4-(1,2,3,6-tetrahydropyridin-4-YL)quinoline derivatives and similar compounds as 5-HT2ar activators for the treatment of neurological diseases

Abstract

The present disclosure relates to compounds of formula (I) useful for activating the 5-hydroxytryptamine 2A receptor (5-HT2AR) for the treatment of neurological diseases, such as e.g. depression, anxiety, substance abuse or headaches. Preferred compounds are e.g. compounds of the following formulae (II), (III), (iv).

Description

4-(1,2,3,6-TETRAHYDROPYRIDIN-4-YL)QUINOLINE DERIVATIVES AND SIMILAR COMPOUNDS AS 5-HT2AR ACTIVATORS FOR THE TREATMENT OF NEUROLOGICAL DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U. S. Provisional Application No.63 / 750,020, filed January 27, 2025, the contents of which is 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 pharmaceuticals 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, are effective as agonists of 5-HT2AR. In some embodiments, the present disclosure provides a compound of formula I:Page 1 of 79BTBV-006 360491-2034 329826723or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

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

[0008] Compounds of the present invention, and pharmaceutical 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:R1°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.Page 2 of 79BTBV-006 360491-2034 329826723

[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 patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

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

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

[0015] In another aspect, the present disclosure provides methods of treating and / or preventing a 5-HT2AR-mediated disorder in a patient in need thereof, and / or methods of activating the 5-hydroxytryptamine 2A receptor (5-HT2AR) in a patient in need thereof, comprising administering to the patient a provided compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, 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 Page 3 of 79BTBV-006 360491-2034 329826723that 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, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C;-C„ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of 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:Page 4 of 79BTBV-006 360491-2034 329826723

[0019] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary 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 form 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-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0021] The term "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, alkenylene, and alkynylene chains that are 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 “cyclopropylenyl” refers to a bivalent cyclopropyl group of thefollowing structure:

[0026] The term “halogen” means F, Cl, Br, or I.

[0027] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “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 Page 5 of 79BTBV-006 360491-2034 329826723contains 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 the like. The term “arylenyl” refers to bivalent aryl groups (e.g., phenylenyl).

[0028] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.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, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, 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 term “heteroarylenyl” refers to bivalent heteroaryl groups (e.g., pyridylenyl).

[0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H- pyrrolyl). NH (as in pyrrolidinyl), or+NR (as in ' substituted pyrrolidinyl).

[0030] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom Page 6 of 79BTBV-006 360491-2034 329826723that 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, H- 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. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[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” applies to one or more hydrogens that are either explicit or implicit from the structureUnless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0033] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)N 4R°: -(CH2)„4OR°: -O(CH2)0.4R°, -O-(CH2)0_ 4C(O)OR°; — (CH2)O ^CH(OR°)2; -(CH2)O^SR°; -(CH2)o ^Ph, which may be substituted with R°; -Page 7 of 79BTBV-006 360491-2034 329826723(CH2)-) ^0(CH2)o -1 Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o^O(CH2)o 1 -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)N 4N(R°)2:-(CH2)O^N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O4N(R°)C(0)NRO2: -N(RO)C(S)NR°2; -(CH2)O4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)O4C(0)RO; -C(S)R°; -(CH2)O4C(0)0RO: -(CH2)O4C(0)SRO: -(CH2)O4C(O)OSIR°3: -(CH2)„40C(0)RO: -OC(0)(CH2)O4S R°; -(CH2)O 4SC(0)RO: -(CH2)O 4C(0)NRO2: -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)„40C(0)NRO2: -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)„4SSRO: -(CH2)O4S(0)2RO: -(CH2)O4S(0)20RO: -(CH2)O40S(0)2RO: -S(O)2NR°2; -(CH2)O4S(0)RO: -N(R°)S(0)2NRO2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -(CH2)„4P(0)2RO: -(CH2)O4P(0)RO2: -(CH2)O40P(0)RO2: -(CH2)O4OP(O)(OR°)2: SiR°3; -(CMstraight or branched alkylene)O-N(R°)2; or -(Ci^ straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C 1 <> aliphatic, -CH2Ph, -O(CH2)0-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 formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o2R*, -(haloR*), -(CH2)0 2OH, -(CH2)O 2OR", -(CH2)O 2CH(OR’)2; -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R", -(CH2)0 2C(O)OH, -(CH2)O 2C(O)OR‘. -(CH2)O 2SR", -(CH2)O 2SH, -(CH2)O 2NH2, -(CH2)O 2NHR‘. -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, -C(O)SR* - (Ci^ 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 Ci^ aliphatic, -CH2Ph, -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, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent Page 8 of 79BTBV-006 360491-2034 329826723occurrence of R* is selected from hydrogen, Ci-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.

[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*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci^ aliphatic, -CH2Ph, -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)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -SCO^NR^, -C(S)NRt2, -C(NH)NRt2, or -N(R' )S(O)2R': wherein each R' is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, 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 aryl mono- or bicyclic ring having 0-4 heteroatoms 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 Ci^ aliphatic, -CH2Ph, -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.

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

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C’i 4alkyl) 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 Page 9 of 79BTBV-006 360491-2034 329826723art.

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

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

[0043] In some embodiments, the present invention provides a compound of formula I:R1°or a pharmaceutically acceptable salt thereof, wherein:is a single or double bond as allowed by valency;X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4;X5is N or CR5;X6is N or CR6;X7is N or CR7;Page 10 of 79BTBV-006 360491-2034 329826723X8is N, C, or CR8;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 C1-6aliphatic, 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;Ring B is a saturated or partially unsaturated 5 -membered monocyclic heterocyclyl having 1 nitrogen heteroatom, a saturated or partially unsaturated 6- to 7-membered monocyclic heterocyclyl having 1-2 nitrogen heteroatoms, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic having 1-2 nitrogen heteroatoms, or a saturated or partially unsaturated 5- to 9-membered fused or bridged bicyclic heterocyclyl having 1-2 nitrogen heteroatoms;R8and R10are independently hydrogen or optionally substituted C1-6 aliphatic;each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted Ci-e aliphatic;n is 0, 1, 2, 3, 4, 5, 6, or 7; andeach R is independently hydrogen or optionally substituted C1-6 aliphatic.

[0044] As defined above and described herein, X1is N or CR1. In some embodiments, X1is N. In some embodiments, X1is CR1.

[0045] As defined above and described herein, X2is N or CR2. In some embodiments, X2is N. In some embodiments, X2is CR2.

[0046] As defined above and described herein, X3is N or CR3. In some embodiments, X3is N. In some embodiments, X3is CR3.

[0047] As defined above and described herein, X4is N or CR4. In some embodiments, X4is N. In some embodiments, X4is CR4.

[0048] As defined above and described herein, X5is N or CR5. In some embodiments, X5is N. In some embodiments, X5is CR5.

[0049] As defined above and described herein, X6is N or CR6. In some embodiments, X6is N. In some embodiments, X6is CR6.

[0050] As defined above and described herein, X7is N or CR7. In some embodiments, X7is N. In some embodiments, X7is CR7.

[0051] As defined above and described herein, X8is N, C, or CR8. In some embodiments, X8is N. In some embodiments, X8is C. In some embodiments, X8is CR8.Page 11 of 79BTBV-006 360491-2034 329826723

[0052] As defined above and described herein, = is a single or double bond. In some embodiments, is a single bond. In some embodiments, is a double bond.

[0053] As defined above and described herein, Ring B is a saturated or partially unsaturated 5-membered monocyclic heterocyclyl having 1 nitrogen heteroatom, a saturated or partially unsaturated 6- to 7-membered monocyclic heterocyclyl having 1-2 nitrogen heteroatoms, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic having 1-2 nitrogen heteroatoms, or a saturated or partially unsaturated 5- to 9-membered fused or bridged bicyclic heterocyclyl having 1-2 nitrogen heteroatoms. It will be appreciated that the 1-2 nitrogen atoms present in Ring B includes the depicted ring nitrogen atom in Formula I to which R10is attached.

[0054] In some embodiments, Ring B is a saturated or partially unsaturated 5-membered monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having 1-2 nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 6-membered monocyclic heterocyclyl having 2 nitrogen heteroatoms. In some embodiments, Ring B is 1,2,3,6-tetrahydropyridinyl.R10

[0055] In some embodiments, RingB is In some embodiments, Ring B isR10R10In some embodiments, Ring B is

[0056] In some embodiments, Ring Bis R10R10In some embodiments, Ring B is. In some embodiments, Ring B is R10Page 12 of 79BTBV-006 360491-2034 329826723

[0057] In some embodiments, Ring B is a saturated or partially unsaturated 7-membered monocyclic heterocyclyl having 1-2 nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 7-membered monocyclic heterocyclyl having 1 nitrogen heteroatom. In some embodiments, Ring B is a saturated or partially unsaturated 7-membered monocyclic heterocyclyl having 2 nitrogen heteroatoms. In some embodiments, Ring B is 1,4-diazepanyl.R10( -j-(R9)

[0058] In some embodiments, RingB is —

[0059] In some embodiments, Ring B is a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic having 1-2 nitrogen heteroatoms. In some embodiments, Ring B is a saturated or partially unsaturated 5- to 9-membered fused or bridged bicyclic heterocyclyl having 1-2 nitrogen heteroatoms.

[0060] 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 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.

[0061] In some embodiments, each of R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ is independently selected from hydrogen, halogen, -CN, -OR^A, -NR₂, -C(O)R, -C(O)NR₂, -C(O)OR, -NRC(O)R, -OC(O)R, or optionally substituted C₁₋₆ aliphatic.

[0062] 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 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.

[0063] 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 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, 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.e 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, - Page 13 of 79BTBV-006 360491-2034 329826723ORA, -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 aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0064] 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 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.

[0065] 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.

[0066] In some embodiments, R1is -ORA. In some embodiments, R1is -OH. In some embodiments, R¹ is -OCH₃. In some embodiments, R¹ is -OCH₂CH₃. In some embodiments, R¹ is -OCH₂F. In someembodiments, R1is -OCHF2. In some embodiments, R1is -OCF3. In some embodiments, R1is

[0067] In some embodiments, R1is -NR2. In some embodiments, R1is -NH2. In some embodiments, R1is -NR2, wherein each R is independently Ci-e aliphatic.

[0068] 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 Ci-6 aliphatic.

[0069] 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.

[0070] In some embodiments, R1is -NRC(O)R. In some embodiments, R1is -NHC(O)R, wherein R is Ci-6 aliphatic. In some embodiments, R1is -NRC(O)H, wherein R is Ci-6 aliphatic. In some embodiments, R1is -NRC(O)R, wherein each R is independently Ci-6 aliphatic.

[0071] 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-6 aliphatic.

[0072] In some embodiments, R1is optionally substituted Ci-6 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.

[0073] In some embodiments, R1is Ci-6 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. InPage 14 of 79BTBV-006 360491-2034 329826723some embodiments, R1is -CH₂CF₃. In some embodiments, R1is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R1is -CH2OH.

[0074] 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 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0075] In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R1is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R1is an optionally substituted cyclopropyl. In some embodiments, R1is an optionally substituted cyclobutyl. In some embodiments, R1is an optionally substituted cyclopentyl. In some embodiments, R1is an optionally substituted cyclohexyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclobutyl. In some embodiments, R1is cyclopentyl. In some embodiments, R1is cyclohexyl.

[0076] 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.

[0077] 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.

[0078] 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, methyl, and ethyl.

[0079] 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-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.

[0080] 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-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 Page 15 of 79BTBV-006 360491-2034 329826723heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 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 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, 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 aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] 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, R² 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.

