et2O (1: 1, v / v) to afford l-methyl-7-(l,2,5,6-tetrahydropyridin-3-yl)phthalazine hydrochloride (1-17, 25.0 mg, 89%) as a red-brown solid. LCMS (m / z): 226.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 9.91 (s. 1H), 9.86 (bs, 2H), 8.54-8.44 (m, 3H), 6.97-6.95 (m, 1H), 4.23 (s, 2H). 3.30-3.23 (m, 2H), 3.21 (s, 3H). 2.66-2.60 (m, 2H).Example 8 (1-7)

[0337] Step 1 : A solution of 6-bromoisoquinolin-4-ol (50 mg, 0.22 mmol) and TMSCEIN2 (2 M in hexane 0.22 mL, 0.45 mmoL) in DCM (3 mL) and MeOH (0.75 mL) was stirred at RT for 2 h. Tire reaction mixture was concentrated. The residue was purified by prep-TLC (DCM:MeOH=20: 1) to give 6-bromo-4- methoxyisoquinoline (37 mg, 71%) as a white solid. LCMS (m / z): 238.0 [M+H]+.

[0338] Step 2: A solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (98.5 mg, 0.32 mmol), Pd(dppf)C12 (20 mg, 0.026 mmol), K2CO3 (110 mg, 0.79 mmol) and 6-bromo-4-methoxyisoquinoline (63 mg, 0.26 mmol) in l,4-dioxane / H2O (10 mL / 4 mL) was stirred at 80 °C for 16 h under N2. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). Tire combined organic phases were dried over Na2SC>4, filtered and concentrated. Tire residue was purified by prep-TLC (DCM:MeOH=20: l) to give tert-butyl 5-(4- ethoxycinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (60 mg, 66%) as a yellow solid. LCMS (m / z): 341.1 [M+H]+.89410095-004WO (221364)BUSINESS.33570224 1

[0339] Step 3: A solution of tert-butyl 5-(4-methoxyisoquinolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (90 mg, 0.26 mmol) in DCM (2mL) and 4 M HCl / dioxane (2 mL) was stirred at RT for 2 h. Tire reaction mixture was concentrated and triturated with McCN to give 4-mcthoxy-6-(l, 2,5,6- tetrahydropyridin-3-yl)isoquinoline hydrochloride (1-7, 70 mg, 97% yield) as an off-white solid. LCMS (m / z): 241.0 [M+H] ; 'HNMR (400 MHz, DMSO-d6) 8 9.67 (bs, 2H), 9.39 (s, 1H), 8.43 (d. J 8.6 Hz, 1H), 8.34 (s, 1H), 8.16 (dd, J 8.8, 1.6 Hz, 2H), 8.13 (d, J 1.6 Hz, 1H), 6.84 (d, J 4.2 Hz, lH), 4.17 (s, 5H), 3.27- 3.23 (m, 2H), 2.62-2.58 (m, 2H).Example 9 (1-14)

[0340] Step 1: A solution of tert-butyl 5-(4-chlorocinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (50 mg, 0.14 mmol), Zn(CN)2 (33 mg, 0.28 mmol) and Pd(PPh3)4 (16 mg, 0.01 mmol) in NMP (1.5 mL) was stirred at 110 °C for 2 h in a sealed tube. The mixture was filtered, diluted with water (15 mL), and extracted with EA (3x15 mL). Tire combined organic layers were washed with water (15 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=30 / l) to afford tert-butyl 5-(4-cyanocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (33 mg, 68% yield) as a light-yellow solid. LCMS (m / z): 337.1 [M+H]+.

[0341] Step 2: A solution of tert-butyl 5-(4-cyanocinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (33 mg, 98.10 pmol) in 4M HCl / dioxane (2 mL) was stirred at RT for 2 h. The reaction was directly concentrated in vacuo and the residue was purified by trituration (hexane) to afford 6-(l, 2,5,6- tetrahydropyridin-3-yl)cinnoline-4-carbonitrile hydrochloride (1-14. 20 mg, 86%) as a green solid. LCMS (m / z): 237.1 [M+H]+; 'HNMR (400 MHz. DMSO-d6) 39.85 (s. 1H), 9.71-9.58 (bs. 2H), 8.66 (d, J 9.2 Hz, 1H), 8.36 (dd, J 9.2, 2.0 Hz, 1H), 7.91 (d, J 1.6 Hz, 1H), 6.96-6.94 (m, 1H), 4.27-4.20 (m, 2H), 3.30-3.22 (m, 2H), 2.66-2.59 (m, 2H).90410095-004WO (221364)BUSINESS.33570224 1Example 10 (1-28)80 °C, 2hStep 3

[0342] Step 1: To a solution of 4-bromo-2-iodoaniline (8.2 g, 27 mmol, 1.0 eq.) in l,4-dioxane / H2O (80 mL / 16 mL) at room temperature was added 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-l-en-2-yl)-l,3,2- dioxaborinane (7.33 g, 33.0 mmol, 1.2 eq.), K2CO3 (11.4 g, 82.6 mmol, 3.0 eq.) and Pd(dppf)C12 (1.0 g, 1.4 mmol, 0.05 eq.). The reaction was stirred at 70 °C overnight under an N2 atmosphere. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine, dried over Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: pet. ether: EtOAc =100 / 1 to 30 / 1) to afford 4-bromo-2- (3,3,3-trifluoroprop-l-en-2-yl)aniline (5.7 g, yield: 78.1%) as yellow oil. LCMS (m / z): 268.0 [M+H]+.

[0343] Step 2: To a solution of 4-bromo-2-(3,3,3-trifluoroprop-l-en-2-yl)aniline (1.68 g, 6.31 mmol, 1.0 eq.) in HCI (16.2 mL, 6 M, 97.3 mmol, 15.4 eq.) at 0 °C was added HBF4 (4.6 mL, 35 mmol, 5.5 eq.) and a solution of NaNO2(453 mg, 6.57 mmol, 1.04 eq.) in H2O (8.1 mL) dropwise. The reaction was stirred at room temperature for Ih. Tire reaction mixture was extracted with EtOAc (5 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated under vacuum to afford 6-bromo-4-(trifluoromethyl)cinnoline (1.8 g, crude, impure) as a yellow oil, which was used directly in the next step. LCMS (m / z): 276.9 [M+H]+.

[0344] Step 3: To a solution of 6-bromo-4-(trifhroromethyl)cinnoline (7.5 g crude, 27 mmol, 1.0 eq.) in l,4-dioxane / H2O (100 mL / 40 mL) at room temperature was added tert-butyl 5-(4,4,5.5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (10 g, 32 mmol. 1.2 eq.), K2CO2( 11.2 g, 81.2 mmol ,3.0 eq.) and Pd(dppf)Cl2(990 mg, 1.35 mmol, 0.05 eq.). The reaction was stirred at 80 °C for 2h under an N2atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered 91410095-004WO (221364)BUSINESS.33570224 1and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: DCM to Pet. Ether: EtOAc =1 / 1), prep-TLC (DCM: MeOH =15 / 1) and prep-HPLC (72% MeCN in water (containing l%0HCOOH)) to afford tert-butyl 5-(4-(trifluoromethyl)cinnolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (60 mg, yield: 0.6%) as a yellow solid. LCMS (m / z): 380.1 [M+H]+.

[0345] Step 4: To a solution of tert-butyl 5-(4-(trifluoromethyl)cinnolin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate (60 mg, 0.16 mmol, 1.0 eq.) in DCM (2 mL) at room temperature was added 4M HCl / l,4-dioxane (2 mL). The mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under vacuum and purified by trituration (EuO) to afford 6-(l,2,5,6-tetrahydropyridin-3-yl)- 4-(trifluoromethyl)cinnoline hydrochloride (1-28, 46.2 mg, yield: 92.6%) as a purple solid. LCMS (m / z): 280.1 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 9.76 (s, 1H), 9.36 (s, 2H), 8.74 (d, J = 9.0 Hz, 1H), 8.34 (dd, J = 9.0. 2.0 Hz. 1H), 7.89 - 7.86 (m, 1H), 6.88 - 6.83 (m, 1H), 4.25 - 4.16 (m, 2H). 3.31 - 3.25 (m,2H), 2.65 - 2.58 (m, 2H).Example 11 (1-20)

[0346] Step 1: A solution of 7-bromophthalazin-l-ol (200 mg, 0.888 mmol) in POCL (50 mL) was stirred at 100 °C for 4 h. Tire reaction mixture was concentrated and quenched with MeOH (6 mL) at 0 °C, and a solution of NaOMe in MeOH (1.04 g, 5.77 mmol. 30% wt) was added at 0 °C. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with water (20 mL) and dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (pet. ether: EtOAc=10: l) to afford 7-bromo-l- methoxyphthalazine (151 mg, 71%) as yellow oil. LCMS (m / z): 239.0 [M+H]+.

[0347] Step 2: To a solution of 7-bromo-l -methoxyphthalazine (180 mg, 0.752 mmol) and tert-butyl 5-(4,4.5.5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3.6-dihydropyridine-l(2H)-carboxylate (233 mg, 0.752 mmol) in 1,4-dioxane (4 mL) and H2O (0.8 mL) was added Pd(dppf)CL (55 mg, 0.075 mmol) and K2CO3 (313 mg, 2.26 mmol). The reaction mixture was stirred at 80 °C overnight under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over Na2SO4, filtered and concentrated. The mixture was purified92410095-004WO (221364)BUSINESS.33570224 1by prep-TLC (pet. ether: EtOAc=l : l) to afford tert-butyl 5-(4-methoxyphthalazin-6-yl)-3,6-dihydro pyridine- l(2H)-carboxylate (183 mg, 71%) as an off-yellow solid. LCMS (m / z): 342.3 [M+H]+.

[0348] Step 3: To a solution of tert-butyl 5-(4-mcthoxyphthalazin-6-yl)-3,6-dihydropyridinc-l(2H)- carboxylate (63 mg, 0.18 mmol) in DCM (2 mL) was added 4 M HCl / l,4-dioxane (5 mL). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (10 mL), adjusted pH to 9- 10 with a K2CO3 aq. solution and extracted with DCM / MeOH=30 / l (30 mL x 2). The combined organic layers were and dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (DCM: MeOH=10: l) to afford l-methoxy-7-(l,2,5,6-tetrahydropyridin-3-yl)phthalazine (1-20, 58 mg, 53%) as an off-yellow solid. LCMS (m / z): 242.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) 5 9.32 (s, 1H), 8.23 - 8.10 (m, 2H), 8.03 (s, 1H), 6.69 (t, J = 4.0 Hz. 1H), 4.20 (s, 3H), 4.13 - 4.06 (m, 2H), 3.20 (t, J = 6.0 Hz, 2H), 2.53 (d, J = 6.5 Hz, 2H).Example 12 (1-31)

[0349] Step 1: To a solution of 4-bromo-2 -fluoroaniline (5.0 g, 26 mmol, 1.0 eq.) in ethanol (30 mL) was added Ag2SC>4 (8.2 g, 26 mmol, 1.0 eq.) and T (12.7 g, 52.6 mmol. 1.9 eq.). The resulting reaction mixture was stirred at room temperature for 3 h under N2. The solvent was evaporated, and the crude compound was washed with a sodium thiosulfate aq. solution (10 mL). After filtration, the filtrate was extracted with EtOAc (3 x 50 mL). Tire combined organic layers were washed with brine (100 mL), dried over Na2SC> , filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with: PE: EA = 80: 1—60: 1, v / v) to afford 4-bromo-2-fluoro- 6-iodoaniline (4.8 g, 56% yield) as a brown solid. ’H NMR (400 MHz. DMSO-d6) 5 7.56 (t, J = 2.0 Hz, 1H), 7.36 (dd, J = 10.5, 2.0 Hz, 1H), 5.34 (s, 2H).93410095-004WO (221364)BUSINESS.33570224 1

[0350] Step 2: To a solution of 4-bromo-2-fluoro-6-iodoaniline (4.8 g, 1 .0 eq., 15 mmol) in DMF (50 mL) was added Pd(PPh3)Ch (107 mg, 0.010 eq., 0.152 mmol), Cui (145 mg, 0.05 eq., 0.76 mmol), TEA (25.7 g, 16.7 cq., 0.254 mol) and cthynyltrimcthylsilanc (1.8 g, 1.2cq., 18 mmol). The mixture was stirred at 40 °C for 16 h under N2. Tire reaction solution was diluted with water (500 mL) and extracted with EtOAc (3 x 100 mL). Tire combined organic layers were washed with brine (200 mL), dried over Na2SC>4, fdtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with: PE: EA = 80: 1-40: 1, v / v) to afford 4-bromo-2-fluoro-6-((trimethylsilyl) ethynyl)aniline (3.4 g, 78 % yield) as a yellow solid. LCMS (m / z): 288.0 [M+H]+.

[0351] Step 3: To a solution of 4-bromo-2-fhioro-6-((trimethylsilyl)ethynyl)aniline (1.0 g, 1.0 eq., 3.5mmol) in 6 N HC1 (15 mL) at 0 °C was added a solution of NaNCL (361.56 mg. 1.5 eq.. 5.25mmol) in water (2 mL). slowly. The mixture was stirred at RT for 2h. The reaction mixture was dissolved in water and adjusted to pH 7-8 with a saturated sodium bicarbonate aq. solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 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: 1-10: 1, v / v) to afford 6-bromo-4-chloro-8-fluorocinnoline (420 mg, 45% yield) as a yellow solid. LCMS (m / z): 260.9 [M+H]+.

[0352] Step 4: To a solution of 6-bromo-4-chloro-8-fhiorocinnoline (420 mg, 1.0 eq., 1.61 mmol) in methanol (4 mL) was added MeONa (260 mg, 3.0 eq., 4.82 mmol). The reaction mixture was stirred at 40 °C for 10 min. The reaction solution was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 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 = 10: 1-2: 1, v / v) to afford 6-bromo-8-fluoro-4-methoxycinnoline (260 mg, 62% yield) as a yellow solid. LCMS (m / z): 259.0 [M+H]+.

[0353] Step 5: A mixture of 6-bromo-8-fluoro-4-methoxycinnoline (220 mg, 0.856 mmol, l.Oeq.), tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (317.6 mg, 1.027 mmol, 1.2eq.), Pd(dppf)C12.DCM (35 mg, 0.043 mmol, 0.05eq.) and K2CO3 (355 mg, 2.57 mmol, 3.0eq.) in 1.4-dioxane (16 mL) and H2O (4 mL) was stirred at 100 °C under N2 for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: methanol = 80: 1-50: 1, v / v) to afford tert-butyl 5-(8-fluoro-4-methoxycinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (300 mg, 97% yield) as a light yellow solid. LCMS (m / z): 360.2 [M+H]+.94410095-004WO (221364)BUSINESS.33570224 1

[0354] Step 6: To a solution of tert-buty l 5-(8-fliioro-4-mcthoxycinnolin-6-yl)-3.6-dihydropyridinc- l(2H)-carboxylate (70 mg, 1.0 eq., 0.20 mmol) in DCM (1 mL) was added 4 M HCI in 1,4-dioxane (1 mL). Tire mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was dissolved with methanol (2 mL). 6N HCI (2 mL) was added, and the mixture was stirred at room temperature for Ih. The reaction solution was concentrated to afford 8-fluoro-6-( 1,2.5.6-tetrahydropyridin- 3-yl)cinnolin-4(lH)-one hydrochloride (1-31, 45.8 mg, 83% yield) as a light-yellow solid. LCMS (m / z): 246.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 13.85 (s, IH), 9.46 (s, 2H), 7.99 (dd, J = 13.0, 2.0 Hz,1H), 7.84 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H), 4.08 (s, 2H), 3.24 - 3.17 (m, 2H), 2.52 (d, J = 4.0Hz, 2H).Step 3

[0355] Step 1: To a solution of 4-bromo-5-fluoro-2-iodoaniline (1 g, 3.16 mmol, 1.0 eq.), CsF (962 mg, 6.33 mmol, 2.0 eq.) and Pd(P(t-Bu)s)2 (81 mg. 0.16 mmol. 0.05 eq.) in 1,4-dioxane (15 mL) was added tributyl(l-ethoxyvinyl)stannane (1.4 g, 3.8 mmol, 1.2 eq.). The reaction was stirred at 80 °C for 5 h under an N2 atmosphere. The reaction mixture was quenched with 10% KF (aq.) (100 mL), filtered, and the filtrate was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: pct. ether: EtOAc=50 / l to 30 / 1) to afford l-(2-amino-5-bromo-4- fhrorophenyl)ethan-l-one (330 mg, 37%) as a yellow solid. LCMS (m / z): 232.0 [M+H]+.

[0356] Step 2: To a solution of l-(2-amino-5-bromo-4-fluorophenyl)ethan-l-one (1.5 g. 6.5 mmol, 1.0 eq.) in 6 M HO (30 mL) at 0 °C was added a solution of NaNCL (535 mg, 7.76 mmol, 1.2 eq.) in H2O (10 mL) dropwise. The reaction was stirred at 0 °C for 2 h and 110 °C for 2 h. The reaction mixture was cooled to 0 °C and diluted with EtOAc (30 mL). The precipitate was filtered and concentrated in vacuum to afford 6-bromo-7-fhiorocinnolin-4(lH)-one (1 g, 64%) as a yellow solid. LCMS (m / z): 243.0 [M+H]+.410095-004WO (221364)BUSINESS.33570224 1

[0357] Step 3: To a solution of 6-bromo-7-fluorocinnolin-4( lH)-one ( 100 mg, 0.4 mmol, 1.0 eq.) in l,4-dioxane / H2O (2.5 mL / 1 mL) was added tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridinc-l(2H) -carboxylate (153 mg, 0.49 mmol , 1.2 eq.), K2CO3 (171 mg, 1.23 mmol ,3.0 eq.) and Pd(dppf)C12 (15 mg, 0.02 mmol, 0.05 eq. ). The reaction was stirred at 80 °C overnight under an N2atmosphere. Hie reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (Pet.Ether: EtOAc=l / 2) to afford tert-butyl 5-(7- fluoro-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (108 mg, 76.1%) as a yellow solid. LCMS (m / z): 290.1 [M+H-56]+.

[0358] Step 4: To a solution of tert-butyl 5-(7-fluoro-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (150 mg, 0.43 mmol, 1.0 eq.) in DCM (5 mL) at room temperature was added 4 M HC1 in dioxane (5 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuum and the residue was purified by trituration (EtOAc) to afford 7-fluoro- 6-(l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one (1-32, 106.7 mg, yield: 87.5%) as a yellow solid. LCMS (m / z): 246.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) 5 13.68 (s, 1H), 9.24 (s, 2H). 8.00 (d, J = 8.0 Hz, 1H). 7.77 (s. 1H), 7.41 (d, J = 11.5 Hz, 1H), 6.31 (s. 1H), 3.96 (s, 2H), 3.29 - 3.22 (m, 2H), 2.54 - 2.51 (m. 2H).410095-004WO (221364)BUSINESS.33570224 1Example 14 (1-18 & 1-36)

[0359] Step 1: To a solution of l-(2-amino-3-hydroxyphenyl)etlran-l-one ( 12.5 g. 82.7 mmol) in DMF (100 mL) at room temperature was added K2CO3 (57.1 g, 413 mmol) and CH3I (17.6 g, 124 mmol). The mixture was stirred at room temperature for 3 h. Tire reaction mixture was diluted with water (800 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SC>4, filtrated and concentrated under vacuum. Tire residue obtained was purified by column chromatography on silica gel (eluent: Pet. Ether / EtOAc=100 / l to 50 / 1) to afford l-(2-amino-3- methoxyphenyl)ethan-l-one (11.15 g. yield: 81.98 %) as a yellow solid. LCMS (m / z): 166.1 [M+H]+.97410095-004WO (221364)BUSINESS.33570224 1

[0360] Step 2: To a solution of l-(2-amino-3-methoxyphenyl)ethan-l -one (22.3 g, 135 mmol) in DMF (200 mL) at 0 °C was added NBS (28.8 g, 162 mmol). The mixture was stirred at 0 °C for 2h. Tire reaction mixture was quenched with saturated NaYCf (aq., 500 mL), diluted with water (300 mL) and extracted with EtOAc (300 mL x 3). Tire combined organic layers were washed with brine (300 mL), dried over Na2SC>4. filtrated and concentrated under vacuum. Tire residue was purified by column chromatography on silica gel (eluent: Pet. Ether / EtOAc= 100 / 1 to 30 / 1) to afford l-(2-amino-5-bromo-3-methoxyphenyl)ethan- 1-one (21 g, yield: 64 %) as a yellow solid. LCMS (m / z): 246.0 [M+H]+.

[0361] Step 3: To a solution of l-(2-amino-5-bromo-3-methoxyphenyl)ethan-l-one (11 g, 45 mmol) in 6M HC1 (110 mL) at 0 °C was added a solution of NaNCL (3.79 g, 54.1 mmol) in H2O (22 mL) dropwise. The mixture was stirred at 0 °C for 1.5 h, room temperature for 0.5 h and 110 °C for 2 h. The reaction mixture was cooled to 0 °C and stirred at 0 °C for Ih. The precipitate was filtrated, concentrated under vacuum and purified by trituration (DCM / MeOH=50 / l) to afford 6-bromo-8-methoxycinnolin-4(lEI)-one (7.08 g, yield: 61.6%) as a yellow solid. LCMS (m / z): 257.0 [M+H]+.

[0362] Step 4: To a solution of 6-bromo-8-methoxycinnolin-4(lH)-one (100 mg, 0.4 mmol) in DCM / MeOH (3 mL / 1.5 mL) at room temperature was added TMSCHN2 (0.6 mL, 1 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum and the residue was purified by prep-TLC (DCM: MeOH=20: l) to afford 6-bromo-8-methoxy-l-methylcinnolin-4(lH)-one (product 1, 50 mg, yield: 48%) and 6-bromo-8-methoxy-2-methylcinnolin-2-ium-4-olate (product 2, 50 mg, yield: 48 %), both as yellow solids. LCMS (m / z): 269.0 [M+H]+(product 1). LCMS (m / z): 271.0 | M+H | (product 2). The regiochemistry of each product was confirmed by ’H, HMBC, and NOESY NMR analysis.

[0363] Step 5: To a solution of 6-bromo-8-methoxy-l-methylcinnolin-4(lH)-one (110 mg, 0.41 mmol) in dioxane / ELO (5 mL / 2 mL) at room temperature was added tert-butyl 5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (152 mg, 0.49 mmol), K2CO3 (169 mg, 1.23 mmol) and Pd(dppf)C12 (15 mg, 0.021 mmol). The reaction was stirred at 80 °C for 2 h under a N2 atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 * 20 mL). The combined organic layers were washed with brine (20 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH=20 / l) to afford tert-butyl 5- (8-m ethoxy- 1 -methyl -4-oxo- 1 ,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine- 1 (2H)-carboxylate (100 mg, yield: 65.8 %) as a yellow solid. LCMS (m / z): 372.3 [M+H]+. The same procedure was applied to product 2 from step 4 to afford 6-(l-(tert-butoxycarbonyl)-l,2,5,6-tetrahydropyridin-3-yl)-8-methoxy-2- methylcinnolin-2-ium-4-olate (175 mg, yield: 76.7%) as a yellow solid. LCMS (m / z): 372.2 [M+H]+.