[0082] 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.

[0083] In some embodiments, R² is -OR^A. In some embodiments, R² is -OH. In some embodiments, R² is -OCH₃. In some embodiments, R² is -OCH₂CH₃. In some embodiments, R² is -OCH₂F. In someembodiments, R² is -OCHF₂. In some embodiments, R² is -OCF₃. In some embodiments, R2is

[0084] In some embodiments, R² is -NR₂. In some embodiments, R² is -NH₂. In some embodiments, R² is -NR₂, wherein each R is independently C₁₋₆ aliphatic.

[0085] In some embodiments, R² is -C(O)NR₂. In some embodiments, R² is -C(O)NH₂. In some embodiments, R² is -C(O)NR₂, wherein each R is independently C₁₋₆ aliphatic.

[0086] 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.

[0087] 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 C1-6 aliphatic.

[0088] In some embodiments, R2is -OC(O)R. In some embodiments, R2is -OC(O)H. In some embodiments, R2is -OC(O)R, wherein R is C1-6 aliphatic.

[0089] In some embodiments, R2is optionally substituted C1-6 aliphatic. In some embodiments, R2is C1-6 aliphatic. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is n-propyl. In some embodiments, R2is isopropyl. In some embodiments, R2is n- Page 16 of 79BTBV-006 360491-2034 329826723butyl. In some embodiments, R2is s-butyl. In some embodiments, R2is t-butyl.

[0090] In some embodiments, R2is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R2is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R2is -CHF2. In some embodiments, R2is -CF3. In some embodiments, R2is -CH₂CF₃. In some embodiments, R2is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R2is -CH2OH.

[0091] 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.

[0092] 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.

[0093] In some embodiments, R2is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0094] 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.

[0095] 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, fluoro, methyl, and ethyl.

[0096] 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-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.Page 17 of 79BTBV-006 360491-2034 329826723

[0097] 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 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, 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 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, 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 C₁₋₆ aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0098] In some embodiments, R³ is selected from hydrogen, bromo, chloro, fluoro, -CN, -OR^A, -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, 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.

[0099] 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.

[0100] In some embodiments, R3is -ORA. In some embodiments, R3is -OH. In some embodiments, R³ is -OCH₃. In some embodiments, R³ is -OCH₂CH₃. In some embodiments, R³ is -OCH₂F. In someembodiments, R³ is -OCHF₂. In some embodiments, R³ is -OCF₃. In some embodiments, R3is

[0101] In some embodiments, R³ is -NR₂. In some embodiments, R³ is -NH₂. In some embodiments, R³ is -NR₂, wherein each R is independently C₁₋₆ aliphatic.

[0102] In some embodiments, R³ is -C(O)NR₂. In some embodiments, R³ is -C(O)NH₂. In some embodiments, R³ is -C(O)NR₂, wherein each R is independently C₁₋₆ aliphatic.

[0103] 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.

[0104] 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 C1-6 aliphatic.

[0105] In some embodiments, R3is -OC(O)R. In some embodiments, R3is -OC(O)H. In some Page 18 of 79BTBV-006 360491-2034 329826723embodiments, R3is -OC(O)R, wherein R is Ci-e aliphatic.

[0106] In some embodiments, R3is optionally substituted Ci-6 aliphatic. In some embodiments, R3is Ci-6 aliphatic. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is n-propyl. In some embodiments, R3is isopropyl. In some embodiments, R3is n-butyl. In some embodiments, R3is s-butyl. In some embodiments, R3is t-butyl.

[0107] In some embodiments, R3is Ci-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci-6 aliphatic. In some embodiments, R3is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R3is -CHF2. In some embodiments, R3is -CF3. In some embodiments, R3is -CH₂CF₃. In some embodiments, R3is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R3is -CH2OH.

[0108] 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.

[0109] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted 3-to 6-membered saturated or partially unsaturated carbocyclyl. In some embodiments, R3is an optionally substituted cyclopropyl. In some embodiments, R3is an optionally substituted cyclobutyl. In some embodiments, R3is an optionally substituted cyclopentyl. In some embodiments, R3is an optionally substituted cyclohexyl. In some embodiments, R3is cyclopropyl. In some embodiments, R3is cyclobutyl. In some embodiments, R3is cyclopentyl. In some embodiments, R3is cyclohexyl.

[0110] In some embodiments, R3is an optionally substituted 3- to 8-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R3is an optionally substituted 3- to 6-membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] 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.

[0112] In some embodiments, R3is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R1is selected from hydrogen, fluoro, methyl, and ethyl.

[0113] In some embodiments, R4is selected from hydrogen, bromo, chloro, fluoro, -CN, -ORA, - Page 19 of 79BTBV-006 360491-2034 329826723NR2, -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.

[0114] 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 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, R⁴ is selected from bromo, chloro, fluoro, -CN, -OR^A, -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 aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0115] 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 C1-6 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.

[0116] 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.

[0117] In some embodiments, R⁴ is -OR^A. In some embodiments, R⁴ is -OH. In some embodiments, R⁴ is -OCH₃. In some embodiments, R⁴ is -OCH₂CH₃. In some embodiments, R4is -OCH2F. In someembodiments, R⁴ is -OCHF₂. In some embodiments, R⁴ is -OCF₃. In some embodiments, R4is

[0118] In some embodiments, R⁴ is -NR₂. In some embodiments, R⁴ is -NH₂. In some embodiments, R⁴ is -NR₂, wherein each R is independently C₁₋₆ aliphatic.

[0119] In some embodiments, R⁴ is -C(O)NR₂. In some embodiments, R⁴ is -C(O)NH₂. In some embodiments, R⁴ is -C(O)NR₂, wherein each R is independently C₁₋₆ aliphatic.

[0120] In some embodiments, R4is -C(O)OR. In some embodiments, R4is -C(O)OH. In some embodiments, R⁴ is -C(O)OR, wherein R is C₁₋₆ aliphatic.Page 20 of 79BTBV-006 360491-2034 329826723

[0121] In some embodiments, R4is -NRC(O)R. In some embodiments, R4is -NHC(O)R, wherein R is Ci-6 aliphatic. In some embodiments, R4is -NRC(O)H, wherein R is Ci-6 aliphatic. In some embodiments, R4is -NRC(O)R, wherein each R is independently Ci-6 aliphatic.

[0122] In some embodiments, R4is -OC(O)R. In some embodiments, R4is -OC(O)H. In some embodiments, R4is -OC(O)R, wherein R is Ci-6 aliphatic.

[0123] In some embodiments, R4is optionally substituted Ci-6 aliphatic. In some embodiments, R4is Ci-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.

[0124] In some embodiments, R4is Ci-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 C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R4is -CH2OH.

[0125] In some embodiments, 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] In some embodiments, R4is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, - Page 21 of 79BTBV-006 360491-2034 329826723OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R1is selected from hydrogen, fluoro, methyl, and ethyl.

[0130] 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-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.

[0131] 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, 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 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, 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 aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0132] 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 heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0133] In some embodiments, R5is 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, R5is bromo. In some embodiments, R5is -CN.

[0134] In some embodiments, R5is -ORA. In some embodiments, R5is -OH. In some embodiments, R5is -OCH3. In some embodiments, R5is -OCH2CH3. In some embodiments, R5is -OCH2F. In someembodiments, R5is -OCHF2. In some embodiments, R5is -OCF3. In some embodiments, R5is

[0135] In some embodiments, R5is -NR2. In some embodiments, R5is -NH2. In some Page 22 of 79BTBV-006 360491-2034 329826723embodiments, R5is -NR2, wherein each R is independently C1-6 aliphatic.

[0136] In some embodiments, R5is -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.

[0137] In some embodiments, R5is -C(O)OR. In some embodiments, R5is -C(O)OH. In some embodiments, R5is -C(O)OR, wherein R is C1-6 aliphatic.

[0138] In some embodiments, R5is -NRC(O)R. In some embodiments, R5is -NHC(O)R, wherein R is C1-6 aliphatic. In some embodiments, R5is -NRC(O)H, wherein R is C1-6 aliphatic. In some embodiments, R5is -NRC(O)R, wherein each R is independently C1-6 aliphatic.

[0139] In some embodiments, R5is -OC(O)R. In some embodiments, R5is -OC(O)H. In some embodiments, R5is -OC(O)R, wherein R is C1-6 aliphatic.

[0140] In some embodiments, R5is optionally substituted C1-6 aliphatic. In some embodiments, R5is C1-6 aliphatic. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is 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.

[0141] In some embodiments, R5is C1-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R5is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R5is -CHF2. In some embodiments, R5is -CF3. In some embodiments, R5is -CH₂CF₃. In some embodiments, R5is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R5is -CH2OH.

[0142] 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.

[0143] 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, R5is 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 cyclopentyl. In some embodiments, R5is an optionally substituted cyclohexyl. In some embodiments, R5is cyclopropyl. In some embodiments, R5is cyclobutyl. In some embodiments, R5is cyclopentyl. In some embodiments, R5is cyclohexyl.

[0144] 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,Page 23 of 79BTBV-006 360491-2034 329826723oxygen, or sulfur.

[0145] 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.

[0146] In some embodiments, R5is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R1is selected from hydrogen, fluoro, methyl, and ethyl.

[0147] 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, 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.

[0148] 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 aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0149] 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 C1-6 aliphatic. In some embodiments, R6is 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.

[0150] In some embodiments, R6is hydrogen. In some embodiments, R6is halogen. In some embodiments, R6is fluoro or chloro. In some embodiments, R6is fluoro. In some embodiments, R6is chloro. In some embodiments, R6is bromo. In some embodiments, R6is -CN.

[0151] 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 Page 24 of 79BTBV-006 360491-2034 329826723embodiments, R6is -OCHF2. In some embodiments, R6is -OCF3. In some embodiments, R6is

[0152] In some embodiments, R6is -NR2. In some embodiments, R6is -NH2. In some embodiments, R6is -NR2, wherein each R is independently C1-6 aliphatic.

[0153] 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.

[0154] In some embodiments, R6is -C(O)OR. In some embodiments, R6is -C(O)OH. In some embodiments, R6is -C(O)OR, wherein R is C1-6 aliphatic.

[0155] 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.

[0156] In some embodiments, R6is -OC(O)R. In some embodiments, R6is -OC(O)H. In some embodiments, R6is -OC(O)R, wherein R is C1-6 aliphatic.

[0157] In some embodiments, R6is optionally substituted C1-6 aliphatic. In some embodiments, R6is C1-6 aliphatic. In some embodiments, R6is methyl. In some embodiments, R6is ethyl. In some embodiments, R6is n-propyl. In some embodiments, R6is isopropyl. In some embodiments, R6is n-butyl. In some embodiments, R6is s-butyl. In some embodiments, R6is t-butyl.

[0158] In some embodiments, R6is C1-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or Ci.e aliphatic. In some embodiments, R6is Ci.e aliphatic, optionally substituted with halogen. In some embodiments, R6is -CHF2. In some embodiments, R6is -CF3. In some embodiments, R6is -CH₂CF₃. In some embodiments, R6is Ci-e aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or Ci-e aliphatic. In some embodiments, R6is -CH2OH.

[0159] 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.

[0160] 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 saturated or partially unsaturated carbocyclyl. In some embodiments, R6is an optionally substituted cyclopropyl. In some embodiments, R6is an optionally substituted cyclobutyl. In some embodiments, R6is an optionally substituted cyclopentyl. In some embodiments, R6is an optionally substituted cyclohexyl. In some embodiments, R6is cyclopropyl. In some embodiments, R6is cyclobutyl. In some embodiments, R6is cyclopentyl. In some embodiments, R6is cyclohexyl.Page 25 of 79BTBV-006 360491-2034 329826723

[0161] 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.