[0364] Step 6: To a solution of tert-butyl 5-(8-methoxy-l-methyl-4-oxo-L4-dihydrocinnolin-6-yl)- 3,6-dihydropyridine-l(2H)-carboxylate (100 mg, 0.4 mmol) in DCM (2 mL) at room temperature was98410095-004WO (221364)BUSINESS.33570224 1added 4M HCl / dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was purified by trituration (Et2O) to afford 8-methoxy-l- methyl-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride (1-18, 50 mg, yield: 60 %) as a yellow solid. LCMS (m / z): 272.2 [M+H]+; ’HNMR (400 MHz, DMSO-d6) 5 9.35 (brs, 2H), 7.75 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 6.68 - 6.63 (m, 1H). 4.30 (s. 3H), 4.09 (brs, 2H), 4.03 (s, 3H). 3.26 - 3.18 (m. 2H), 2.56 - 2.52 (m, 2H).

[0365] The same procedure was applied to 6-(l-(tert-butoxycarbonyl)-l,2,5,6-tetrahydropyridin-3- yl)-8-methoxy-2-methylcinnolin-2-ium-4-olate from step 5 to afford 8-methoxy-2-methyl-6-(l, 2,5,6- tetrahydropyridin-3-yl)cinnolin-2-ium-4-olate hydrochloride (1-36, 70 mg, yield: 48.3%) as a yellow solid. LCMS (m / z): 272.2 | M+H | : ’H NMR (400 MHz, DMSO-d6) 5 9.27 (brs, 2H), 8.24 (s, 1H). 7.54 (d, J = 1.8 Hz, 1H). 7.34 (d, J = 1.6 Hz, 1H), 6.73-6.69 (m. 1H), 4.31 (s, 3H), 4.12 (brs, 2H). 4.01 (s, 3H), 3.27 - 3.20 (m, 2H), 2.58 - 2.53 (m, 2H).Example 15 (1-34)

[0366] Step 1: To a solution of l-(2-amino-5-bromophenyl)ethan-l-one (2 g, 9 mmol) in DCM (50 mL) at room temperature was added NCS (1.37 g. 10.3 mmol). The reaction was stirred at 30 °C overnight. The reaction mixture was concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: 3% EtOAc in Pet. Ether) to afford l-(2-amino-5-bromo-3- chlorophenyl)ethan-l-one (1.2 g, 52.1%) as a yellow solid. LCMS (m / z): 250.0 [M+H]+.

[0367] Step 2: To a solution of l-(2-amino-5-bromo-3-chlorophenyl)ethan-l-one (1.0 g, 4.0 mmol) in 6 M HC1 (40 mL) at 0 °C was added a solution of NaNCL (306 mg, 4.43 mmol) in H2O (2 mL) drop-wise.410095-004WO (221364)BUSINESS.33570224 1The reaction was stirred at RT for 1 h and 60 °C for 2 h. The reaction mixture was cooled to 0 °C and diluted with water (50 mL). The precipitate was fdtered, and the filter cake was dried under vacuum to afford 6- bromo-8-chlorocinnolin-4(lH)-one (300 mg, 28.8 %) as a yellow solid. LCMS (m / z): 258.9 [M+H]+.

[0368] Step 3: To a solution of 6-bromo-8-chlorocinnolin-4(lH)-one (200 mg, 0.775 mmol) in dioxanc / lLO (5 mL / 1 mL) at room temperature was added tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (219 mg, 0.775 mmol), K2CO3 (320 mg, 2.32 mmol) and Pd(dppf)CL (56 mg, 78 pmol). The reaction was stirred at 65 °C overnight under a N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). Tire combined organic layers were washed with brine (30 mL), dried over Na^SCL. filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (Pet.Ether: EtOAc=2 / l) to tert-butyl 5-(8- chloro-4-oxo-l,4,4a,8a-tetrahydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (100 mg, 36 %) as a yellow solid. LCMS (m / z): 723.1 [2M+H]+.

[0369] Step 4: To a solution of tert-butyl 5-(8-chloro-4-oxo-l,4,4a,8a-tetrahydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (100 mg, 0.30 mmol) in DCM (5 mL) at room temperature was added 4M HC1 in dioxane (5 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and purified by trituration with Et2O to afford 8-chloro-6-(l,2,5,6- tetrahydropyridin-3-yl)-4a,8a-dihydrocinnolin-4(lH)-one hydrochloride salt (1-34, 61.7 mg. yield: 74.9 %) as a yellow solid. LCMS (m / z): 262.0 [M+H]+: ’HNMR (400 MHz, DMSO-de) 5 13.48 (s, 1H), 9.65 - 9.55 (m, 2H), 8.16 (d, J = 2.0 Hz, 1H), 7.89-7.86 (m, 2H), 6.62 (t, J = 4.2 Hz, 1H), 4.06 (brs, 2H), 3.22 - 3.17 (m, 2H), 2.52 (brs, 2H).100410095-004WO (221364)BUSINESS.33570224 1Example 16 (1-37 & 1-38)

[0370] Step 1: A solution of 6-bromocinnolin-4(lH)-one (200 mg. 0.9 mmol). K2CO3 (982 mg, 7.12 mmol) in DMF (15 mL) was added Mel (758 mg, 5.34 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50 mL), extraction with EtOAc (50 mL x 2). The combined organic phases were washed with water (80 mL) and brine (80 mL), dried over Na2SCL, filtered and concentrated. The residue was purified by prcp-TLC (DCM:McOH=20: 1) to give 6-bromo-l- methylcinnolin-4(lH)-one (80 mg, 38 % yield) as an off-white solid and 6-bromo-2-methylcinnolin-2-ium- 4-olate (80 mg. 38 % yield) as an off-white solid. LCMS (m / z): 241.0 [M+H]1(both products). The regiochemistry of each product was confirmed by 'H, HMBC, and NOESY NMR analysis.

[0371] Step 2: A solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H) -carboxylate (124.6 mg, 0.4030 mmol), Pd(dppf)CL (12.28 mg, 0.01678 mmol), 6- bromo-l-methylcinnolin-4(lH)-one (80 mg, 0.33 mmol) and K2CO3 (138 mg, 0.999 mmol) in dioxane (10 mL) and H2O (4 mL) was stirred at 80 °C for 2 h under N2. The reaction mixture was diluted with water (30 mL), extracted with EtOAc (20 mLx 3). Tire combined organic phases were dried overNa2SO4, filtered101410095-004WO (221364)BUSINESS.33570224 1and concentrated. The residue was purified by prep-TLC (DCM: MeOH =20: 1) to give tert-butyl 5-(l- methyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (68 mg, 60 % yield) as an off-white solid. LCMS (m / z): 342.1 [M+H]+.

[0372] 6-(l-(tert-butoxycarbonyl)- 1,2, 5, 6-tetrahydropyridin-3-yl)-2-methylcinnolin-2-ium -4-olate(70 mg, 60% yield) as an off-white solid was obtained using the same method as above from 6-bromo-2- methylcinnolin-2-ium-4-olate (80 mg). LCMS (m / z): 342.1 [M+H]+.

[0373] Step 3: A solution of tert-butyl 5-(l-methyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (68 mg, 0.19 mmol) in DCM (2 mL) and 4M HCl / dioxane (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated, and the residue was triturated with CHsCN and freeze-dried to afford l-methyl-6-(1.2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one (55 mg HC1 salt. 99% yield) as a yellow-green solid. LCMS (m / z): 242. 1 [M+H]+; H NMR (400 MHz. DMSO- d6) 5 9.42 (brs, 2H), 8.07 (dd, J = 9.0, 2.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.76 (s, 1H), 6.63 - 6.58 (m, 1H), 4.12-4.08 (m, 5H), 3.26 - 3.20 (m, 2H), 2.55-2.50 (m, 2H).

[0374] 2-methyl-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnolin-2-ium-4-olate (56.5 mg HC1 salt, 99% yield) as a yellow-green solid was obtained using the same method as above from 6-(l-(tertbutoxycarbonyl)-!, 2, 5, 6-tetrahydropyridin-3-yl)-2-methylcinnolin-2-ium-4-olate (70 mg). LCMS (m / z): 242.2 [M+H]+; 'H NMR (400 MHz, DMSO-ds) 5 9.39 (brs, 2H), 8.28 (s, 1H), 8.01 (dd, J = 9.0, 2.2 Hz,1H), 7.97 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 6.67 (t, J = 3.0 Hz, 1H), 4.32 (s, 3H), 4.12 (brs, 2H),3.28-3.19 (m, 2H), 2.58-2.50 (m, 2H).Example 17 (1-35)102410095-004WQ (221364)BUSINESS.33570224 1

[0375] Step 1 : A solution of 6-bromo-8-methoxycinnolin-4( lH)-one prepared as in example method 14 (100 mg, 0.39 mmol) in POCls (3 mL) was stirred at 60 °C for 30 min. Tire reaction mixture was quenched with saturated NaHCO?, (aq., 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over NazSCL, fdtered and concentrated under vacuum to afford crude 6-bromo-4-chloro-8-methoxycinnoline (107 mg) as yellow oil, which was used directly into the next step. LCMS (m / z): 273.0 [M+H]+.

[0376] Step 2: To a solution of 6-bromo-4-chloro-8-methoxycinnoline (107 mg, 0.391 mmol) in MeOH (3 mL) at room temperature was added 30 % NaOMe (141 mg, 0.783 mmol). The reaction was stirred at 25 °C overnight. Hie reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL). dried over NaiSCL, filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH=20 / l) to afford 6-bromo-4, 8 -dimethoxy cinnoline (70 mg, yield: 66.7%) as a yellow solid. LCMS (m / z): 271.0 [M+H]+.

[0377] Step 3: To a solution of 6-bromo-4,8-dimethoxycimioline (165 mg, 0.613 mmol) in dioxane / LLO (5 mL / 2 mL) at room temperature was added tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (228 mg, 0.737 mmol). K2CO3 (254 mg, 1.84 mmol) and Pd(dppf)Cli (22 mg, 0.030 mmol). The reaction was stirred at 80 °C for 2h under a N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried overNa2SC>4, filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH=15 / l) to afford tert-butyl 5- (4.8-dimethoxycinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (200 mg, yield: 87.8%) as a red solid. LCMS (m / z): 372.2 [M+H]+.

[0378] Step 4: To a solution of tert-butyl 5-(4,8-dimethoxycinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (200 mg, 0.54 mmol) in DCM (3 mL) at room temperature was added 4M HC1 in dioxane (3 mL). The mixture was stirred at room temperature for 2h. Tire reaction mixture was concentrated under vacuum. The residue was purified by prep-TLC (DCM: MeOH=10 / l) and prep-HPLC (13% ACN / l%o HCOOH in H2O) to afford 4,8-dimethoxy-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnoline (35 mg. yield: 24 %) as a yellow solid. LCMS (m / z): 272.2 [M+H]+; ’HNMR (400 MHz, DMSO-ds) 59.16 (s, 1H), 7.47 - 7.42 (m, 1H), 131 - 7.33 (m, 1H), 6.63 (s, 1H), 4.14 (s, 3H), 4.08 (s, 3H), 3.68 - 3.65 (m, 2H), 2.85 (t, J = 5.7 Hz, 2H), 2.28 - 2.19 (m, 2H).103410095-004WO (221364)BUSINESS.33570224 1Example 18 (1-29)

[0379] Step 1: A solution of 6-amino-3-bromo-2-fluorobenzonitrile (300 mg, 1.40 mmol) in anhydrous THF (9 mL) was added to MeMgBr (1 M in THF. 2.32 mL. 6.98 mmol) slowly at room temperature under an N; atmosphere. The reaction was stirred at 45 °C overnight. The reaction mixture was cooled to room temperature, added 6N HCI to adjust pH=3-4. The mixture was stirred at 100 °C for 2 h. After cooling to room temperature, the mixture was adjusted to pH = 6~7 with Na2COs solid, diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50mL). dried over Na2SO4, filtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (eluent Pet.Ether: EtOAc=10 / l) to afford l-(6-amino-3-bromo-2- fluorophenyl)ethan-l-one (80 mg, 24.7 %) as a yellow solid. LCMS (m / z): 232.0 [M+H]+.

[0380] Step 2: To a solution of l-(6-amino-3-bromo-2-fluorophenyl)ethan-l-one (1.64 g, 7.07 mmol) in I PO (11 mL) at 0 °C was added cone. HCI (11 mL). Hie reaction was stirred at 0 °C for 20 min, a solution ofNaNCL (512.0 mg, 7.421 mmol) in H>O (27 mL) was added. The reaction was stirred at 0 °C for 2 h and then warmed to 65 °C. then stirred at 65 °C for 2h. The reaction mixture was filtered. The filter was concentrated under vacuum to afford 6-bromo-5-fluorocinnolin-4(lH)-one (850 mg, 49.7%) as a yellow solid. LCMS (m / z): 242.9 [M+H]+.

[0381] Step 3: To a solution of 6-bromo-5-fluorocinnolin-4(lH)-one (850 mg, 3.497 mmol) in dioxane / H2O (20 mL / 5 mL) at room temperature was added tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.08 mg, 3.50 mmol), K2CO3 (966.7 mg, 6.994 mmol) and Pd(dppf)Cl2(255.9 mg, 0.3497 mmol). The reaction was stirred at 80 °C for 2h under a N2atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 0 mL).104410095-004WQ (221364)BUSINESS.33570224 1The combined organic layers were washed with brine (50 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column (eluent: Pet.Ether: EtOAc=10 / l to 2 / 1) to afford tert-butyl 5-(5-fluoro-4-oxo-l,4,4a,8a-tetrahydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (500 mg, 41.6 %) as yellow oil. LCMS (m / z): 290 [M-55]+.

[0382] Step 4: To a solution of tert-butyl 5-(5-fluoro-4-oxo-l,4,4a.8a-tetrahydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxy late (100 mg, 0.289 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4- dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum to afford 5-fluoro-6-(l,2,5,6-tetrahydropyridin-3-yl)-4a,8a-dihydrocinnolin- 4(lH)-one (79 mg HC1 salt, 96.5%) as an off-yellow solid. LCMS (m / z): 246.1 [M+H]+; 'H NMR (400 MHz, DMSO-de) 8 13.70 (s. 1H), 9.31 (brs, 2H), 7.75 (t, J = 7.2 Hz. 1H), 7.66 (s, 1H), 7.44 (d, J = 8.9 Hz, 1H). 6.29 - 6.20 (m. 1H), 3.93 (brs, 2H), 3.30 - 3.20 (m, 2H). 2.51 (brs. 2H).Example 19 (1-40)

[0383] Step 1: To a solution of 6-bromocinnolin-4(lH)-one (500 mg, 2.22 mmol) in THF (3 mL) at 0 °C was added POCI3 (0.62 mL, 6.7 mmol). The reaction was stirred at 60 °C for 1 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (100 mL), adjusted pH=6~7 with saturated NaHCOs (aq.) solution and extracted with EtOAc (100 mL*3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum to afford 6-bromo-4- chlorocinnoline (580 mg) as yellow oil, which was used directly at the next step. LCMS (m / z): 244.8 [M+H]+.[00384J Step 2: To a solution of 6-bromo-4-chlorocinnoline (541 mg, 2.22 mmol) in MeOH (5 mL) at room temperature was added 30 % NaOMe (400 mg, 2.22 mmol). The reaction was stirred at 60 °C for 2h.105410095-004WO (221364)BUSINESS.33570224 1The reaction mixture was diluted with water (100 mL) and extracted with DCM ( 100 mL x 3 ) . The combined organic layers were washed with brine (100 mL), dried over Na2SCL, fdtered and concentrated under vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH =20 / 1) to afford 6-bromo-4- methoxycinnoline (170 mg, 32%) as a yellow solid. LCMS (m / z): 241.0 [M+H]+.

[0385] Step 3: To a solution of 6-bromo-4-methoxycinnoline (50 mg, 0.21 mmol) in dioxanc / FLO (2 mL / 0.4 mL) at room temperature was added tert-butyl l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3- azabicyclo[3.1.0]hexane-3-carboxylate (71 mg, 0.23 mmol), CS2CO3 (204 mg, 0.626 mmol) and PCysPd G2 (6 mg, 0.01 mmol). The reaction was stirred at 100 °C overnight under a N2 atmosphere in a sealed tube. Tire reaction mixture w as diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na?SO4. filtered and concentrated under vacuum. Hie residue obtained was purified by prep-TLC (DCM: MeOH =20 / 1) to afford tert-butyl l-(4- methoxycinnolin-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (56.8 mg, 80 %) as a yellow solid. LCMS (m / z): 342.2 [M+H]+.

[0386] Step 4: To a solution of tert-butyl l-(4-methoxycinnolin-6-yl)-3-azabicyclo[3.1.0]hexane-3- carboxylate (70 mg, 0.21 mmol) in DCM (2mL) at room temperature was added 4M HCl / dioxane (2 mL). The mixture w as stirred at room temperature for 2h. The reaction mixture was concentrated under vacuum to afford 6-(3-azabicyclo[3.1.0]hexan-l-yl)-4-methoxycinnoline (57 mg. HC1 salt, yield: 100%) as ayellow solid, which was used directly in the next step. LCMS (m / z): 242.2 [M+H]+.

[0387] Step 5: To a solution of 6-(3-azabicyclo[3.1.0]hexan-l-yl)-4-methoxycinnoline (49.5 mg, 0.21 mmol) in MeOH (3 mL) at room temperature was added 6M HC1 (3 mL). The mixture was stirred at 60 °C overnight and 80 °C for 5 h in a sealed tube. The reaction mixture was concentrated under vacuum. To the residue was added MeOH (5mL) and K2CO3 (50 mg). The mixture was stirred at room temperature for Ih. The mixture was filtrated and the filtrate was concentrated under vacuum. The residue was purified by trituration (DCM) to afford 6-(3-azabicyclo[3.1.0]hexan-l-yl)cinnolin-4(lH)-one (43.2 mg, yield: 93%) as a yellow solid. LCMS (m / z): 228.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 8 7.84 (d, J = 2.0 Hz, IH), 7.73 (s, IH). 7.65 (dd, J = 8.8, 2.0 Hz, IH), 7.59 (d, J = 8.8 Hz, IH), 3.50 (d, J = 11.0 Hz, IH), 3.29 - 3.23 (m, 2H). 3.16 (d, J = 11.2 Hz, IH), 2.05 - 1.98 (m, IH), 1.27 (t, J = 5.0 Hz, IH), 1.09 - 1.01 (m, IH).106410095-004WO (221364)BUSINESS.33570224 1Example 20 (1-42 & 1-43) i) n-BuLi, THF, 20 min, -78 °C

[0388] Step 1: To a solution of 6-bromocinnolin-4(lH)-one (10 g, 0.044 mmol) in THF (100 mL) was added POCL (20.44g, 0.1333 mol). The reaction mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (1000 mL) and extracted with EtOAc (3 * 200 mL). The combined organic layers were washed with brine (600 mL), dried over Na2SC>4, fdtered and concentrated to obtain 6-bromo-4- chlorocinnoline (10 g, 70 % yield) as a brown solid. LCMS (m / z): 242.9 [M+H]+.

[0389] Step 2: To a solution of 6-bromo-4-chlorocinnoline (10 g. 0.041 mmol) in methanol (100 mL) was added NaOCTL (22.2 g, 0.123 mol). The reaction mixture was stirred at 60 °C for 1 h. The reaction solution was diluted with water (1000 mL) and extracted with EtOAc (3 x 200 mL). Tire combined organic layers were washed with brine (600 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: MeOH = 100: 1-50: 1, v / v) to afford 6-bromo-4-methoxycinnoline (7.3 g, 70 % yield) as a brown solid. LCMS (m / z): 239.0 [M+H]+.107410095-004WO (221364)BUSINESS.33570224 1

[0390] Step 3: To a solution of 6-bromo-4-methoxycinnoline (7.3 g, 0.031 mol) in THF (80 mL) at - 78 °C was added n-BuLi (3.0 g, 0.047 mol) drop-wise. The resulting solution was stirred for 20 min at -78 °C and a solution of tert-butyl (3-oxocyclobutyl)carbamatc (6.78 g, 0.0366 mol) in THF (30 mL) was added drop-wise. Tire reaction mixture was stirred for 20 min at -78 °C. The mixture was diluted with water (500 mL) and extracted with EtOAc (3 x 50 mL). Tire combined organic layers were washed with brine (200 mL), dried over NazSC filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: 1-30: 1, v / v) to afford tert-butyl (3- hydroxy-3-(4-methoxycinnolin-6-yl)cyclobutyl)carbamate (1.0 g, 12 % yield) as a brown solid. LCMS (m / z): 346.2 [M+H]+.

[0391] Step 4: To a solution of tert-butyl (3 -hydroxy-3 -(4-methoxycinnolin-6- yl)cyclobutyl)carbamate (1.0 g, 2.9 mmol) in DCM (50 mL) was added TEA (878.8 mg, 8.686 mmol) and MsCl (500 mg, 4.34 mmol). The mixture was stirred at room temperature for 2 h under N2. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). Tire combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by prep-TLC (DCM: MeOH=20: l,v / v) to afford tert-butyl (3-(4-methoxycinnolin-6-yl)cyclobut-2-en-l- yl)carbamate (285 mg, 30 % yield) as a yellow solid. LCMS (m / z): 328.2 [M+H]+.

[0392] Step 5: To a solution of tert-butyl (3-(4-methoxycinnolin-6-yl)cyclobut-2-en-l-yl)carbamate (160 mg, 0.488 mmol) in MeOH (20 mL) was added Pd / C (16 mg). The reaction mixture was stirred at room temperature for 16 h under H2. Tire reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by prep-HPLC (52% ACN in water (0.1% HCOOH)) to afford tert-butyl ((lr,3r)-3-(4-methoxycinnolin-6-yl)cyclobutyl)carbamate (eluting fraction 1, 10 mg. 7% yield) and tert-butyl (( ls,3s)-3-(4-methoxycinnolin-6-yl)cyclobutyl)carbamate (eluting fraction 2, 32 mg, 10% yield) as white solids. LCMS (m / z): 330.2 [M+H]+(both fractions). The stereochemistry of each fraction w as determined by NOESY analysis.

[0393] Step 6: To a solution of tert-butyl ((lr,3r)-3-(4-methoxycinnolin-6-yl)cyclobutyl)carbamate (eluting fraction 1 from step 5, 10 mg, 0.030 mmol) in DCM (1 mL) was added 4 M HC1 in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was dissolved in MeOH (2 mL) and 6N HC1 (2 mL). The reaction mixture was stirred at 60 °C overnight. The mixture was concentrated, and the residue was purified by trituration (DCM, 2mL) to afford 6-((lr,3r)-3-aminocyclobutyl)cinnolin-4(lH)-one hydrochloride (5.5 mg, HC1 salt, 72 % yield) as a yellow solid. LCMS (m / z): 216.0 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 13.54 (s, 1H), 8.10 (brs, 3H), 7.89 (s. 1H), 7.76-7.72 (m, 2H), 7.60 (d, J = 8.7 Hz, 1H), 3.90 - 3.83 (m, 2H), 2.57 - 2.53 (m, 4H).108410095-004WO (221364)BUSINESS.33570224 1

[0394] To a solution of tert-butyl ((ls,3s)-3-(4-methoxycinnolin-6-yl)cyclobutyl)carbamate (32 mg, 0.097 mmol) in DCM (2 mL) was added 4 M HC1 in 1,4-dioxane (2 mL). Tire reaction mixture was stirred at room temperature for 1 h. Tire mixture was concentrated, and the residue was dissolved in MeOH (2 mL) and 6N HC1 (2 mL). The reaction mixture was stirred at 60 °C overnight. The mixture was concentrated, and the residue was dissolved in methanol (2 mL). K2CO3 (5 mg) was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was filtered and the filtrate was concentrated to obtain the crude product, which was purified by prep-TLC (DCM / MeOH=10: l, 1 drop of ammonia hydroxide, v / v,) to afford 6-((ls,3s)-3-aminocyclobutyl)cinnolin-4(lH)-one (5.0 mg, 24 % yield) as a yellow solid. LCMS (m / z): 216.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 7.89 - 7.82 (m, 1H), 7.74 - 7.66 (m, 2H), 7.54 (d, J = 8.6 Hz, 1H). 3.26 - 3.21 (m. 1H), 3.10 - 3.02 (m, 1H), 2.63 - 2.56 (m, 2H), 1.80 - 1.71 (m. 2H).Example 21 (1-44 & 1-45)B2(Pin)2,Pd(dppf)CI2Eluting fraction 1 & 2 From eluting fraction 1 & 2

[0395] Step 1: To a solution of 6-bromocinnolin-4(lH)-one (600 mg, 2.64 mmol) and B2(Pin)2 (1.35 g, 5.32 mmol), Pd(dppf)C12 (97 mg, 0.13 mmol) and KOAc (523 mg, 5.33 mmol) in 1,4-dioxane (10 mL) was stirred at 90 °C overnight under N2 in sealed tube. The reaction mixture was diluted with water (100109410095-004WO (221364)BUSINESS.33570224 1mL) and extracted with DCM (3 x 40 mL). The combined organic layers were dried over Na^SO^ filtered and concentrated to afford crude 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cinnolin-4(lH)-one, which was used into next step directly. LCMS (m / z): 273.2 [M+H]+.