[0162] 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.

[0163] In some embodiments, R6is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R1is selected from hydrogen, fluoro, methyl, and ethyl.

[0164] 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 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.

[0165] 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 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, 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 C1-6 aliphatic, phenyl, or a 5 - to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R7is selected from 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 aliphaticphenyl, or a 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0166] 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 C1-6 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.

[0167] In some embodiments, R7is hydrogen. In some embodiments, R7is halogen. In some Page 26 of 79BTBV-006 360491-2034 329826723embodiments, R7is fluoro or chloro. In some embodiments, R7is fluoro. In some embodiments, R7is chloro. In some embodiments, R7is bromo. In some embodiments, R7is -CN.

[0168] 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 someembodiments, R7is -OCHF2. In some embodiments, R7is -OCF3. In some embodiments, R7is

[0169] In some embodiments, R7is -NR2. In some embodiments, R7is -NH2. In some embodiments, R7is -NR2, wherein each R is independently C1-6 aliphatic.

[0170] 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.

[0171] 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.

[0172] 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 C1-6 aliphatic.

[0173] 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.

[0174] In some embodiments, R7is optionally substituted C1-6 aliphatic. In some embodiments, R7is C1-6 aliphatic. In some embodiments, R7is methyl. In some embodiments, R7is ethyl. In some embodiments, R7is n-propyl. In some embodiments, R7is isopropyl. In some embodiments, R7is n-butyl. In some embodiments, R7is s-butyl. In some embodiments, R7is t-butyl.

[0175] In some embodiments, R7is C1-6 aliphatic, optionally substituted with halogen or -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R7is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R7is -CHF2. In some embodiments, R7is -CF3. In some embodiments, R7is -CH₂CF₃. In some embodiments, R7is C1-6 aliphatic, optionally substituted with -OR°, wherein R° is hydrogen or C1-6 aliphatic. In some embodiments, R7is -CH2OH.

[0176] 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.

[0177] 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-Page 27 of 79BTBV-006 360491-2034 329826723to 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.

[0178] 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.

[0179] 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.

[0180] In some embodiments, R7is selected from hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, and. In some embodiments, R1is selected from hydrogen, fluoro, methyl, and ethyl.

[0181] As defined above and described herein, RAis hydrogen or an optionally substituted group selected from C1-6 aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0182] In some embodiments, RAis hydrogen or an optionally substituted C1-6 aliphatic. In some embodiments, RAis hydrogen. In some embodiments, RAis optionally substituted C1-6 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.

[0183] 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.

[0184] In some embodiments, RAis an optionally substituted 3-to 8-membered saturated or Page 28 of 79BTBV-006 360491-2034 329826723partially 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.

[0185] As defined above and described herein, R8and R10are independently hydrogen or optionally substituted Ci-6 aliphatic.

[0186] In some embodiments, R8is hydrogen or optionally substituted Ci-6 aliphatic. In some embodiments, R8is hydrogen. In some embodiments, R8is optionally substituted Ci-6 aliphatic. In some embodiments, R8is 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.

[0187] In some embodiments, R8is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R8is -CH2F. In some embodiments, R8is -CHF2. In some embodiments, R8is -CF3.

[0188] In some embodiments, R10is hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R10is hydrogen. In some embodiments, R10is optionally substituted C1-6 aliphatic. In some embodiments, R10is C1-6 aliphatic. In some embodiments, R10is methyl. In some embodiments, R10is ethyl. In some embodiments, R10is n-propyl. In some embodiments, R10is isopropyl. In some embodiments, R10is n-butyl. In some embodiments, R10is s-butyl. In some embodiments, R10is t-butyl. In some embodiments, R10is a 3-6 membered saturated or partially unsaturated carbocycle. In some embodiments, R10is a 3-6 membered saturated carbocycle. In some embodiments, R10is cyclopropyl. In some embodiments, R10is cyclobutyl. In some embodiments, R10is cyclopentyl. In some embodiments, R10is cyclohexyl.

[0189] In some embodiments, R10is C1-6 aliphatic, optionally substituted with halogen. In some embodiments, R10is -CH2F. In some embodiments, R10is -CHF2. In some embodiments, R10is -CF3.

[0190] As defined above and described herein, each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6 aliphatic.

[0191] 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 C1-6 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 Page 29 of 79BTBV-006 360491-2034 329826723cyclohexyl. In some embodiments, R9is Ci-6 aliphatic, optionally substituted with halogen. In some embodiments, R9is Ci-6 aliphatic, optionally substituted with fluoro. In some embodiments, R9is -CF3.

[0192] 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 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0193] As defined above and described herein, each R is independently hydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is C1-6 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.

[0194] In some embodiments, the present disclosure provides a compound of formulae Il-a, Il-b, II-c, Il-d, or li e:R10R10R10R10or a pharmaceutically acceptable salt thereof, wherein each of Ring B, X1, X2, X3, X4, X5, X6, X7, X8, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0195] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae Il-a, Il-b, II-c, Il-d, or Il-e, embodiments of variables Ring B, X1, X2, X3, X4, X5, X6, X7, X8, R9, R10, and n as defined above and described in classes and subclasses herein, also Page 30 of 79BTBV-006 360491-2034 329826723apply to compounds of formulae Il-a, Il-b, II-c, Il-d, or Il-e, both singly and in combination.

[0196] In some embodiments, the present disclosure provides a compound of formulae II-a1, II-b1, II-c1, or II-d1:or a pharmaceutically acceptable salt thereof, wherein each of Ring B, X8, R1, R2, R3, R4, R5, R6, R7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0197] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae II-a1, II-b1, II-c1, or II-d1, embodiments of variables Ring B, X8, R1, R2, R3, R4, R5, R6, R7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae II-a1, II-b1, II-c1, or II-d1, both singly and in combination.

[0198] In some embodiments, the present disclosure provides a compound of formulae III-a1, III-b1, III-c1, III-d1, or III-e1:Ill-elor a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, X7, R9, R10, and n Page 31 of 79BTBV-006 360491-2034 329826723is defined and described in classes and subclasses herein, both singly and in combination.

[0199] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae III-a1, III-b1, III-c1, III-d1, or III-e1, embodiments of variables X1, X2, X3, X4, X5, X6, X7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae III-a1, III-b1, III-c1, III-d1, or III-e1, both singly and in combination.

[0200] In some embodiments, the present disclosure provides a compound of formulae III-a2, III-b2, III-c2, III-d2, or III-e2:III-b2 III-c2III-e2or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, X7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0201] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae III-a2, III-b2, III-c2, III-d2, or III-e2, embodiments of variables X1, X2, X3, X4, X5, X6, X7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae III-a2, III-b2, III-c2, III-d2, or III-e2, both singly and in combination.

[0202] In some embodiments, the present disclosure provides a compound of formulae III-a3, III-b3, III-c3, III-d3, or III-e3:Page 32 of 79BTBV-006 360491-2034 329826723III-a3 III-d3III-e3or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, X7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0203] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae III-a3, III-b3, III-c3, III-d3, or III-e3, embodiments of variables X1, X2, X3, X4, X5, X6, X7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae III-a3, III-b3, III-c3, III-d3, or III-e3, both singly and in combination.

[0204] In some embodiments, the present disclosure provides a compound of formulae III-a4, III-b4, III-c4, III-d4, or III-e4:Page 33 of 79BTBV-006 360491-2034 329826723or a pharmaceutically acceptable salt thereof, wherein each of X1, X2, X3, X4, X5, X6, X7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0205] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae III-a4, III-b4, III-c4, III-d4, or III-e4, embodiments of variables X1, X2, X3, X4, X5, X6, X7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae III-a4, III-b4, III-c4, III-d4, or III-e4, both singly and in combination.

[0206] In some embodiments, the present disclosure provides a compound of formulae IV-a1, IV-b1, IV-c1, or IV-d1:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0207] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV-a1, IV-b1, IV-c1, or IV-d1:bl, IV-cl, or IV-dl, embodiments of variables R1, R2, R3, R4, R5, R6, R7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a1, IV-b1, IV-c1, or IV-d1:bl, IV-cl, or IV-dl, both singly and in combination.

[0208] In some embodiments, the present disclosure provides a compound of formulae IV-a2, IV- b2, IV-c2, or IV-d2:Page 34 of 79BTBV-006 360491-2034 329826723IV-a2 IV-b2 IV-c2 IV-d2or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0209] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV- a2, IV-b2, IV-c2, or IV-d2, embodiments of variables R1, R2, R3, R4, R5, R6, R7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a2, IV-b2, IV-c2, or IV-d2, both singly and in combination.

[0210] In some embodiments, the present disclosure provides a compound of formulae IV-a3, IV-b3, IV-c3, or IV-d3:or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0211] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV- a3, IV-b3, IV-c3, or IV-d3, embodiments of variables R1, R2, R3, R4, R5, R6, R7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a3, IV-b3, IV-c3, or IV-d3, both singly and in combination.

[0212] In some embodiments, the present disclosure provides a compound of formulae IV-a4, IV-b4, IV-c4, or IV-d4:Page 35 of 79BTBV-006 360491-2034 329826723or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, R7, R9, R10, and n is defined and described in classes and subclasses herein, both singly and in combination.

[0213] It will be understood that, unless otherwise specified or prohibited by the foregoing definition of formulae IV- a4, IV-b4, IV-c4, or IV-d4, embodiments of variables R1, R2, R3, R4, R5, R6, R7, R9, R10, and n as defined above and described in classes and subclasses herein, also apply to compounds of formulae IV-a4, IV-b4, IV-c4, or IV-d4, both singly and in combination.

[0214] In some embodiments, the present disclosure provides a compound selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.Table 1.Page 36 of 79BTBV-006 360491-2034 329826723BTBV-006 360491-2034 329826723

[0215] 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

[0216] 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.

[0217] In some embodiments, the present invention provides a pharmaceutical composition comprising a provided compound (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically 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 pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0218] The term “patient” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0219] The term “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 formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in Page 38 of 79BTBV-006 360491-2034 329826723the 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.

[0220] 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, the 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.

[0221] 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.

[0222] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers may be included. Lubricating agents are also typically added. For oral administration in a capsule form, 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.

[0223] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing Page 39 of 79BTBV-006 360491-2034 329826723the 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.

[0224] 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 the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0225] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0226] 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 the active components suspended or dissolved in one or more pharmaceutically acceptable carriers

[0227] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated 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.

[0228] 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.

[0229] 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.

[0230] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.Uses of Compounds and Pharmaceutically Acceptable Compositions

[0231] In some embodiments, provided compounds and compositions are for use in medicine.

[0232] Compounds and compositions described herein are generally useful as agonists of 5- Page 40 of 79BTBV-006 360491-2034 329826723HT2AR.

[0233] According to one embodiment, the invention relates to a method of activating 5-HT2AR, or a mutant thereof, in a biological sample comprising contacting said biological sample with a provided compound, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

[0234] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. In some embodiments, 5-HT2AR is from a biological sample. In some embodiments, the biological sample is taken from a subject.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for treating a 5-HT2AR-mediated disorder as described herein. Such disorders are described in detail herein.

[0239] 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 - Page 41 of 79BTBV-006 360491-2034 329826723arrestins. See Kossatz, E., et al. Nature Communications 2024, 15:4307. In some embodiments, the invention also provides a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, for use in a method for binding 5-HT2AR, or a mutant thereof, resulting in increased (“biased”) activation of a particular signaling pathway (e.g., a G protein signaling pathway) over others (e.g., a 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 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.

[0240] In some embodiments, provided methods include increasing activation of a G protein signaling pathway associated with 5-HT2AR over a β-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.

[0241] In some embodiments, G protein signaling pathways are evaluated through detection of calcium, e.g., as described in Example 10. In some embodiments, P-arrestin signaling pathways are evaluated as described in Example 11.

[0242] 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 10) as compared to P-arrestin signaling pathways (e.g., as measured in Example 11).

[0243] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions described herein, may exhibit anxiolytic, anti-depressive, and anti -drug abuse actions, without exhibiting substantial psychedelic actions, for example, hallucinogenic actions. For example, a provided compound, or a pharmaceutically acceptable salt thereof, may confer anti-depressant 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.

[0244] The activity of a compound, or a pharmaceutically acceptable salt thereof, utilized in this invention as an activator of 5-HT2AR, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine activation and / or the subsequent functional consequences of activated 5-HT2AR, or a mutant thereof. Alternate in vitro assays quantitate the ability of the agonist to bind to 5-HT2AR, or a mutant thereof. Agonist binding may be measured by Page 42 of 79BTBV-006 360491-2034 329826723radiolabeling 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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 depressive disorder includes treatment resistant depressions.

[0251] In some embodiments, the present invention provides a method for treating an anxiety Page 43 of 79BTBV-006 360491-2034 329826723disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the anxiety disorder is generalized anxiety disorder. In other embodiments, the anxiety disorder is social anxiety disorder.

[0252] In some embodiments, the present invention provides a method for treating trauma and / or stress disease, disorder, or condition comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, such a disorder is post-traumatic stress disorder. In other embodiments, such a disorder is an adjustment disorder.

[0253] 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 pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0254] 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.

[0255] 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.

[0256] In some embodiments, the present invention provides a method for treating a psychotic disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the psychotic disorder is schizophrenia. In other embodiments, the psychotic disorder is schizoaffective disorder. In still other embodiments, the psychotic disorder is schizotypal personality disorder.

[0257] 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, may be useful in facilitating smoking cessation.

[0258] 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 pharmaceutically acceptable Page 44 of 79BTBV-006 360491-2034 329826723composition thereof. In some embodiments, the neurocognitive disorder includes those due to a primary neurodegenerative disease, for example, Alzheimer's disease or Parkinson’s disease.

[0259] In some embodiments, the present invention provides a method for treating a personality disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof.

[0260] 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.

[0261] In some embodiments, the present invention provides a method for treating a bipolar disorder comprising administering to a patient in need thereof provided compound, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable composition thereof. In some embodiments, the bipolar disorder is bipolar I disorder. In some embodiments, the bipolar disorder is bipolar II disorder.

[0262] 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 pharmaceutically acceptable salt thereof, or pharmaceutically 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

[0263] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0264] General SchemePage 45 of 79BTBV-006 360491-2034 329826723i) Aromatic substitution (if applicable) ii) Aromatic dehalogenation (if applicable) iii) N-alkylation (if applicable) From reactant set A iv) Chiral separation (if applicable)v) Deprotection (if applicable) Suzuki orVarious routes aromatic substitutionX=Br or B(OR)2Z= CH, CF, N= CH, CMe, N= CH, CMe, CEt, CF= CH, CMe, Cl= CH= CH, N= CH, NZ = Heterocycle derived from reactant set AExample 1 (1-8)Br 4 M HCI / 1,4-dioxane,DCM, 0°C-RT, 1-16hK3PO4, PdCI2(dppf). DCM, Step 21,4-dioxane, H2O, 100°C,2-16hStep 1

[0265] Step 1: To a stirred solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.2 g, 0.65 mmol, 1.0 eq.) and 4-bromo-8-fluoroquinoline (0.22 g, 0.97 mmol, 1.5 eq.) in 1,4-dioxane (2 mL, 10 vol) and water (0.2 mL, 0.1 vol) was added potassium phosphate (K3PO4) (0.41 g, 1.94 mmol, 3.0 eq.). The reaction mixture was purged with nitrogen gas for 30 minutes and Pd(dppf)C12. dichloromethane complex (0.05 g, 0.06 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was stirred at 100°C for 12 h. The completion of the reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over sodium sulphate and concentrated under a high vacuum to afford the crude material. The crude material was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane as eluent to afford tert-butyl 5-(8-fluoroquinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Qty: 0.09 g, 42%). LCMS (m / z): 329.3 [M+H]+.

[0266] Step 2: To a stirred solution of tert-butyl 5-(8-fluoroquinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.09 g, 0.27 mmol, 1.0 eq.) in dichloromethane (0.9 mL, 10 vol) was added 4M hydrochloric acid in 1,4-dioxane (0.45 mL, 5 vol) at 0 °C. The resulting reaction mixture was stirred at Page 46 of 79BTBV-006 360491-2034 329826723room temperature for 3h. The completion of the reaction was monitored by TLC using 80% ethyl acetate in hexane and LCMS analysis. The reaction mixture was concentrated under reduced pressure. The isolated solid material was triturated with diethyl ether (2 x 25 mL) and dried in vacuo to afford 8-fluoro-4-(l,2,5,6-tetrahydropyridin-3-yl)quinoline hydrochloride (1-8, 0.04 g, 55%). LCMS (m / z): 229.2 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 59.76 (s, 2H), 8.98 (d, J = 4.5 Hz, 1H), 8.09 (t, J = 2.0 Hz, 1H), 7.70-7.66 (m, 2H), 7.53 (d, J = 4.5 Hz, 1H), 6.08 (s, 1H), 3.90 (s, 2H), 3.35 (d, J = 5.0 Hz, 2H), 2.57 (d, J = 3.0 Hz, 2H).

[0267] Additional Exemplary Compounds Prepared via Example 1 MethodsStructure of Salt MS (m / z) starting material Compound Structure Proton NMRForm [M+H] used (differing from Example 1) HN 'HNMR (400 MHz,DMSO-de) 59.40 (s,2H), 8.96 (d, J = 4.58-fluoro-4- Hz, 1H), 8.02 (d, J =(1, 2,5,6- HC1 7.0 Hz, 1H), 7.70-7.63 229.2 tetrahydropyridin- (m, 2H), 7.46 (d, J =3-yl)quinoline4.5 Hz, 1H), 5.91 (s,1H), 3.81 (s, 2H), 3.411-5 (s, 2H), 2.68 (s, 2H). 6 [■Joe ’HNMR (400 MHz,DMSO-de) 59.88 (s, J b 1H), 9.38 (s, 1H),H 9.21 (d, J = 4.0 Hz,N 1H), 9.14 (d, J = 8.5Hz, 1H), 8.28 (d, J =5-(3-methyl- 8.5 Hz, 1H), 8.05 (t, J1, 2,3,6- [■Joe HC1 = 7.5 Hz, 1H), 7.92 (q, 225.2 tetrahydropyridin- J = 1.0 Hz, 1H), 7.624-yl)quinoline Br (d, J = 7.0 Hz, 1H),5.79 (s, 1H), 3.84-3.721-9 (m, 2H), 3.57-3.54 (m,1H), 3.17 - 3.04 (m,2H), 0.81 (d, J = 7.0 with Hz, 3H). PdCl2(dppf). DCM and K2CO3. ’HNMR (400 MHz,DMSO-de) 59.65 (s,2H), 9.18 (d, J = 3.5Hz, 1H), 9.07 (d, J=8.0 Hz, 1H), 8.26 (d, J5-(l, 2,5,6- Br = 8.5 Hz, 1H), 8.02 (t,tetrahydropyridin- HC1 211.2J= 7.5 Hz, 1H), 7.90- 3-yl)quinoline7.87 (m, 1H), 7.69 (d,J= 7.0 Hz, 1H), 6.001-2 (s, 1H), 3.88 (s, 2H),3.35 (s, 2H), 2.57 (s,2H).Page 47 of 79BTBV-006 360491-2034 329826723'HNMR (400 MHz,DMSO-de) 59.44 (s, (J H " B" N 2H), 9.15 (d, J = 4.5Hz, 1H), 9.00 (d, J = A 8.5 Hz, 1H), 8.21 (d, J5-(l, 2,3,6- = 8.5 Hz, 1H), 7.99 (t,tetrahydropyridin- HC1 211.2J = 8.0 Hz, 1H), 7.86- 4-yl)quinoline E-lo c 7.83 (m, 1H), 7.64 (d,J = 7.0 Hz, 1H), 5.83 Br 1-13 (s, 1H), 3.80 (s, 2H),3.41 (s, 2H), 2.68 (s,2H).'HNMR (400 MHz,DMSO-de) 59.70 (s,2H), 9.63 (s, 1H),8.55-8.51 (m, 1H),6-fluoro-4- 8.47 (s, 1H), 8.13 (d, J(1, 2,5,6- Br HC1 = 9.0 Hz, 1H), 7.85 229.2 tetrahydropyridin- (td, J = 2.0, 9.0 Hz,3-yl)isoquinoline1H), 6.11 (s, 1H), 3.871-3 (s, 2H), 3.35 (d, J =3.0 Hz, 2H), 2.58 (s,2H).’HNMR (400 MHz,DMSO-de) 59.71 (bs,2H), 9.12 (bs, 1H),8.33 (bs, 1H), 8.07 (t,2-methyl-5- J= 7.5 Hz,1H), 7.91(1, 2,5,6- Br HC1 (d, J= 7.0 Hz, 1H), 225.2 tetrahydropyridin- 7.71 (d,. / 7.0 Hz.3-yl)quinoline1H), 6.00 (s, 1H), 3.88jOi 1-11 (s, 2H), 3.36 (d, J =3.0 Hz, 2H), 2.96 (s,3H), 2.57 (s, 2H).Example 2 (1-14)BocBr 4 M HCI / 1,4-dioxane,DCM, 0°C-RT, 1-16h NaOtBu, BINAP, Pd2(dba)3> Step 2 Toluene, 100 °C, 16h Step 11-14

[0268] Step 1: To a stirred solution of 5 -bromoquinoline (0.2 g, 0.96 mmol, 1.0 eq.) and tert-butyl 1,4-diazepane-1-carboxylate (0.21 g, 1.06 mmol, 1.1 eq.) in toluene (2 mL, 10 vol) was added sodium tert-butoxide (Na-O-tbu) (0.13 g, 1.35 mmol, 1.4 eq.). The reaction mixture was purged with nitrogen gas for 20 minutes and Pd2(dba)3 (0.01 g, 0.01 mmol, 0.02 eq.) and BINAP (0.01 g, 0.01 mmol, 0.02Page 48 of 79BTBV-006 360491-2034 329826723eq.) were added at room temperature. The reaction mixture was further stirred at 100°C for 16 h. The completion of reaction was monitored by TLC using 50% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to obtain the crude residue. The material was purified by flash column chromatography on silica gel using 30% ethyl acetate in hexane as eluent to afford tert-butyl 4-(quinolin-5-yl)-1,4-diazepane-1-carboxylate (0.09 g, 29%). LCMS (m / z): 328.3 [M+H]+.