[0396] Step 2: A mixture of 3 -bromo-5 -methylpyridine (6.0 g, 35 mmol), PMBC1 (6.0 g, 38 mmol) and KI (578 mg. 3.48 mmol) in toluene (50 mL) was stirred at 110 °C overnight. The reaction mixture was directly concentrated and purified by column chromatography (DCM / MeOH=l :0 ~ 8: 1) to afford 3-bromo- l-(4-methoxybenzyl)-5-methylpyridin-l-ium (8.7 g, 87%) as yellow oil. LCMS (m / z): 295.0 [M+H]+.

[0397] Step 3: To a solution of 3-bromo-l-(4-methoxybenzyl)-5-methylpyridin-l-ium (1 g, 3 mmol) in MeOH / DCE (5 mL / 20mL) at 0 °C was added NaBH.CN (645 mg, 10.2 mmol) and AcOH (1.02 g, 17. 1 mmol). The mixture was stirred at room temperature overnight. Four parallel reaction mixtures were combined and diluted with water (300 mL), then extracted with DCM (3 x 100 mL). Tire combined organic layers were dried over NaiSCL, filtered and concentrated. The mixture was purified by column chromatography (DCM / MeOH=LO ~ 100: 1) and prep-TLC (DCM / MeOH=30: 1) to afford 5-bromo-l-(4- methoxybenzyl)-3-methyl-l,2,3,6-tetrahydropyridine (470 mg, 9% yield) as yellow oil. LCMS (m / z): 298. 1 [M+H]+.

[0398] Step 4: A mixture of 5-bromo-l-(4-methoxybenzyl)-3-methyl-L2.3,6-tetrahydropyridine (60 mg, 0.20 mmol) in ACE-CI (3mL) was stirred at 50 °C overnight. The mixture was concentrated, and the residue was stirred at 80 °C in MeOH (2 mL) for 1 hour. The reaction mixture was directly used in the next step. LCMS (m / z): 176.0 [M+H]+.

[0399] Step 5: A mixture of crude 5-bromo-3-methyl-l,2,3,6-tetrahydropyridine (326 mg, 1.85 mmol), K2CO3 (513 mg. 3.71 mmol), TEA (206 mg, 2.04 mmol) and BOC2O (445 mg, 2.04 mmol) in MeOH (8 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and exacted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Tire mixture was purified by prep-TLC (DCM / MeOH=30: 1) to afford tert-butyl 5-bromo-3- methyl-3,6-dihydropyridine-l(2H)-carboxylate (370 mg, 72 % yield) as yellow oil. LCMS (m / z): 222.0 [M-55]+.

[0400] Step 6: A mixture of tert-butyl 5-bromo-3-methyl-3,6-dihydropyridine-l(2H)-carboxylate (370 mg, 1.34 mmol), 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cinnolin-4(lH)-one (1.09 g, 4.00 mmol), Xphos Pd G3 (57 mg, 0.067 mmol) and K3PO4 (853 mg, 4.02 mmol) in l,4-dioxane / H2O (10 mL / 2 mL) was stirred at 100 °C overnight under N2 in scaled tube. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Tire mixture was purified by column (DCM / MeOH=L0 ~ 40: 1) to afford tertbutyl 3-methyl-5-(4-oxo-l,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (260 mg, 56 %110410095-004WO (221364)BUSINESS.33570224 1yield) as a yellow solid. The racemic mixture (200 mg) was purified by chiral HPLC to separate the enantiomers. (Column: Daicel OZ (30 mm x 250 mm, 10 pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 70% A for 7 mins; Wavelength: 214 nm; Sample Solvent: MeOH (6 mL), Injection volume: 0.2 mL). Analytical chiral HPLC (Column: Daicel OZ (3 mm x 100 mm, 3 pm): Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 70 %A for 10 mins: Wavelength: 214 nm: RT1 = 7.541 min. RT2 = 8.548 min). Eluting fraction 1: 46 mg, yellow solid; LCMS (m / z): 286.1 [M-55]+. Eluting fraction 2: 58 mg, yellow solid; LCMS (m / z): 286.1 [M-55]+.

[0401] Step 7: A mixture of tert-butyl 3-methyl-5-(4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate eluting fraction 1 from step 6 (46 mg, 0.13 mmol) in 4M HCl / dioxane (2mL) / DCM (4 mL) was stirred at room temperature for 2 hours. The mixture was directly concentrated, and the residue was triturated with DCM / hexane (1 mL / 1 mL) to afford 6-(5-methyl-l, 2,5,6- tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride from eluting fraction 1 (1-44, 35 mg HC1 salt) as a yellow solid. LCMS (m / z): 242.1 [M+Hf; 'H NMR (400 MHz, DMSO-d6) 5 13.70 (s, 1H), 9.42 (brs, 1H), 9.28 (brs, 1H), 8.00 (dd, J = 8.8, 2.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 4.14 - 3.99 (m, 2H), 3.44 - 3.36 (m, 1H), 2.82 - 2.71 (m, 2H), 1.14 (d, J = 6.6 Hz, 3H).

[0402] The same procedure was applied to eluting fraction 2 (58mg, 0.16 mmol) from step 6. From eluting fraction 2: 6-(5-methyl-l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride from eluting fraction 2 (1-45, 42.9 mg HC1 salt) as a yellow solid. LCMS (m / z): 242.1 [M+H]+; 'H NMR (400 MHz, DMSO-ds) 8 13.70 (s, 1H), 9.41 (brs, 1H), 9.27 (brs, 1H), 8.00 (dd, J = 8.8, 2.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H). 7.78 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 6.42 (s, 1H), 4.12-3.99 (m, 2H), 3.44 - 3.36 (m, 1H), 2.82-2.71 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H).

[0403] Additional Exemplary Compounds Prepared via Example 21 Method111410095-004WO (221364)BUSINESS.33570224 1Example 22 (1-52)

[0404] Step 1: To a solution of tert-butyl 5-(8-chloro-4-oxo-l,4,4a,8a-tetrahydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H)-carboxylate (300 mg, 0.829 mmol, prepared as in example method 15) in DCM (4 mL) was added TMSCHN2 (2M in hexanes. 2.07 mL, 4.14 mmol). The mixture was stirred at 35 °C overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by p-TLC (DCM: MeOH = 30: 1) to afford tert-butyl 5-(8-chloro-l-methyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxy late (80 mg, 26 % yield) as a white solid. LCMS (m / z): 376.0 [M+H]+. The rcgiochcmistry of the methylation step was confirmed by HMBC analysis.

[0405] Step 2: To a solution of tert-butyl 5-(8-chloro-l-methyl-4-oxo-l,4-dihydrociimolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (40 mg, 0.11 mmol) in DCM (2 mL) was added 4 M HC1 in dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to afford 8-chloro-l-methyl-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride (30 mg, 97 % yield) as a white solid. LCMS (m / z): 276.1 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 9.21 (br s, 2H), 8.16 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 2.2 Hz. 1H), 7.86 (s, 1H), 6.70 - 6.63 (m. 1H), 4.42 (s, 3H), 4.14 - 4.05 (m, 2H). 3.26 - 3.19 (m. 2H), 2.52-2.49 (m, 2H).112410095-004WO (221364)BUSINESS.33570224 1Example 23 (1-55)

[0406] Step 1: To a solution of 6-bromo-8-chlorocinnolin-4(lH)-one (200 mg, 0.771 mmol, prepared as in example method 15) in DCM (2 mL) was added TMSCHN2 (2M, 1.34 mL, 2.70 mmol). The mixture was stirred at 35 °C overnight. The mixture was fdtered and concentrated. Tire residue was purified by prep-TLC (DCM: MeOH = 30: 1) to afford 6-bromo-8-chloro-l-methylcinnolin-4(lH)-one (23 mg, 10.9 % yield) as a white solid. LCMS (m / z): 274.9 [M+H]+.

[0407] Step 2: A solution of 6-bromo-8-chloro-l-methylcinnolin-4(lH)-one (500 mg, 1.83 mmol), Pd(dppf)C12 (133 mg, 0.183 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-l(2H)-carboxylate (678.3 mg, 2.194 mmol) and K2CO3 (757.94 mg, 5.48mmol) in 1,4- dioxanc / FLO (10 mL / 2.5mL) was stirred at 60 °C overnight under a N2 atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by prep-TLC (DCM: MeOH = 30: 1) to afford tert-butyl 5-(8-chloro-l-methyl-4-oxo-l,4- dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (478 mg, 69.5 %) as a yellow solid. LCMS (m / z): 376.1 [M+H]+.113410095-004WO (221364)BUSINESS.33570224 1

[0408] Step 3: A solution of tert-butyl 5-(8-chloro-l -methyl -4-oxo- l,4-dihydrocinnolin-6-yl)-3, 6- dihydropyridine-l(2H) -carboxylate (189.4 mg, 0.5049 mmol), Pd(dppf)C12 (36.9 mg, 0.0505 mmol ), C2H3BF3K (81.15 mg, 0.6059 mmol) and tricthylaminc (51.09 mg, 0.5049 mmol) in IPA (3 mL) was stirred at 130 °C overnight under a N2 atmosphere in sealed tube. Tire reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL - 3). The combined organic phases were washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated. The residue obtained was purified by prep-TLC (DCM: MeOH = 30: 1) to afford tert-butyl 5-(l-methyl-4-oxo-8-vinyl-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (73.7 mg, 39.7 %) as a yellow solid. LCMS (m / z): 368.0 [M+H]+.

[0409] Step 4: To a solution of tert-butyl 5-(l-methyl-4-oxo-8-vinyl-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (280 mg, 0.762 mmol) in MeOH (4 mL) was added Pd / C (28 mg, 0.26 mmol). The mixture was stirred at room temperature for 30 min under a H2 atmosphere. The mixture was filtered and concentrated. Tire residue was purified by prep-HPLC (0.1% HCOOH in water, 59% MeCN) to afford tert-butyl 5-(8-ethyl-l-methyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (72 mg, 26 %) as a white solid. LCMS (m / z): 370.2 [M+H]+.