[0269] Step 2: To a stirred solution of tert-butyl 4-(quinolin-5-yl)-1,4-diazepane-1-carboxylate (0.07 g, 0.21 mmol, 1.0 eq.) in dichloromethane (0.7 mL, 10 vol) was added 4 M hydrochloric acid in 1, 4 dioxane (0.4 mL, 5 vol) at 0 °C. The resulting mixture stirred at room temperature for 3h. The completion of the reaction was monitored by TLC using 80% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford solid material, which was triturated with diethyl ether (3 x 10 mL) to afford 5-(l,4-diazepan-l-yl)quinoline hydrochloride (1-14, 0.03 g, 53% ) as orange solid. LCMS (m / z): 228.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 59.45 (s, 2H), 9.17 (d, J = 4.5 Hz, 1H), 9.11 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 5.0 Hz, 2H), 7.91 (dd, J = 8.5, 5.0 Hz, 1H), 7.51 (t, J = 4.0 Hz, 1H), 3.57-3.56 (m, 2H), 3.38-3.32 (m, 6H), 2.17-2.16 (m, 2H).Example 3 (1-4)4 M HCI / 1,4-dioxane, DCM, 0°C-RT, 1-16h Step 3

[0270] Step 1: To a stirred solution of 5 -bromoquinoline (0.20 g, 0.96 mmol, 1 eq.) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.30 g, 0.96 mmol, 1 eq.) in 1, 4 dioxane (2 mL, 10 vol) and water (0.1 mL, 1 vol) was added tri potassium phosphate (K3PO4) (0.61 g, 2.88 mmol, 3.0 eq.). The reaction mixture was purged with nitrogen gas for 15 minutes and Pd(dppf)C12. DCM complex (0.08 g, 0.10 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was stirred at 100°C for 12h. The completion of the reaction was monitored by TLC using 50% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction Page 49 of 79BTBV-006 360491-2034 329826723mixture quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over sodium sulphate and concentrated under a high vacuum to afford the crude. The obtained crude material was purified by flash column chromatography on silica gel using 26% ethyl acetate in hexane as eluent to afford tert-butyl 4-(quinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.23 g, 77%). LCMS (m / z): 311.2 [M+H]+.

[0271] Step 2: To a stirred solution of tert-butyl 4-(quinolin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate(0.23 g, 0.74 mmol, 1 eq.) in methanol (4.6 mL, 20 vol) was added 10 % w / w Pd / C (50 % wet basis) (0.11 g, 50% w / w) at room temperature. The reaction mixture was stirred with hydrogen gas purging at room temperature for 5 h. The completion of the reaction was monitored by TLC using 50% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was filtered through a celite bed. The celite bed was washed with methanol (2 X 10 mL). The combined filtrates were dried over anhydrous sodium sulphate and concentrated in vacuo to afford the crude material. The obtained crude material was purified by flash column chromatography on silica gel using 48% ethyl acetate in hexane as the eluent to afford tert-butyl 4-(quinolin-5-yl)piperidine-1-carboxylate (0.09 g, 39%). LCMS (m / z): 313.3 [M+H]+.

[0272] Step 3: To a stirred solution of tert-butyl 4-(quinolin-5-yl)piperidine-1-carboxylate (0.09 g, 0.29 mmol, 1.0 eq.) in dichloromethane (0.9 mL, 10 vol) was added 4M hydrochloric acid in 1, 4 dioxane (0.45 mL, 5 vol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3h. The completion of the reaction was monitored by TLC using 5% methanol in dichloromethane and LCMS analysis. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The isolated solid material was further triturated with diethyl ether (2 X 5 mL) and dried in vacuo to afford 5-(piperidin-4-yl)quinoline hydrochloride (0.07 g, 98%). 'H NMR (400 MHz, DMSO): 59.29 (d, J = 9.0 Hz, 1H), 9.22 (d, J = 4.0 Hz, 1H), 9.18-9.00 (m, 2H), 8.21 (d, J = 8.5 Hz, 1H), 8.05-7.96 (m, 2H), 7.70 (d, J = 7.0 Hz, 1H), 3.86-3.81 (m, 1H), 3.41 (d, J = 13.0 Hz, 2H), 3.16 (d, J = 11.0 Hz, 2H), 2.03 (d, J = 15.0 Hz, 4H).

[0273] Step 4: To a stirred solution of 5-(piperidin-4-yl)quinoline hydrochloride (0.05 g, 0.24 mmol, 1.0 eq.) and cyclopropylboronic acid (0.04 g, 0.47 mmol, 2.0 eq.) in dichloroethane (1.0 mL, 20 vol) was added sodium carbonate (Na2COs) (0.05 g, 0.47 mmol, 2.0 eq.). The reaction mixture was stirred for 5 minutes, and then a suspension of copper acetate (Cu(OAc)2) (0.05 g, 0.23 mmol, 1.0 eq.) and bipyridine (0.03 g, 0.23 mmol, 0.1 eq.) was added. The reaction mixture was stirred at 70 °C for 24h. The completion of the reaction was monitored by TLC using 5% methanol in dichloromethane and LCMS analysis. After completion of the reaction, the reaction mixture quenched with water (10 mL) and extracted with dichloromethane (2 X 10 mL). The combined organic layer was dried over sodium sulphate and concentrated under a high vacuum to afford the crude product. The obtained crude product was purified by reverse phase preparative HPLC. The pure fractions were lyophilized to afford 5-(l-cyclopropylpiperidin-4-yl)quinoline (1-4, 0.0026 g, 4%). LCMS (m / z): 253.3 [M+H]+; 1H NMR (400Page 50 of 79BTBV-006 360491-2034 329826723MHz, DMSO-d6) 5 8.90-8.89 (m, 1H), 8.62 (d, J= 9.0 Hz, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.71 (t, J = 7.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.49 (d, J= 7.0 Hz, 1H), 3.33 (m, 1H), 3.08 (d, J= 11.5 Hz, 2H), 2.44 (d, J= 10.0 Hz, 2H), 1.82 (d, J= 12.0 Hz, 2H), 1.70-1.67 (m, 3H), 0.45 (m, 2H), 0.33 (m, 2H).Example 4 (1-12)Boc^BF3K Cs2CO3, Pd(dppf)CI2’ THF, Toluene, H2O 100 °C, 12h Step 21-12

[0274] Step 1: To a stirred solution of 6-bromo-4-iodoquinoline (0.4 g, 1.20 mmol, 1.0 eq.) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.56 g, 1.80 mmol, 1.5 eq.) in 1,4-dioxane (4 mL, 10 vol) and water (0.4 mL, 1 vol) was added tripotassium phosphate (K3PO4) (0.76 g, 3.59 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and Pd(dppf)C12. DCM complex (0.10 g, 0.12 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was stirred at 100°C for 12h. The completion of the reaction was monitored by TLC using 70% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (100 mb) and extracted with ethyl acetate (2 X 100 mb). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to give the crude product. The obtained crude product was purified by flash column chromatography on silica gel using 38% ethyl acetate in hexane as eluent to afford tert-butyl 5-(6-bromoquinolin-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.2 g, 63%). LCMS (m / z): 389.3 [M+H]+.

[0275] Step 2: To a stirred solution of tert-butyl 5-(6-bromoquinolin-4-yl)-3,6-dihydropyridine-1(2H) -carboxylate (0.15 g, 0.39 mmol, 1.0 eq.) and potassium ethyltrifluoroborate (0.10 g, 0.77 mmol, 2.0 eq.) in a mixture of toluene (0.4 mb, 10 vol.), THF (1.5 mb, 10 vol.) and water (0.4 mb, 2.5 vol) was added caesium carbonate (Cs₂CO₃) (0.38 g, 1.16 mmol, 3 eq.). The reaction mixture was purged with nitrogen gas for 10 minutes and PdC12(dppf) (0.03 g, 0.04 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was stirred at 100 °C for 12 h. The completion of the reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layers were dried over sodium sulphate and concentrated under high Page 51 of 79BTBV-006 360491-2034 329826723vacuum to afford the crude product. The obtained crude material was purified by flash column chromatography on silica gel using 17% ethyl acetate in hexane as eluent to afford tert-butyl 5-(6-ethylquinolin-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate (Qty: 0.09 g, 69%). LCMS (m / z): 339.3 [M+H]+.

[0276] Step 3: To a stirred solution of tert-butyl 5-(6-ethylquinolin-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.09 g, 0.26 mmol, 1.0 eq.) in dichloromethane (0.9 mL, 10 vol) was added 4 M hydrochloric acid in 1, 4 dioxane (0.5 mL, 5 vol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3h. The completion of the reaction was monitored by TLC using 50% ethyl acetate in hexane and LCMS analysis. After completion of reaction, the reaction mixture was directly evaporated under high vacuum to afford the crude product, which was purified by reverse phase preparative HPLC. The pure fractions were lyophilized to afford 6-ethyl-4-(l,2,5,6-tetrahydropyridin-3-yl) quinoline (1-12, 0.008 g, 13%) as light yellow solid. LCMS (m / z): 239.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J= 4.5 Hz, 1H), 7.97 (d, J= 8.5 Hz, 1H), 7.88 (s, 1H), 7.67 (d, J= 8.5 Hz, 1H), 7.30 (d, J= 4.5 Hz, 1H), 6.01 (s, 1H), 3.74 (s, 2H), 3.20 (t, J= 6.0 Hz, 2H), 2.84-2.79 (m, 2H), 2.43 (bs, 2H), 1.28 (t, J= 7.0 Hz, 3H).Example 5 (1-1)i) 12 M HCI, H2O0 °C, 20 mins Cl Br MeMgBr, THF, ii)0NaNO2, HgO, POCI2, 45 °C, 16h 0 C, 2h, 65 C, 2h 100 °C, 2h Step 1 Step 2 Step 34 M HCI / 1,4-dioxane, DCM, 0°C-RT, 1-16h K2CO3, PdCI2(dppf), Step 6 1,4-dioxane, H2O, 80°c, 2-16h1-1 Step 4

[0277] Step 1: To a solution of 2-amino-6-bromobenzonitrile (2 g, 10.15 mmol, 1.0 eq.) in anhydrous THF (20 mL) was added to a solution of MeMgBr in THF (33.8 mL, 101.5 mmol, 10.0 eq.) slowly at room temperature under an N2 atmosphere. The reaction mixture was stirred at 45 °C overnight. The reaction mixture was cooled down to room temperature, diluted with water (100 mL), adjusted to pH = 6~7 with solid Na2COs and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel (eluent: pet. ether: EtOAc=50 / l to 30 / 1) to afford l-(2-amino-6-bromophenyl)ethan-l-one (900 mg, 41.5%) as a yellow solid. LCMS (m / z): 213.9 and 215.9 [M+H]+.Page 52 of 79BTBV-006 360491-2034 329826723

[0278] Step 2: To a solution of l-(2-amino-6-bromophenyl)ethan-l-one (3 g, 14.01 mmol, 1.0 eq.) in H2O (20 mL) at 0 °C was added HC1 (18 mL, 12 M, 215.97 mmol, 15.41 eq.). The reaction was stirred at 0 °C for 20 min. A solution of NaNO₂ (1 g, 14.58 mmol, 1.04 eq.) in H2O (10 mL) was added. The reaction was stirred at 0 °C for 2h, then warmed to 65 °C and stirred at 65 °C for 2h. The reaction mixture was diluted with EtOAc (60 mL) and filtrated. The filtrate was concentrated in vacuum to afford 5-bromocinnolin-4-ol (830 mg, 13.17%) as yellow solid. LCMS (m / z): 224.9 [M+H]+.

[0279] Step 3: A solution of 5-bromocinnolin-4-ol (280 mg, 1.24 mmol, 1.0 eq.) in anhydrous POCI3 (5mL) was stirred at 100 °C for 2h under a N2 atmosphere. The reaction mixture was cooled to 0 °C, diluted with water (50 mL), adjusted pH to7~8 with solid Na2COs and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to afford 5-bromo-4-chlorocinnoline (300 mg, 99%) as a yellow solid. LCMS (m / z): 244.9 [M+H]+.