[0410] Step 5: A solution of tert-butyl 5-(8-ethyl-l-methyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (71.6 mg. 0.194 mmol) in 4 M HCl / dioxane (2 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was removed under vacuum to afford 8-ethyl- l-methyl-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride (50.6 mg, 85.7 % yield) as a white solid. LCMS (m / z): 270.2 [M+H]+;]H NMR (400 MHz, DMSO-d6) 59.26 (br s, 2H), 7.94 (d, J = 2.4 Hz, 1H). 7.89 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 6.63 - 6.56 (m, 1H), 4.29 (s, 3H), 4.14 - 4.05 (m, 2H), 3.26 - 3.16 (m, 4H), 2.52-2.50 (m, 2H), 1.27 (t, J = 7.4 Hz. 3H).114410095-004WO (221364)BUSINESS.33570224 1Example 24 (1-50)

[0411] Step 1: A solution of 6-bromo-4-metlioxycinnoline (300 mg, 1.26 mmol, prepared as in example method 19), tert-butyl piperazine- 1 -carboxylate (280.5 mg, 1.506 mmol). Pd2(dba)s (57.46 mg, 0.0628 mmol), Xant-phos (108.9 mg, 0.1883 mmol) and CS2CO3 (1.23 g. 3.77 mmol) in 1,4-dioxane (8 mL) was stirred at 1200C for 16 h under N2. The mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO.+, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: 1-80: 1, v / v) to afford tert-butyl 4-(4-methoxycinnolin-6- yl)piperazine-l -carboxylate (400 mg, 90 % yield) as a yellow solid. LCMS (m / z): 345.2 [M+H]+.

[0412] Step 2: To a solution of tert-butyl 4-(4-methoxycinnolin-6-yl)piperazine-l -carboxylate (100 mg, 0.3 mmol) in DCM (3 mL) was added 4 M HCI in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and triturated with DCM (5 mL). The solid was collected by filtration to afford 4-methoxy-6-(piperazin-l-yl)cinnoline (95 mg, HCI salt, 85% yield) as a yellow solid. LCMS (m / z): 245.1 [M+H]+.

[0413] Step 3: To a solution of 4-methoxy-6-(piperazin-l-yl)cinnoline hydrochloride (75 mg, 0.31 mmol) in MeOH (3 mL) was added 6N HCI (3 mL). The mixture was stirred at 60 °C for 16 h in sealed tube. The reaction mixture was concentrated, and the residue was dissolved with methanol (2 mL), K2CO, (20 mg) was added, and tire mixture was stirred for 30 min. Tire reaction solution was filtered to remove the solid. The filtrate was concentrated to obtain the crude product. The crude was purified by prep-TLC (DCM:MeOH=10: 1 with 0.5 mL ammonium hydroxide) to afford 6-(piperazin-l-yl)cinnolin-4(lH)-one115410095-004WO (221364)BUSINESS.33570224 1(23.2 mg, 33% yield) as a yellow solid. LCMS (m / z): 231.2 [M+H]+; H NMR (400 MHz, DMSO-d6) 8 7.64 (dd, J = 9.2, 2.8 Hz, 1H), 7.62 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 3.18 - 3.14 (m, 4H), 2.91 - 2.87 (m, 4H).4M HCI / dioxane, .DCM,H] 9RT 2h- QStep 3 NH

[0414] Step 1: To a solution of 6-bromocinnolin-4(lH)-one (200 mg, 0.889 mmol) tert-butyl 4- (4.4.5.5-tetramethyl-l,3.2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (329.74 mg, 1.0664 mmol), Pd(dppf)C12 (65.02 mg, 0.08887 mmol) and K2CO3 (245.6 mg, 1.777 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was stirred at 80 °C overnight under a N2atmosphere. The mixture was diluted with EtOAc (20 mL) and filtered. The solid was collected and dried to afford tert-butyl 4-(4-oxo-l,4- dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (186 mg, 63.9% yield) as a brown solid. LCMS (m / z): 328.2 [M+H]+.

[0415] Step 2: A solution of tert-butyl 4-(4-oxo-l,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate (186 mg, 0.565 mmol) and Pd / C (18.6 mg, 0.173 mmol) in CH3OH (2 m ) was stirred at 30 °C overnight under an H2atmosphere. The mixture was fdtered, and the fdtrate was concentrated to afford tert-butyl 4-(4-oxo-l,4-dihydrocinnolin-6-yl)piperi dine- 1 -carboxylate (110 mg, 58.8 % yield) as a grey solid. LCMS (m / z): 330.1 [M+H]+.

[0416] Step 3: To a solution of tert-butyl 4-(4-oxo-l,4-dihydrocinnolin-6-yl)piperidine-l-carboxylate (110 mg, 0.334 mmol) in DCM (2 mL) was added 4M HC1 in dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to afford 6-(piperidin-4- yl)cinnolin-4(lH)-one HC1 salt (88.0 mg, 98 % yield) as a grey solid. LCMS (m / z): 230.1 [M+H]+; 'H116410095-004WO (221364)BUSINESS.33570224 1NMR (400 MHz, DMSO-dfi) 5 13.64 (s, 1H), 9.23 - 8.68 (m, 2H), 7.87 - 7.83 (m, 1H), 7.78 - 7.66 (m, 2H), 7.66 - 7.61 (m, 1H), 3.38 (d, J = 12.6 Hz, 2H), 3.08 - 2.93 (m, 3H), 2.05 - 1.79 (m, 4H).Example 26 (1-48)

[0417] Step 1: To a solution of tert-butyl 5-(8-chloro-4-oxo-l,4,4a,8a-tetrahydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (200 mg, 0.5527 mmol, prepared as in example method 15) in dioxane (6 rnL) at room temperature was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (138.8 mg, 0.5527 mmol), K2CO3 (114.6 mg, 0.8291 mmol) and Pd(dppf)C12 (40.44 mg, 0.05527 mmol). The reaction was stirred at 100 °C under a N2 atmosphere overnight. Tire reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL><3). The combined organic phases were washed with water (30 mLx3), dried over Na2SC>4, fdtered and concentrated. The residue obtained was purified by prep-TLC (PE:EtOAc = 1: 1) to afford tert-butyl 5-(4-hydroxy-8-methylcinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (120 mg, 63.5%) as a white solid. LCMS (m / z): 683.2 [2M+H]+.

[0418] Step 2: A solution of tert-butyl 5-(4-hydroxy-8-methylcinnolin-6-yl)-3,6-dihydropyridine- l(2H)-carboxylate (78.3 mg, 0.229 mmol) in 4 M HCl / dioxane (2 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to 8-methyl-6-(l,2,5,6- tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride (45 mg, 81 % yield) as a yellowish solid. LCMS (m / z): 242.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 13.19 (s, 1H), 9.34 (brs, 2H), 7.82 (t, J = 7.6 Hz, 3H), 6.54 (s. 1H), 4.07 (s, 2H), 4.02-3.98 (m, 2H). 3.26 - 3.17 (m. 2H), 2.56 (s, 3H).117410095-004WO (221364)BUSINESS.33570224 1Example 27 (1-41)

[0419] Step 1: To a solution of l-(2-amino-5-iodophenyl)ethan-l-one (6.0 g, 23 mmol) in 6N HCI (60 mL) at 0 °C was added a solution ofNaNCh (1.65 g. 23.9 mmol) in water (20 mL) slowly. The mixture was stirred at 0 °C for 30 min and warmed to 65 °C for 3 h. The resulting precipitate was filtered, washed with water and the solid was dried under vacuum to afford 6-iodocinnolin-4(lH)-one (4.8 g, 76% yield) as a brown solid. LCMS (m / z): 273.0 [M+H]+.

[0420] Step 2: To a solution of 6-iodocinnolin-4(lH)-one (2 g, 7.4 mmol) in THF (30 mL) was added POCI3 (5.63 g, 36.8 mmol). The mixture was stirred at 70 °C for 40 min. The reaction solution was diluted with water (300 mL) and adjusted the pH = 7~8 with saturated sodium bicarbonate solution, extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to obtain 4-chloro-6-iodocinnoline (2.4 g, 70% yield) as a brown solid, which was used into the next step directly. LCMS (m / z): 290.9 [M+H]+.

[0421] Step 3: To a solution of 4-chloro-6-iodocinnoline (2.4 g, 8.3 mmol) in MeOH (30 mL) was added CHiONa (4.46 g, 24.8 mmol). The reaction mixture was stirred at 60 °C for 1 h. The reaction solution was diluted with water (300 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (200 mL), dried overNa2SO4, filtered and concentrated under reduced pressure to obtain the crude product. Tire residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 100: l~50: 1, v / v) to afford 6-iodo-4-methoxycinnoline (2 g, 85 % yield) as a brown solid. LCMS (m / z): 287.0 [M+H]1.118410095-004WO (221364)BUSINESS.33570224 1

[0422] Step 4: To a solution of t-BubpyCAMCN (94 mg 0.28 mmol) and NiBr2(dme) (86.4 mg, 0.280 mmol) in DMAc (2 mL) was added 6-iodo-4-methoxycinnoline (400 mg, 1.4 mmol), 1,3-dioxoisoindolin- 2-yl 3-((tcrt-butoxycarbonyl)amino)bicyclo[l.l.l]pcntanc-l-carboxylatc (782 mg, 2.10 mmol) and Zn(dust) (182 mg, 2.78 mmol) at room temperature. Hie reaction mixture was stirred at room temperature for 16 h under N2. The reaction solution was diluted with water (30 mL) and filtered, and the aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over NajSCL, filtered and concentrated under reduced pressure to obtain the crude product. The residue obtained was purified by column chromatography on silica gel (eluting with: DCM: Methanol = 80: 1-50: 1, v / v) and prep-HPLC (0.1% HCOOH-ACN, 62% ACN) to afford tert-butyl (3-(4- methoxycinnolin-6-yl)bicyclo[l.l. l]pentan-l-yl)carbamate (18 mg, 2.1 % yield) as a white solid. LCMS (m / z): 342.2 [M+H]1.

[0423] Step 5: To a solution of tert-butyl (3-(4-methoxycinnolin-6-yl)bicyclo[l.l. l]pentan-l- yl)carbamate (10 mg, 0.029 mmol) in DCM (0.5 mL) was added 4 M HC1 in 1,4-dioxane (0.5 mL). The mixture was stirred at room temperature for 1 h. Tire reaction mixture was concentrated, and the residue was dissolved in methanol (2 mL). Tire mixture solution was added 6N HC1 (2 mL) and stirred at 40 °C for 16 h. Tire reaction solution was concentrated to afford 6-(3-aminobicyclo[l.l.l]pentan-l-yl)cinnolin- 4(lH)-one hydrochloride (1.6 mg. 20% yield) as a grey solid. LCMS (m / z): 228.0 [M+H]+. 'H NMR (400 MHz, DMSO-de) 8 13.62 (s, 1H), 8.78 (brs, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.76-7.74 (m, 2H), 7.60 (d, J = 8.6 Hz, 1H), 2.34 (s, 6H).Example 28 (1-49)

[0424] Step 1: A solution of tert-butyl 5-(8-chloro-4-oxo-l,4,4a.8a-tetrahydrocinnolin-6-yl)-3,6- dihydropyridine-l (2H)-carboxylate (50 mg, 0.14 mmol, prepared as in example method 15), Pd(dppf)C12 (10.11 mg, 0.01382 mmol), C2H3BF3K (22.21 mg, 0.1658 mmol), triethylamine (13 mg, 0.14 mmol) in IPA119410095-004WO (221364)BUSINESS.33570224 1(1.5 mL) was stirred at 130 °C overnight under a N2atmosphere in sealed tube. The reaction mixture w as diluted with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water (50 mL x 3) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by prep-TLC (PE: EtOAc=l: l) to afford tert-butyl 5-(4-oxo-8-vinyl-l,4,4a,8a- tetrahydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (18.0 mg, 37.5 %) as a yellow solid. LCMS (m / z): 707.2 [2M+H]+.

[0425] Step 2: To a solution of tert-butyl 5-(4-oxo-8-vinyl-l,4,4a,8a-tetrahydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxylate (100 mg, 0.283 mmol) in MeOH (2 mL) was added Pd / C (10 mg, 0.094 mmol). Tire mixture was stirred at 30 °C for 2h under a H2atmosphere. The mixture was filtered and concentrated, purified by prep-HPLC (40% MeCN in water (0.1% HCOOH)) to afford tert-butyl 5-(8-ethyl- 4-oxo-1.4-dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (30 mg, 29.8 %) as a white solid. LCMS (m / z): 356.1 [M+H]+.

[0426] Step 3: To a solution of tert-butyl 5-(8-ethyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine -1(2H) -carboxylate (50 mg, 0.1406 mmol) in DCM (2 mL) was added 4 M HC1 in dioxane (2 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture as concentrated under vacuum to afford 8-ethyl-6-(l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one hydrochloride (24.6 mg, 68.4 % yield) as a yellow solid. LCMS (m / z): 256.1 [M+H]+. 'H NMR (400 MHz. DMSO-de) 5 13.22 (s, 1H), 9.40 - 9.31 (m, 2H), 7.82 (d, J = 3.0 Hz, 3H), 6.65 - 6.45 (m, 1H), 4.12 - 4.04 (m, 2H), 3.57 - 3.52(m, 2H), 3.27 - 3.15 (m, 2H), 2.98 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H).Example 29 (1-53 & 1-54)BocEluting fraction 1 & 2 From eluting fraction 1 & 2120410095-004WO (221364)BUSINESS.33570224 1

[0427] Step 1 : A solution of 6-bromocinnolin-4( lH)-one (2 g, 9 mmol), K2CO3 (9.82 g, 71.2 mmol) and Mel (7.58 g, 53.4 mmol) in DMF (150 mL) was stirred at room temperature overnight. Tire reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). Tire combined organic phases were washed with water (3 x 200mL) and brine (200 mL), dried over TsfeSCL, fdtered and concentrated. The residue was purified by column (PE / EA=5: 1 to 3: 1) to afford 6-bromo-l-methylcinnolin- 4(lH)-one (910 mg, 39 % yield) as a yellow solid. LCMS (m / z): 239.0 [M+H]+.

[0428] Step 2: A mixture of 6-bromo-l-methylcinnolin-4(lH)-one (740 mg, 3.11 mmol), B2(pin)2 (1.58 g, 6.22 mmol), Pd(dppf C12 (113.8 mg, 0.1554 mmol) and KOAc (610.36 mg, 6.2193 mmol) in dioxane (20 mL) was stirred at 90 °C overnight under N2 in sealed tube. The mixture was concentrated, and the residue was used to the next step directly. LCMS (m / z): 287. 1 [M+H]+.

[0429] Step 3: A mixture of tert-butyl 5-bromo-3-methyl-3,6-dihydropyridine-l(2H)-carboxylate (434.4 mg, 1.573 mmol, prepared as in example method 21), l-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cinnolin-4(lH)-one (1.24 g, 4.33 mmol), XphosPdG3 (66.6 mg, 0.0786 mmol) and K3PO4 (1.0 g, 4.7 mmol) in dioxanc / I FO (20 mL / 4 mL) was stirred at 100 °C overnight under an N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x 100 mL). The combined organic phases were washed with brine ( 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The mixture was purified by prep-TLC (DCM / MeOH=30: l) to afford tert-butyl 3-methyl-5-( 1 -methyl-4-oxo-l ,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine- 1 (2H)- carboxylate (520 mg, 93% yield) as a yellow solid. The racemic mixture of tert-butyl 3 -methyl-5 -( 1 -methyl - 4-oxo-l,4-dihydrocinnolin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate (520 mg) was purified by chiral HPLC to separate the enantiomers. (Column: Daicel AD (20 mm x 250 mm, 10 pm); Mobile Phase A: Liquid CO2. Mobile Phase B: MeOH; Flow rate: 55 mL / min; Gradient: 75% Afor 8 mins; Wavelength: 214 nm; Sample Solvent: MeOH (10 mL), Injection volume: 0.2 mL). Analytical chiral HPLC (Column: Daicel AD (3 mm x 100mm, 3pm); Mobile Phase A: Liquid CO2, Mobile Phase B: MeOH; Flow rate: 1 mL / min; Gradient: 75 % A for 5 mins; Wavelength: 214 nm; RT1 = 3.235 min, RT2 = 3.551 min). Eluting fraction 1: 70 mg, yellow solid; LCMS (m / z): 356.1 [M+H]+. Eluting fraction 2: 70 mg, yellow solid; LCMS (m / z): 356.1 [M+H]+.

[0430] Step 4: A mixture of tert-butyl 3-methyl-5-(l-methyl-4-oxo-l,4-dihydrocinnolin-6-yl)-3,6- dihydropyridine-l(2H) -carboxy late eluting fraction 1 from step 3 (70 mg, 0.20 mmol) in HCl / dioxane (4M, 2mL) / DCM (2 mL) was stirred at room temperature for 2 hours. The mixture was directly concentrated to afford l-methyl-6-(5-methyl-l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one (1-53, 40.1 mg, HC1 salt) as a yellow solid. LCMS (m / z): 256.1 [M+H]+. ’HNMR (400 MHz, DMSO-de) 8 9.71 - 9.39 (m, 2H), 8.14121410095-004WO (221364)BUSINESS.33570224 1- 7.96 (m, 2H), 7.87 - 7.71 (m, 2H), 6.47 (d, J = 2.4 Hz, 1H), 4.16 - 4.07 (m, 5H), 3.45 - 3.33 (m, 1H), 2.90 - 2.67 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H).

[0431] The same procedure was applied to eluting fraction 2 (70 mg, 0.20 mmol) from step 3. From eluting fraction 2: l-methyl-6-(5-methyl-l,2,5,6-tetrahydropyridin-3-yl)cinnolin-4(lH)-one (1-54, 51.4 mg, HC1 salt) as a yellow solid. LCMS (m / z): 256.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 9.84 - 9.30 (m, 2H), 8.10 - 8.04 (m, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.83 - 7.74 (m, 2H), 6.50 - 6.43 (m, 1H), 4.22- 4.07 (m, 5H), 3.48 - 3.33 (m, 1H), 2.88 - 2.69 (m, 2H), 1.15 (d, J = 6.6 Hz, 3H).Example 30: h5-HT2A Receptor Calcium Assay

[0432] 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.

[0433] Data analysis was performed using Dotmatics. Briefly, data was nonnalized 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.

[0434] h5-HT2A Receptor Calcium Assay results are shown in Table 2. Tire letter codes for pECso include: Tire letter codes for pECso include: A (>6); B (>5 - 6); and C (<5). Hie letter codes for Emax % include: A (>90%); B (>70 - 90%); C (>50 - 70%); and D (<50%).Table 2. h5-HT2A Receptor Calcium Assay Results122410095-004WO (221364)BUSINESS.33570224 1123410095-004WO (221364)BUSINESS.33570224 1Example 31: h5-HT2A Receptor NanoBiT / 0- Arrestin Assay

[0435] 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. The 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 30.Example 32: h5-HT2B Receptor Calcium Assay

[0436] HEK cells over expressing human 5-HT2B receptor are trypsinizcd, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per w ell and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pl assay buffer (20 rnM 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. Tire 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 arc 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 30.Example 33: h5-HT2C Receptor Calcium Assay

[0437] 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 ex / em: 488 nm / 510-570 nm in order to monitor compounds as 124410095-004WO (221364)BUSINESS.33570224 1agonists. 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 30.Example 34: m5-HT2A Receptor Calcium Assay

[0438] 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: EIBSS, 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 perfomied in 100% DMSO then transferred to intennediate 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 perfomied as described in Example 30.Example 35: Head Twitch Response and Locomotor Activity in mice.

[0439] The 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. Hie response is a rapid, sidc-to-sidc 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 Behav 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 betw een the potency of hallucinogens in the mouse hcad-twitch response assay and their behavioural and subjective effects in other species. Neuropharmacology. 2020; 167: 107933. Whole brain and plasma samples are collected for drug metabolism and pharmacokinetics (DMPK).

[0440] Sixty (60) male C57BL / 6J mice (8-9 weeks 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 arc 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.125410095-004WO (221364)BUSINESS.33570224 1

[0441] The number of head twitches are counted by a trained observer who is blind to treatment, and sessions are recorded using video capture equipment (Ethovision v!7) for a period of time post dosing. The locomotor activity of all groups is measured using the Ethovision system. Other behaviours of note arc 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.

[0442] Terminal plasma', following confirmation of death, as much blood as possible is removed from the animal to individual K3EDTA tubes, which are 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.

[0443] Brairr. 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.

[0444] 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.Example 36: Forced Swim Test in mice.

[0445] 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 Arc Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression. Front Psychiatry 2021, 11, 599588.126410095-004WO (221364)BUSINESS.33570224 1

[0446] 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.

[0447] 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 the minimum 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).

[0448] The 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. Tire 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.Example 37: Chronic Social Defeat Methodology.

[0449] 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 tire 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.

[0450] 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 min 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- 1 mouse is placed in the perforated cylinder (“target present”). Tire “interaction zone” is defined as the area127410095-004WO (221364)BUSINESS.33570224 1surrounding the perforated cylinder. The social preference score is calculated by dividing the time spent in the “interaction zone” when the target is present by the time spent in the “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 are 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 drag administration with either 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 drag effect on social avoidance. Then, all groups are submitted to the 3rd SP test (mild) to assess the long-tenn drug effect on social avoidance on Day 21 or 28. Body weight and animal welfare are monitored daily.128410095-004WO (221364)BUSINESS.33570224 1

Claims

CLAIMS1. A compound of formula I” :i” or a pharmaceutically acceptable salt thereof, wherein: each independently is a single or double bond as allowed by valency:X1is N, NR, CR1, or C=O:X2is N, NR, or CR2;X3is N, NR, or CR3;X4is N, NR, CR4, or C=O;X5is N or CR5;X6is N or CR6;X7is N or CR7; wherein at least one of X1and X2is N or NR; each of R1, R2, R3, R4, R5, R°, and R7is independently selected from hydrogen, halogen, -CN, -ORA, -NR2, -C(O)R, -C(0)NR2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from C1-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;RAis hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R8is hydrogen or optionally substituted Ci-6 aliphatic, each R9is independently selected from halogen, -CN, -OR, -NR?, or an optionally substituted Cue aliphatic; or an R8and an R9group 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or129410095-004WQ (221364)BUSINESS.33570224 1two 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;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 4- to 6-membered monocyclic heterocyclyl having one or two nitrogen heteroatoms, 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;X8is N, CH, or Ci-e aliphatic;L1is a covalent bond or an optionally substituted bivalent C1.3 saturated or unsaturated, straight or branched, hydrocarbon chain; n is 0, 1. 2, 3, 4, 5. 6, or 7; and each R is independently hydrogen or optionally substituted C1-6 aliphatic.(R9)Tire compound of claim 1, wherein R10isTire compound of claim 1 or 2, wherein RingThe compound of any one of claims 1-3, wherein the compound is of formula I”-A:130410095-004WO (221364)BUSINESS.33570224 1I”-A or a pharmaceutically acceptable salt thereof.The compound of claim 1, wherein R10isTire compound of claim 1 or 5, wherein RingTire compound of claim 1 or 5, wherein Ring8. The compound of any one of claims 1 or 5-7, wherein the compound is of formulae I”-B1 or I”-B2:or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is of formula I’:I’131410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof, wherein: each independently is a single or double bond as allowed by valency;X1is N, NR, CR1, or C=O;X2is N, NR, or CR2;X3is N, NR, or CR3;X4is N, NR, CR4. or C=O;X5is N or CR5;X6is N or CR6;X7is N or CR7; wherein at least one of X1and X2is N or NR; each of R1, R2, R3. R4, R5, R6, and R7is independently selected from hydrogen, halogen, -CN, -ORA. -NR2, -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;RAis hydrogen or an optionally substituted group selected from Ci-e aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;R8is hydrogen or optionally substituted Ci.e aliphatic, each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; or an R8and an R9group may be taken together to fonn 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two 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; n is 0, 1, 2, 3, 4, 5, 6, or 7; and each R is independently hydrogen or optionally substituted Ci-e aliphatic.

10. The compound of any one of claims 1-9, wherein X1is C=O.132410095-004WO (221364)BUSINESS.33570224 111. The compound of any one of claims 1-9, wherein X1is NR.

12. Tire compound of any one of claims 1-11, wherein X4is C=O.

13. The compound of any one of claims 1, 8. or 9, wherein the compound is of formulae Il-al or II- bl:ILal Il-bl or a pharmaceutically acceptable salt thereof.