[0280] Step 4: To a solution of 5-bromo-4-chlorocinnoline (50 mg, 0.21 mmol, 1.0 eq.) in 1,4-dioxane / H2O (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-1(2H)-carboxylate (57 mg, 0.18 mmol, 0.9 eq.), K2CO3 (85 mg, 0.62 mmol, 3.0 eq.) and Pd(dppf)CL (7.5 mg, 0.01 mmol, 0.05 eq.). The reaction was stirred at 80 °C under an N2 atmosphere for 2h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue obtained was purified by prep-TLC (Pet. Ether: EtOAc=2 / l) to afford tert-butyl 5-(4-chlorocinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (40 mg, 56.33%) as a yellow oil. LCMS (m / z): 346.2 [M+H]+.

[0281] Step 5: To a solution of tert-butyl 5-(4-chlorocinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (40 mg, 0.12 mmol, 1.0 eq.) in DME (3 mL) at room temperature was added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (44 mg, 0.35 mmol, 3.0 eq.), K2CO3 (48 mg, 0.35 mmol,3.0 eq.) and Pd(dppf)C12 (8.5 mg, 0.01 mmol, 0.1 eq.). The reaction was stirred at 90 °C under an N2 atmosphere overnight in a sealed tube. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue obtained was purified by prep-TLC (DCM: MeOH=20 / l) to afford tert-butyl 5-(4-methylcinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (21 mg, 56.76%) as a yellow oil. LCMS (m / z): 326.1 [M+H]+.

[0282] Step 6: To a solution of tert-butyl 5-(4-methylcinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (21 mg, 0.06 mmol, 1.0 eq.) in DCM (2 mL) at room temperature was added 4M HC1 in dioxane (1 mL). The mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuum and purified by trituration (DCM) to afford 4-methyl-5-(l, 2,5,6-tetrahydropyridin-3-yl)cinnoline hydrochloride (1-1, 16.8 mg, yield: 99%) as a black solid. LCMS (m / z): 226.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 9.59 (s, 2H), 9.22 (s, 1H), 8.50 - 8.42 (m,Page 53 of 79BTBV-006 360491-2034 3298267231H), 8.00 - 7.93 (m, 1H), 7.77 - 7.68 (m, 1H), 5.88 - 5.80 (m, 1H), 3.92 (q, J = 17.0 Hz, 2H), 3.29 (s, 2H), 2.72 (s, 3H), 2.62 - 2.53 (m, 1H), 2.47 - 2.39 (m, 1H).Example 6 (1-10)Na2CO3, 1,4- dioxane, 90°C 3h Step 3

[0283] Step 1: A solution of 5-bromo-4-chloro-3-methylcinnoline (216 mg, 0.84 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (233.4 mg, 0.75 mmol), Pd(dppf)C12 (30.8 mg, 0.42 mmol) and K2CO3 (348 mg, 0.13 mmol) in l,4-dioxane / H2O (5 mL / 1.3 mL) was stirred at 80 °C for 2 h under N2. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated. The residue was purified by pre-TLC (pet. ether / EtOAc=5 / l) to give tert-butyl 5-(4-chloro-3-methylcinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (202 mg, 67%) as yellow oil. LCMS (m / z): 360.2 [M+H]+.

[0284] Step 2: A solution of tert-butyl 5-(4-chloro-3-methylcinnolin-5-yl)-3,6-dihydropyridine-1(2H) -carboxylate (252 mg, 0.56 mmol) and Ts-NH-NEE (209.1 mg, 1.12 mmol) in CHCh (3 mL) was stirred at 60 °C overnight. The mixture was concentrated, and the residue was used directly for the next step. LCMS (m / z): 510.2 [M+H]+.

[0285] Step 3: A solution of tert-butyl 5-(3-methyl-4-(2-tosylhydrazinyl)cinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (286 mg, 0.56 mmol) and Na2CO3 (535.3 mg, 5.05 mmol) in 1,4-dioxane / H₂O (0.3 mL / 3 mL) was stirred at 90 °C for 3 h. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH=20 / l) to give tert-butyl 5-(3-methylcinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (32 mg, 17.5% yield) as a yellow oil. LCMS (m / z): 326.2 [M+H]+.

[0286] Step 4: To a solution of tert-butyl 5-(3-methylcinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (32 mg, 98.3 umol) in DCM (0.5 mL) was added 4 M HCl / dioxane (1 mL). The mixture was stirred at rt. for 1 h. The mixture was concentrated and purified by trituration (DCM, 2 mL) to give 3-methyl-5-(l,2,5,6-tetrahydropyridin-3-yl)cinnoline (1-10, 22 mg, 85.6% yield) as a brown solid.Page 54 of 79BTBV-006 360491-2034 329826723LCMS (m / z): 226.2 [M+H]+; 1HNMR (400 MHz, DMSO-d6) 59.44 (s, 2H), 8.41 (d, J = 8.5 Hz, 1H), 8.23 (s, 1H), 7.88 (dd, J = 8.5, 7.0 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 6.01 (d, J = 2.5 Hz, 1H), 3.87 (s, 2H), 3.40 - 3.32 (m, 2H), 2.90 (s, 3H), 2.60 - 2.54 (m, 2H).Example 7 (1-7)4 M HCI / 1,4-dioxane, DCM, 0°C-RT, 1-16h i) CHCb, 65 °C, 16h Step 2 ii) Na2CO3, H2O,1,4-dioxane, 95 °C, 3h 1-7Step 1

[0287] Step 1: To a solution of tert-butyl 5-(4-chlorocinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (prepared in example 5, 190 mg, 0.55 mmol, 1.0 eq.) in CHCh (5 mL) was added 4-methylbenzene sulfonohydrazide (205 mg, 1.09 mmol, 2.0 eq.). The reaction was stirred at 65 °C overnight. The mixture was concentrated in vacuum. The residue obtained was dissolved with H2O / dioxane (10 mL / I mL) at room temperature and Na2COs (52.4 mg, 4.94 mmol, 9.0 eq.) was added. The reaction was stirred at 95 °C for 3h. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue obtained was purified by prep-TLC (eluent: DCM: MeOH=20 / l) to afford tert-butyl 5-(cinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (51.45 mg, 30.09%) as a yellow oil. LCMS (m / z): 312.1 [M+H]+.

[0288] Step 2: To a solution oftert-butyl 5-(cinnolin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (65 mg, 0.21 mmol, 1.0 eq.) in DCM (2 mL) at room temperature was added 4M HCl in dioxane (2 mL). The mixture was stirred at room temperature for 2h. The reaction mixture was concentrated in vacuum and purified by trituration (DCM) to afford 5-(l, 2, 5, 6-tetrahydropyridin-3-yl)cinnoline hydrochloride salt (1-7, 51.4 mg, yield: 99.4%) as a yellow solid. LCMS (m / z): 212.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 9.73 (s, 2H), 9.43 (d, J = 6.0 Hz, 1H), 8.48 (t, J = 7.0 Hz, 2H), 8.04 -7.94 (m, 1H), 7.78 (d, J = 7.0 Hz, 1H), 6.06 - 5.95 (m, 1H), 3.91 - 3.82 (m, 2H), 3.40 - 3.27 (m, 2H), 2.63 - 2.54 (m, 2H).Example 8 (1-6)Page 55 of 79BTBV-006 360491-2034 329826723

[0289] To a stirred solution of 5 -bromoquinoline (0.04 g, 0.19 mmol, 1 eq.) and 1 -cyclopropyl -4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (0.05 g, 0.19 mmol, 1 eq.) in 1, 4 dioxane (0.4 mb, 10 vol) and water (0.04 mL, 1 vol) was added tri-potassium phosphate (K3PO4) (0.12 g, 0.58 mmol, 3.0 eq.). The reaction mixture was purged with nitrogen gas for 15 minutes and Pd(dppf)C12. DCM complex (0.02 g, 0.02 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for 12h. The completion of the reaction was monitored by TLC using 80% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 X 15 mL). The combined organic layers were dried over sodium sulphate and concentrated under high vacuum to afford the crude product. The obtained crude product was purified by flash column chromatography on silica gel using 25% ethyl acetate in hexane as eluent to afford 5-(l-cyclopropyl-l,2,3,6-tetrahydropyridin-4-yl)quinoline (1-6, 0.030 g, 62%). LCMS (m / z): 251.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 58.90 (m, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.73 (t, J = 7.0 Hz, 1H), 7.55-7.52 (m, 1H), 7.42 (d, J = 7.0 Hz, 1H), 5.73 (s, 1H), 3.31 (d, J = 3.0 Hz, 2H), 2.91 (t, J = 5.5 Hz, 2H), 2.43 (s, 2H), 1.82-1.78 (m, 1H), 0.51-0.48 (m, 2H), 0.42 (d, J = 3.0 Hz, 2H).Example 9 (1-15, 1-16 and 1-17)

[0290] Step 1: A stirred solution of 3 -bromo-5 -methylpyridine (10 g, 58.13 mmol, 1 eq.) and (bromomethyl) benzene (9.94 g, 58.13 mmol, 1 eq.) in acetone (100 mL, 10 vol) was stirred at 50 °C for 16h. The completion of the reaction was monitored by TLC using 80% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the precipitated solid was fdtered out and dried under a high vacuum to afford l-benzyl-3 -bromo-5 -methylpyridin-l-ium (16 g, quantitative). LCMS (m / z): 262.1 [M]+.

[0291] Step 2: To a stirred solution of l-benzyl-3 -bromo-5 -methylpyridin-l-ium (2.0 g, 7.43 mmol, 1 eq.) in methanol (20 mL, 10 vol) and acetic acid (2.23 g, 37.15 mmol, 5 eq.) was added sodium cyanoborohydride (NaCNBHs) (1.4 g, 22.29 mmol, 3.0 eq.) portion wise at room temperature. The reaction mixture was allowed to stir at room temperature for 3h. The completion of the reaction was monitored by TLC using 10% ethyl acetate in hexane and LCMS analysis. After completion of the Page 56 of 79BTBV-006 360491-2034 329826723reaction, the reaction mixture quenched with water (200 mL) and extracted with ethyl acetate (2 X 200 mL). The combined organic layers were dried over sodium sulphate and concentrated under a high vacuum to afford the crude product. The obtained crude material was purified by flash column chromatography on silica gel using 8% ethyl acetate in hexane as eluent to afford l-benzyl-5-bromo-3-methyl-l,2,3,6-tetrahydropyridine (0.35 g, 18%). LCMS (m / z): 266.1 [M+H]+.

[0292] Step 3: To a stirred solution of quinolin-5-ylboronic acid (0.35 g, 1.01 mmol, 1 eq.) and 1-benzyl-5-bromo-3 -methyl- 1,2, 3, 6-tetrahydropyridine (0.27 g, 1.01 mmol, 1 eq.) in 1, 4 dioxane (3.5 mL, 10 vol) and water (0.35 mL, 1 vol) was added tri potassium phosphate (K3PO4) (0.65 g, 3.04 mmol, 3.0 eq.). The reaction mixture was purged with nitrogen gas for 15 minutes and Pd(dppf)C12. DCM complex (0.08 g, 0.10 mmol, 0.1 eq.) was added at room temperature. The reaction mixture was allowed to stir at 100 °C for 12h. The completion of the reaction was monitored by TLC using 30% ethyl acetate in hexane and LCMS analysis. After completion of the reaction, the reaction mixture quenched with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layer was dried over sodium sulphate and concentrated under a high vacuum to afford the crude material. The obtained crude material was purified by flash column chromatography on silica gel using 25% ethyl acetate in hexane as eluent to afford 5-(l-benzyl-5-methyl-l,2,5,6-tetrahydropyridin-3-yl)quinoline (0.18 g, 57%). LCMS (m / z): 315.2 [M+H]+.

[0293] Step 4: To a stirred solution of 5-(l-benzyl-5-methyl-l,2,5,6-tetrahydropyridin-3-yl)quinoline (0.14 g, 0.44 mmol, 1.0 eq.) in dichloromethane (1.4 mL, 10 vol) was added 1-chloroethyl chloroformate (0.12 mL, 5 vol) at room temperature. The reaction mixture was stirred at room temperature for 6h. After completion of the reaction, the reaction mixture was concentrated under reduce pressure to afford the crude material. The isolated crude material was dissolved in methanol (2.0 mL, 15 vol) and stirred at 80 °C for Ih. The completion of the reaction was monitored by TLC using 10% methanol in dichloromethane and LCMS analysis. The obtained crude material was purified by reverse phase preparative HPLC. The pure fractions were lyophilized to afford 5 -(5 -methyl- 1,2, 5,6-tetrahydropyridin-3-yl)quinoline (0.025 g, 25%). The isolated racemic 5 -(5 -methyl- 1,2, 5,6-tetrahydropyridin-3-yl)quinoline (1-15, 0.025 g) was submitted to chiral prep HPLC purification. (Column: CHIRALPAK IG (250mm x 50mm x 5pm; Mobile Phase A: 0.1% methanolic ammonia in hexane - IPA: MeOH-50-50 (80-20), Mobile Phase B: N / A; Flow rate: 45 mL / min; Gradient: 100 % A in 38 mins; Wave Length: 230 nm; RTl(min) 28.0; RT2(min): 32.0; Sample Solvent: DCM: Mobile phase; Sample Loading: 3 mg; Number Of Runs: 8).

[0294] First eluting isomer: 5-(5-methyl-l,2,5,6-tetrahydropyridin-3-yl)quinoline (1-16, 6.9 mg, light yellow liquid). LCMS (m / z): 225.2 [M+H]+; ’HNMR (400 MHz, DMSO-6): 58.91 (m, IH), 8.47 (d, J = 8.5 Hz, IH), 7.96 (d, J = 8.5 Hz, IH), 7.74 (t, J = 7.0 Hz, IH), 7.57-7.54 (m, IH), 7.42 (d, J = 7.0 Hz, IH), 5.69 (s, IH), 3.51 (s, 2H), 3.19-3.15 (m, IH), 2.60-2.55 (m, IH), 1.23 (s, IH), 1.08 (d, J = 7.0 Hz, 3H).Page 57 of 79BTBV-006 360491-2034 329826723

[0295] Second eluting isomer: 5-(5-methyl-l,2,5,6-tetrahydropyridin-3-yl)quinoline (1-17, 7.3 mg, light yellow liquid). LCMS (m / z): 225.2 [M+H]+; ’HNMR(400 MHz, DMSO-6): 58.90-8.89 (m, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.74 (t, J = 7.0 Hz, 1H), 7.56-7.53 (m, 1H), 7.41 (d, J = 7.0 Hz, 1H), 5.67 (s, 1H), 3.46 (s, 2H), 3.15- 3.11 (m, 1H), 2.55-2.50 (m, 1H), 1.23 (s, 1H), 1.07 (d, J = 7.0 Hz, 3H).Example 10: h5-HT2A Receptor Calcium Assay

[0296] 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.

[0297] Data analysis was performed using Dotmatics. Briefly, data was normalized to low (DMSO) and high controls (5-HT Emax)). Assay Z’ should be greater than 0.5, and on-plate control 5-HT should be within 0.25 log of average.

[0298] h5-HT2A Receptor Calcium Assay results are shown in Table 2. The letter codes for pECso include: The letter codes for pECso include: A (>6); B (>5 - 6); and C (<5). The letter codes for Emax % include: A (>90%); B (>70 - 90%); C (>50 - 70%); and D (<50%).Table 2. h5-HT2A Receptor Calcium Assay ResultsCompound ID pECso Emax1-1 B c1-2 A B1-3 A B1-4 B D1-5 B B1-6 A A1-7 B B1-8 B C1-9 A B1-10 B DI- 11 B B1-12 A B1-13 A D1-14 A C1-15 A APage 58 of 79BTBV-006 360491-2034 3298267231-16 A A1-17 B BExample 11: h5-HT2A Receptor NanoBiT / β-Arrestin Assay

[0299] HEK cells expressing LgBiT tagged 5-HT2A and smBiT P-Arrestin are trypsinized, 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 of NanoGio 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 10.Example 12: h5-HT2B Receptor Calcium Assay

[0300] HEK cells over expressing human 5-HT2B receptor are trypsinized, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pl assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pl Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37°C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 10.Example 13: h5-HT2C Receptor Calcium Assay

[0301] 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 Page 59 of 79BTBV-006 360491-2034 329826723with dye, and fluorescence monitored every 1 second. After 20 seconds 10 µl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 10.Example 14: m5-HT2A Receptor Calcium Assay

[0302] HEK cells over expressing mouse 5-HT2A receptor are trypsinized, counted, and seeded in black, clear-bottomed 384 well plates at a density of 12,500 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media is removed from cell plates and 30 pL assay buffer (20 mM HEPES: HBSS, pH 7.4) is added. 10 pl Calcium 5 dye solution (Molecular Devices: R8186) is added to the wells and incubated at 37°C for 40 minutes. Dye solution is made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time (<10 minutes) just before adding to the cell plate. The plates are placed in the FLIPR, after incubation with dye, and fluorescence monitored every 1 second. After 20 seconds 10 pl test compounds and controls are added to the wells and the fluorescence monitored for 5 minutes at ex / em: 488 nm / 510-570 nm in order to monitor compounds as agonists. All compounds are screened in duplicate using a 9 point half-log dose -response curve on 2 separate occasions. Data analysis is performed as described in Example 10.Example 15: Head Twitch Response and Locomotor Activity in mice.

[0303] 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. The response is a rapid, side-to-side movement of the head and neck. Halberstadt, A. L., Geyer, M. A. Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacology (Berl). 2013; 227(4):727-739; Halberstadt, A. L., Geyer, M. A.. Effect of Hallucinogens on Unconditioned Behavior. Curr Top 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 between the potency of hallucinogens in the mouse head-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).

[0304] 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 are weighed prior to dosing and body weight recorded.Page 60 of 79BTBV-006 360491-2034 329826723A reference (e.g., lysergic acid diethylamide (LSD) or 2,5-dimethoxy-4-iodoamphetamine (DOI)) may be used.

[0305] 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 vl7) for a period of time post dosing. The locomotor activity of all groups is measured using the Ethovision system. Other behaviours of note are also scored. At the conclusion of the observation period (T=30) each mouse will be humanely euthanized using CO2and a cardiac puncture performed prior to confirming death via cervical dislocation. The mice are utilized for brain and blood sampling / DMPK.

[0306] 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.

[0307] Brain: following confirmation of death, the brain is removed from each mouse, rinsed in purified water, blotted dry, weighed, and snap frozen in individual 7 mL precellys tubes, samples to be stored at -80 °C for subsequent analysis of compound levels.

[0308] 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+1) 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 ANOVA on square-root transformed data with treatment and day as factors.Example 16: Forced Swim Test in mice.

[0309] The experiment is designed to utilize the forced swim test (FST), a method with predictive capabilities for evaluating the efficacy of antidepressant medications. Petit-Demouliere, B., Chenu, F., Bourin, M. Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology (Berl). 2005, 177(3), 245-255; Malikowska-Racia, N., Salat, K., Nowaczyk, A., Fijalkowski, L., Popik, P. Dopamine D2 / D3 receptor agonists attenuate PTSD-like symptoms in mice exposed to single prolonged stress. Neuropharmacology 2019, 155, 1-9; McDonnell, C. W., Dunphy-Doherty, F., Rouine, J., et al. The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression. Front Psychiatry 2021, 11, 599588.

[0310] 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 Page 61 of 79BTBV-006 360491-2034 329826723interpreted 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. The 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.

[0311] 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).

[0312] 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. The animal is observed and recorded for a duration of 6 minutes after placement in the tank. After recording, the mouse is delicately dried with a soft paper towel and placed back in its cage under a heat lamp for an additional 6 minutes to warm up. Using ANY-maze software, the active swim time, drift time, and attempts to climb the cylinder wall are analyzed based on the last 4 minutes of the recording. A decrease in active swimming time and lack of attempts to escape the cylinder are indicative of depressive-like symptoms.Example 17: Chronic Social Defeat Methodology.

[0313] In the first part of the CSD study, CD-I male mice undergo aggression screening (mild) in order to score aggressive behaviour toward C57BL / 6J mice to ensure the defeat of the intruder during chronic social defeat (CSD) procedure. The C57BL / 6J male mice are subjected to 10 days of CSD procedure (moderate) followed by the 1st social preference test.

[0314] 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-I mouse is placed in the perforated cylinder (“target present”). The “interaction zone” is defined as the area surrounding 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 Page 62 of 79BTBV-006 360491-2034 329826723interaction time of the test mice with the other individual additional parameters: time spent in the corner 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 drug 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 drug effect on social avoidance. Then, all groups are submitted to the 3rd SP test (mild) to assess the long-term drug effect on social avoidance on Day 21 or 28. Body weight and animal welfare are monitored daily.Page 63 of 79BTBV-006 360491-2034 329826723

Claims

CLAIMS1. A compound of formula I:R10or a pharmaceutically acceptable salt thereof, wherein:is a single or double bond as allowed by valency;X1is N or CR1;X2is N or CR2;X3is N or CR3;X4is N or CR4;X5is N or CR5;X6is N or CR6;X7is N or CR7;X8is N, C, or CR8;each of R1, R2, R3, R4, R5, R6, 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 C1-6aliphatic, 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 C1-6aliphatic or 3-to 8-membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;Ring B is a saturated or partially unsaturated 5 -membered monocyclic heterocyclyl having 1 nitrogen heteroatom, a saturated or partially unsaturated 6- to 7-membered monocyclic heterocyclyl having 1-2 nitrogen heteroatoms, a saturated or partially unsaturated 7- to 8-membered bicyclic spirocyclic having 1-2 nitrogen heteroatoms, or a saturated or partially unsaturated 5- to 9-membered fused or bridged bicyclic heterocyclyl having 1-2 nitrogen heteroatoms;R8and R10are independently hydrogen or optionally substituted C1-6aliphatic;each R9is independently selected from halogen, -CN, -OR, -NR2, or an optionally substituted C1-6Page 64 of 79BTBV-006 360491-2034 329826723aliphatic;n is 0, 1, 2, 3, 4, 5, 6, or 7; andeach R is independently hydrogen or optionally substituted C1-6aliphatic.