14. The compound of anyone of claims 1, 8, or 9, wherein the compound is of formula I:or a pharmaceutically acceptable salt thereof, wherein:X1is N or CR1;X2is N or CR2;X3is N or CR3;X is N or CR4;X5is N or CR5;X6is N or CR6;X7is N or CR7; wherein at least one of X1and X2is N; each of R1, R2, R3, R4, R5, R6, and R7is independently selected from hydrogen, halogen, -CN, -ORA. -NR2,133410095-004WO (221364)BUSINESS.33570224 1-C(O)R, -C(O)NR.2, -C(O)OR, -NRC(O)R, -OC(O)R, or an optionally substituted group selected from Ci-6 aliphatic, a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;RAis 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;R8is hydrogen or optionally substituted Ci-e aliphatic, each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic; or an R8and an R9group 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 two R9groups on the same atom may be taken together to form an optionally substituted 3- to 8- membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two 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; n is 0, 1, 2, 3, 4, 5, 6, or 7; and each R is independently hydrogen or optionally substituted Ci-e aliphatic.

15. The compound of any one of claims 1-9, or 14, wherein X1is N.

16. The compound of any one of claims 1-9, or 14, wherein X1is CR1.

17. Tire compound of any one of claim 1-16, wherein X2is N.

18. The compound of any one of claim 1-16, wherein X2is CR2.

19. The compound of any one of claims 1, 4, 8, 9, or 14, wherein the compound is of formulae II-a,Il-b, or II-c:134410095-004WO (221364)BUSINESS.33570224 1II-c or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19, wherein the compound is of fonnulae IV-a. IV-b. or IV-c:or a pharmacally acceptable salt thereof.

21. The compound of any one of claims 1-20. wherein X3is N.135410095-004WO (221364)BUSINESS.33570224 122. The compound of any one of claims 1-20, wherein X3is CR3.

23. Tire compound of any one of claims 1-9, or 14-20, wherein X4is N.

24. The compound of any one of claims 1-9, or 14-20, wherein X4is CR4.

25. The compound of any one of claim 1, 8, 9, or 13, wherein the compound is of formulae of IV-d,IV-e, IV-f, or IV-g:or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-25. wherein X3is N.

27. The compound of any one of claims 1-25, wherein X5is CR5.

28. Tire compound of any one of claims 1-27, wherein X6is N.

29. The compound of any one of claims 1-27. wherein X6is CR6.136410095-004WO (221364)BUSINESS.33570224 130. The compound of any one of claims 1-29, wherein X7is N.

31. Tire compound of any one of claims 1-29, wherein X7is CR7.

32. The compound of any one of claims 1, 4, 8, 9. 14, or 19, wherein the compound is of formulae V- a, V-b, V-c, V-d, V-e, V-f. or V-g:137410095-004WO (221364)BUSINESS.33570224 1V-g or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1, 8, 9, 13, or 25, wherein the compound is of formulae of VII- h, VTI-i, Vll-j, VH-k, VII-1, or Vll-m:138410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1-33, wherein n is 0.

35. The compound of any one of claims 1-34, wherein R8is hydrogen.

36. The compound of any one of claims 1-34, wherein R8is Cue aliphatic.

37. Tire compound of any one of claims 1-33, wherein an R8and an R9group are 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.

38. The compound of any one of claims 1-33 or 35-36, wherein two R9groups on the same atom are taken together to form an optionally substituted 3- to 8-membered saturated or partially unsaturated spirocarbocyclyl or spiroheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

39. The compound of any one of claims 1-33 or 35-36, 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.

40. The compound of any one of claims 1, 8, 9.

13. or 25. w herein the compound is of formulae IX-a,139410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof.

41. The compound of clam 40, wherein the compound is of formulae X-a, X-b. X-c, X-d. X-e, X-f. orX-g140410095-004WO (221364)BUSINESS.33570224 1X-g or a pharmaceutically acceptable salt thereof.

42. The compound of any one of claims 1, 8. 9, 13, 25, or 33, wherein the compound is of formulae141410095-004WO (221364)BUSINESS.33570224 1or a pharmaceutically acceptable salt thereof.

43. The compound of any one of claims 1-42, wherein each of R1, R2, R3, R4, R’, R . and R7is independently selected from hydrogen, halogen, -CN, -ORA, -NR2, -C(O)R, -C(O)NR2, -C(O)OR, - NRC(O)R, -OC(O)R, or optionally substituted Ci-g aliphatic.

44. The compound of any one of claim 1-9, 12, 14, 16-24, 26-32, 34-41, or 43. wherein R1is hydrogen.

45. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41, or 43, wherein R1is fluoro or chloro.

46. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41, or 43, wherein R1is -CN.

47. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41. or 43. wherein R1is -ORA.

48. The compound of claim 47, wherein RAof R1is hydrogen or an optionally substituted Ci-e aliphatic.

49. The compound of claim 48, wherein RAof R1is Ci-6 aliphatic optionally substituted with halogen.

50. The compound of any one of claims 1-9, 12, 14. 16-24, 26-32, 34-41. or 43. wherein R1is -NR2.142410095-004WO (221364)BUSINESS.33570224 151. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41, or 43, wherein R1is - C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

52. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41, or 43, wherein R1is optionally substituted Cue aliphatic.

53. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41, or 43, wherein R1is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

54. The compound of any one of claims 1-9, 12, 14, 16-24, 26-32, 34-41, or 43, wherein R1is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, or.

55. The compound of any one of claim 1-54, wherein R2is hydrogen.

56. The compound of any one of claims 1-54, wherein R2is fluoro or chloro.

57. Tire compound of any one of claims 1-54, wherein R2is -CN.

58. The compound of any one of claims 1-54. wherein R2is -ORA.

59. The compound of claim 58, wherein RAof R2is hydrogen or an optionally substituted Cue aliphatic.

60. Tire compound of claim 59, wherein RAof R2is Cue aliphatic optionally substituted with halogen.

61. The compound of any one of claims 1-54. wherein R2is -NR2.

62. The compound of any one of claims 1-54, wherein R2is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.143410095-004WO (221364)BUSINESS.33570224 163. The compound of any one of claims 1-54, wherein R2is optionally substituted Ci .6 aliphatic.

64. The compound of any one of claims 1-54, wherein R2is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

65. The compound of any one of claims 1-54, wherein R2is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl,66. The compound of any one of claim 1-65, wherein R3is hydrogen.

67. The compound of any one of claims 1-65, wherein R3is fluoro or chloro.

68. Tire compound of any one of claims 1-65, wherein R3is -CN.

69. The compound of any one of claims 1-65. wherein R3is -ORA.

70. The compound of claim 69, wherein RAof R3is hydrogen or an optionally substituted Ci-e aliphatic.

71. Tire compound of claim 70, wherein RAof R3is C1-6 aliphatic optionally substituted with halogen.

72. The compound of any one of claims 1-65. wherein R3is -NR2.

73. The compound of any one of claims 1-65, wherein R3is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

74. The compound of any one of claims 1-65. wherein R3is optionally substituted Ci-6 aliphatic.

75. The compound of any one of claims 1-65, wherein R3is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3144410095-004WO (221364)BUSINESS.33570224 1heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

76. Tire compound of any one of claims 1-65, wherein R3is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCHs. -OCH2CH3, -OCF3, methyl, ethyl,77. The compound of any one of claim 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is hydrogen.

78. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is fluoro or chloro.

79. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is -CN.

80. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is -NR2.

81. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

82. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is optionally substituted C1-6 aliphatic.

83. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.145410095-004WO (221364)BUSINESS.33570224 184. The compound of any one of claims 1-11, 14-19, 21, 22, 24, 26-32, 34-41, or 43-76, wherein R4is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, or85. The compound of claim 20 or 41, wherein R ' is hydrogen or an optionally substituted Cue aliphatic.

86. The compound of claim 85, wherein RAis C1-6 aliphatic optionally substituted with halogen.

87. Tire compound of any one of claim 1-86, wherein R5is hydrogen.

88. The compound of any one of claims 1-86, wherein R5is fluoro or chloro.

89. The compound of any one of claims 1-86, wherein R5is -CN.

90. Tire compound of any one of claims 1-86, wherein R5is -ORA.

91. The compound of claim 90, wherein RAof R’ is hydrogen or an optionally substituted C1-6 aliphatic.

92. The compound of claim 91, wherein RAof R5is C1-6 aliphatic optionally substituted with halogen.

93. Tire compound of any one of claims 1-86, wherein R5is -NR2.

94. The compound of any one of claims 1-86, wherein R5is -C(O)NR2. -C(O)OR, -NRC(O)R, or - OC(O)R.

95. The compound of any one of claims 1-86, wherein R5is optionally substituted Ci-e aliphatic.

96. Tire compound of any one of claims 1-86, wherein R5is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.146410095-004WO (221364)BUSINESS.33570224 197. The compound of any one of claims 1-86, wherein R3is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl,98. Hie compound of any one of claim 1-97, wherein R6is hydrogen.

99. The compound of any one of claims 1-97, wherein Rbis fluoro or chloro.

100. Tire compound of any one of claims 1-97, wherein R6is -CN.

101. The compound of any one of claims 1-97, wherein R6is -ORA.

102. The compound of claim 101, wherein RAof R6is hydrogen or an optionally substituted Cue aliphatic.

103. Hie compound of claim 102, wherein RAof R6is Ci-e aliphatic optionally substituted with halogen.

104. The compound of any one of claims 1-97. wherein R6is -NR2.

105. The compound of any one of claims 1-97, wherein R6is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

106. The compound of any one of claims 1-97. wherein R6is optionally substituted Ci-6 aliphatic.

107. The compound of any one of claims 1-97, wherein R is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

108. The compound of any one of claims 1-97, wherein R6is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl,147410095-004WO (221364)BUSINESS.33570224 1109. The compound of any one of claim 1-108, wherein R7is hydrogen.

110. Tire compound of any one of claims 1-108, wherein R7is fluoro or chloro.

111. The compound of any one of claims 1-108, wherein R7is -CN.

112. The compound of any one of claims 1-108, wherein R7is -ORA.

113. Tire compound of claim 112, wherein RAof R7is hydrogen or an optionally substituted Ci-e aliphatic.

114. The compound of claim 113, wherein RAof R7is Ci-6 aliphatic optionally substituted with halogen.

115. The compound of any one of claims 1-108, wherein R7is -NR2.

116. The compound of any one of claims 1-108, wherein R7is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

117. The compound of any one of claims 1-108, wherein R7is optionally substituted Ci.e aliphatic.

118. Tire compound of any one of claims 1-108, wherein R7is an optionally substituted group selected from a 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, and a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

119. The compound of any one of claims 1-108, w herein R7is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3. methyl, ethyl,120. The compound of claim 1, wherein the compound is of Table 1, or a pharmaceutically acceptable salt thereof.148410095-004WO (221364)BUSINESS.33570224 1121. A pharmaceutical composition comprising a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

122. Amethod 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 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.

123. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a 0-arrestin signaling pathway associated with 5-HT2AR in a biological sample, comprising administering to the biological sample a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.

124. 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 1-120, or a pharmaceutically acceptable salt thereof, or a pharmacal composition of claim 121.

125. A method of activating 5-HT2AR, or a mutant thereof, in a patient comprising administering a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.

126. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a 0-arrestin signaling pathway associated with 5-HT2AR in a patient in need thereof, comprising administering to the patient a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.

127. 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 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.

128. A method for treating a 5-HT2AR-mediated disorder comprising administering to a patient a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.149410095-004WO (221364)BUSINESS.33570224 1129. A method for treating a neurological disease, disorder, or condition comprising administering to a patient a compound of any one of claims 1-120, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 121.

130. The method of claim 129, wherein neurological disease, disorder, or condition is depression, anxiety, substance abuse, and headaches.

131. The method of any one of claims 125-130, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.150410095-004WO (221364)BUSINESS.33570224 1

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