2. The compound of claim 1, wherein X1is CR1.

3. The compound of claim 1 or 2, wherein X1is N.

4. The compound of any one of claims 1-3, wherein X2is CR2.

5. The compound of any one of claims 1-3, wherein X2is N.

6. The compound of any one of claims 1-5, wherein X3is CR3.

7. The compound of any one of claims 1-5, wherein X3is N.

8. The compound of any one of claims 1-7, wherein X6is CR6.

9. The compound of any one of claims 1-7, wherein X6is N.

10. The compound of any one of claims 1-9, wherein X7is CR7.

11. The compound of any one of claims 1-9, wherein X7is N.

12. The compound of claim 1, wherein the compound is of formulae Il-a, Il-b, II-c, Il-d, or Il-e:R10R10Page 65 of 79BTBV-006 360491-2034 329826723R10li eor a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is of formulae II-a1, II-b1, II-c1, or II-d1:or a pharmaceutically acceptable salt thereof.R1014. The compound of any one of claims 1-13, wherein Ring Bis Rio R10R10The compound of claim 14, wherein Ring B isPage 66 of 79BTBV-006 360491-2034 329826723R10The compound of claim 14, wherein Ring BisR1°17. The compound of claim 14, wherein Ring Bis18. The compound of claim 17, wherein R8is hydrogen.R1°19. The compound of claim 14, wherein Ring Bis20. The compound of any one of claims 1-12, wherein X8is N.

21. The compound of any one of claims 1-12, wherein X8is C.

22. The compound of any one of claims 1-12, wherein X8is CR8.

23. The compound of claim 1 or 12, wherein the compound is of formulae Ill-al, Ill-bl, III-cl, Ill-dl, or Ill-el:Page 67 of 79BTBV-006 360491-2034 329826723Ill-elor a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 or 12, wherein the compound is of formulae III-a2, III-b2, III-c2, III-d2, or III-e2:III-e2or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 or 12, wherein the compound is of formulae III-a3, III-b3, III-c3, III-d3, or III-e3:Page 68 of 79BTBV-006 360491-2034 329826723R10R10III-d3or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1-12 or 14-25, wherein X4is CR4.

27. The compound of any one of claims 1-12 or 14-25, wherein X4is N.

28. The compound of any one of claims 1-12 or 14-25, wherein X5is CR5.

29. The compound of any one of claims 1-12 or 14-25, wherein X5is N.

30. The compound of any one of claims 1, 12, 13, or 23, wherein the compound is of formulae IV-a1, IV-b1, IV-c1, or IV-d1:bl, IV-cl, or IV-dl:Page 69 of 79BTBV-006 360491-2034 329826723IV-al IV-bl IV-cl IV-dlor a pharmaceutically acceptable salt thereof.

31. The compound of any one of claims 1, 12, 13, or 24, wherein the compound is of formulae IV-a1, IV-b1, IV-c1, or IV-d1:b2, IV-c2, or IV-d2:

32. The compound of any one of claims 1, 12, 13, or 25, wherein the compound is of formulae IV-a3, IV-b3, IV-c3, or IV-d3:or a pharmaceutically acceptable salt thereof.

33. The compound of any one of claims 1-32, wherein n is 0 or 1.

34. The compound of any one of claims 1-33, wherein R9is Ci-6 aliphatic.

35. The compound of claim 34, wherein R9is methyl.Page 70 of 79BTBV-006 360491-2034 32982672336. The compound of anyone of claims 1-35, wherein R10is hydrogen or optionally substituted C1-6 aliphatic.

37. The compound of anyone of claims 1-35, wherein R10is cyclopropyl.

38. The compound of any one of claims 1-37, wherein 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 C1-6aliphatic.

39. The compound of any one of claim 1-38, wherein R1is hydrogen.

40. The compound of any one of claims 1-38, wherein R1is fluoro or chloro.

41. The compound of any one of claims 1-38, wherein R1is -CN.

42. The compound of any one of claims 1-38, wherein R1is -ORA.

43. The compound of claim 42, wherein RAis hydrogen or an optionally substituted C1-6 aliphatic.

44. The compound of claim 43, wherein RAis C1-6 aliphatic optionally substituted with halogen.

45. The compound of any one of claims 1-38, wherein R1is -NR2.

46. The compound of any one of claims 1-38, wherein R1is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

47. The compound of any one of claims 1-38, wherein R1is optionally substituted C1-6aliphatic.

48. The compound of any one of claims 1-38, 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.

49. The compound of any one of claims 1-38, wherein R1is hydrogen, fluoro, chloro, bromo, -CN,-OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, orPage 71 of 79BTBV-006 360491-2034 32982672350. The compound of any one of claim 1-49, wherein R2is hydrogen.

51. The compound of any one of claims 1-49, wherein R2is fluoro or chloro.

52. The compound of any one of claims 1-49, wherein R2is -CN.

53. The compound of any one of claims 1-49, wherein R2is -ORA.

54. The compound of claim 53, wherein RAis hydrogen or an optionally substituted Ci-6aliphatic.

55. The compound of claim 54, wherein RAis C1-6aliphatic optionally substituted with halogen.

56. The compound of any one of claims 1-49, wherein R2is -NR2.

57. The compound of any one of claims 1-49, wherein R2is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

58. The compound of any one of claims 1-49, wherein R2is optionally substituted C1-6 aliphatic.

59. The compound of any one of claims 1-49, 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.

60. The compound of any one of claims 1-49, wherein R2is hydrogen, fluoro, chloro, bromo, -CN,-OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, orThe compound of any one of claim 1-60, wherein R3is hydrogen.

62. The compound of any one of claims 1-60, wherein R3is fluoro or chloro.The compound of any one of claims 1-60, wherein R3is -CN.

64. The compound of any one of claims 1-60, wherein R3is -ORA.Page 72 of 79BTBV-006 360491-2034 32982672365. The compound of claim 64, wherein RAis hydrogen or an optionally substituted C1-6aliphatic.

66. The compound of claim 65, wherein RAis C1-6aliphatic optionally substituted with halogen.

67. The compound of any one of claims 1-60, wherein R3is -NR2.

68. The compound of any one of claims 1-60, wherein R3is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

69. The compound of any one of claims 1-60, wherein R3is optionally substituted C1-6aliphatic.

70. The compound of any one of claims 1-60, wherein 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.

71. The compound of any one of claims 1-60, wherein R3is hydrogen, fluoro, chloro, bromo, -CN,-OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, or.

72. The compound of any one of claim 1-71, wherein R4is hydrogen.

73. The compound of any one of claims 1-71, wherein R4is fluoro or chloro.

74. The compound of any one of claims 1-71, wherein R4is -CN.

75. The compound of any one of claims 1-71, wherein R4is -ORA.

76. The compound of claim 75, wherein RAis hydrogen or an optionally substituted C1-6aliphatic.

77. The compound of claim 76, wherein RAis C1-6aliphatic optionally substituted with halogen.

78. The compound of any one of claims 1-71, wherein R4is -NR2.Page 73 of 79BTBV-006 360491-2034 32982672379. The compound of any one of claims 1-71, wherein R4is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

80. The compound of any one of claims 1-71, wherein R4is optionally substituted Ci-6 aliphatic.

81. The compound of any one of claims 1-71, 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.

82. The compound of any one of claims 1-71, wherein R4is hydrogen, fluoro, chloro, bromo, -CN,-OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, or83. The compound of any one of claim 1-82, wherein R5is hydrogen.

84. The compound of any one of claims 1-82, wherein R5is fluoro or chloro.

85. The compound of any one of claims 1-82, wherein R5is -CN.

86. The compound of any one of claims 1-82, wherein R5is -ORA.

87. The compound of claim 86, wherein RAis hydrogen or an optionally substituted C1-6 aliphatic.

88. The compound of claim 87, wherein RAis C1-6 aliphatic optionally substituted with halogen.

89. The compound of any one of claims 1-82, wherein R5is -NR2.

90. The compound of any one of claims 1-82, wherein R5is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

91. The compound of any one of claims 1-82, wherein R5is optionally substituted C1-6aliphatic.

92. The compound of any one of claims 1-82, wherein R5is an optionally substituted group selected from a 3- to 8 -membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3Page 74 of 79BTBV-006 360491-2034 329826723heteroatoms 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.

93. The compound of any one of claims 1-82, wherein R5is hydrogen, fluoro, chloro, bromo, -CN,-OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, or94. The compound of any one of claim 1-93, wherein R6is hydrogen.

95. The compound of any one of claims 1-93, wherein R6is fluoro or chloro.

96. The compound of any one of claims 1-93, wherein R6is -CN.

97. The compound of any one of claims 1-93, wherein R6is -ORA.

98. The compound of claim 97, wherein RAis hydrogen or an optionally substituted C1-6 aliphatic.

99. The compound of claim 98, wherein RAis C1-6 aliphatic optionally substituted with halogen.

100. The compound of any one of claims 1-93, wherein R6is -NR2.

101. The compound of any one of claims 1-93, wherein R6is -C(O)NR2, -C(O)OR, -NRC(O)R, or - OC(O)R.

102. The compound of any one of claims 1-93, wherein R6is optionally substituted C1-6 aliphatic.

103. The compound of any one of claims 1 -93, wherein 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.

104. The compound of any one of claims 1-93, wherein R6is hydrogen, fluoro, chloro, bromo, -CN,-OH, -OCH3, -OCH2CH3, -OCF3, methyl, ethyl, CF3, or105. The compound of any one of claim 1-104, wherein R7is hydrogen.Page 75 of 79BTBV-006 360491-2034 329826723106. The compound of any one of claims 1-104, wherein R7is fluoro or chloro.

107. The compound of any one of claims 1-104, wherein R7is -CN.

108. The compound of any one of claims 1-104, wherein R7is -ORA.

109. The compound of claim 108, wherein RAis hydrogen or an optionally substituted C1-6aliphatic.

110. The compound of claim 109, wherein RAis C1-6aliphatic optionally substituted with halogen.

110. The compound of any one of claims 1-104, wherein R7is -NR2.

112. The compound of any one of claims 1-104, wherein R7is -C(O)NR2, -C(O)OR, -NRC(O)R, or -OC(O)R.

113. The compound of any one of claims 1-104, wherein R7is optionally substituted C1-6 aliphatic.

114. The compound of any one of claims 1-104, 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.

115. The compound of any one of claims 1-104, wherein R7is hydrogen, fluoro, chloro, bromo, -CN, -OH, -OCH3, -OCH2CH3, -OCF3 methyl, ethyl, CF3, or116. The compound of claim 1, wherein the compound is of Table 1, or a pharmaceutically acceptable salt thereof.

117. A pharmaceutical composition comprising a compound of any one of claims 1-116, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.Page 76 of 79BTBV-006 360491-2034 329826723118. A method of activating 5-HT2AR, or a mutant thereof, in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

119. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a β-arrestin signaling pathway associated with 5-HT2AR in a biological sample, comprising administering to the biological sample a compound of any one of claims 1-116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

120. A method of selectively activating 5 -HT2AR, or a mutant thereof, (e.g., over the 5 -HT2B and / or 5-HT2C receptors, or mutants thereof) in a biological sample comprising contacting said biological sample with a compound of any one of claims 1-116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

121. A method of activating 5-HT2AR, or a mutant thereof, in a patient comprising administering a compound of any one of claims 1 - 116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

122. A method of increasing activation of a G protein signaling pathway associated with 5-HT2AR over a β-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 1-116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

123. 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 1-116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

124. A method for treating a 5-HT2AR-mediated disorder comprising administering to a patient a compound of any one of claims 1 - 116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.

125. A method for treating a neurological disease, disorder, or condition comprising administering to a patient a compound of any one of claims 1 - 116, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 117.Page 77 of 79BTBV-006 360491-2034 329826723126. The method of claim 125, wherein neurological disease, disorder, or condition is depression, anxiety, substance abuse, and headaches.

127. The method of any one of claims 121-126, wherein the patient does not experience a hallucinogenic effect as a result of the activating or treating.Page 78 of 79BTBV-006 360491-2034 329826723

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