Adenosine ligands for the treatment of neurological disorders or chronic heart failure

Abstract

Disclosed are compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein each of A, V, X, Y, Z, R7, R8, R9, R10, R11, R12, R19, R20, R21, R22, R4, m, I and n is defined herein, and their use in the treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome, FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome, CDD and / or one or more symptoms associated with CDD, CHD8-NDD and / or one or more symptoms associated with CHD8-NDD, chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid-range ejection fraction (HFmrEF).

Description

ADENOSINE LIGANDS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS OR CHRONIC HEART FAILURE CROSS REFERENCE TO RELATED APPLICATIONS The benefit of priority is claimed to the United States Provisional Application Number 63 / 532,730,filed 15 August 2023 (15.8.2023), the entire contents of which are included herein and incorporated herein by reference in accordance with PCT Rule 20.6. BACKGROUND

[0001] Adenosine is a purine nucleoside comprised of an adenine group attached to a ribose sugar by a glycosidic bond. Adenosine is present in all cells and released by certain physiological and pathophysiological stimuli. Adenosine is formed intracellularly as an intermediate during the degradation of adenosine 5'-phosphate (AMP) and S-adenosylhomocysteine, but it can be released from the cell, acting as a neurotransmitter by binding to specific receptors. Thus, adenosine may act as both a precursor and a metabolite of adenine nucleotides and, by providing the structural building block of adenosine triphosphate (ATP), it plays a central role in the basic energy transfer of all living organisms (Layland J, Carrick D, Lee M, Oldroyd K, Berry C, JACC Cardiovasc Interv.2014 Jun;7(6):581-91.)

[0002] Adenosine exerts a variety of physiological effects by interacting with cell surface G-protein- coupled receptor subtypes, namely A1, A2A, A2B, and A3 adenosine receptors (ARs). Each receptor is encoded by a different gene. "Adenosine receptor selective agonists" are substances that bind selectively to one or more subtypes of the adenosine receptors, thus mimicking the action of adenosine.

[0003] The actions of these adenosine receptors are mediated intracellularly by the messenger cAMP. In the case of A1 AR agonists (coupling preferably via Gi / o proteins), a decrease of the intracellular cAMP concentration is observed (preferably aEer direct pre-stimulation of adenylate cyclase by forskolin). Correspondingly, A2A and A2B AR agonists (coupling preferably via Gs proteins) lead to an increase of cAMP concentration in the cells, and A2A and A2B AR antagonists lead to a decrease of the cAMP concentration in the cells. As a classical neurotransmitter, adenosine is neither stored nor released and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides (Huang ZL, Urade Y, Hayaishi O, Curr Top Med Chem.2011;11(8):1047-57).BRIEF SUMMARY

[0004] In some aspects, the present disclosure provides the recognition that certain adenosine agonists may be useful in the treatment Rett syndrome and / or one or more symptoms associated with Rett syndrome; FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome; CDKL5 deficiency disorder (CDD) and / or one or more symptoms associated with CDD; CHD8-related neurodevelopmental disorder (CHD8-NDD) and / or one or more symptoms associated with CHD8-NDD; chronic heart failure; heart failure with preserved ejection fraction (HFpEF); heart failure with reduced ejection fraction (HFrEF); or heart failure with mid-range ejection fraction (HFmrEF).

[0005] In some aspects, the present disclosure provides a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -N(R5)C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is -H, halo, -CN, -OR1, or -NR17R18; R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with thenitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); R4is hydrogen or C1-6alkyl; each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C1-6alkyl, or C1-6haloalkyl; R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl; R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; l is 0 or 1; m is 0 or 1; andn is 0, 1, 2, or 3, provided that one or more of the following is true: (A) V is –(CR14R15)- or -N(R16)-; (B) Y is C1-6haloalkyl or C3-6heterocyclyl; (C) Z is -H, halo, -CN, or -NR17R18; (D) R1is C3-6cycloalkyl; (E) at least one of R2and R3is C3-6cycloalkyl; (F) R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; (G) R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; (H) R7is halo; (J) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; (K) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring; (L) R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 0 and l is 1; (M) R10is C1-6alkyl; (N) R19is halo, C1-6alkyl, or C1-6haloalkyl; (O) R20is halo, C1-6alkyl, or C1-6haloalkyl; (Q) R21is halo, C1-6alkyl, or C1-6haloalkyl; (R) R22is halo, C1-6alkyl, or C1-6haloalkyl; (S) l is 0; and (T) n is 3; and further provided that (a) when V is -O-, Y is -NH2, X is S, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, and R21is hydrogen, R22is -F, Z is -OR1, and R1and R9taken together with the atoms to which they are attached form a tetrahydrofuran, then A is not substituted phenyl or substituted thiazolyl;(b) when V is -O-, Y is -NH2, X is S, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -H, then A is not -OH; (c) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring (e.g., piperidinyl), X is -S-, n is 1, m is 0, l is 1, and each of R1, R7, R8, R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -OR1, then A is not substituted thiazolyl; (d) when V is -O-, Y is -NH2, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R7, R8, R9, R10, R11, R12, R19, R20, and R21is -H, R22is -F, then A is not substituted oxazolyl; (e) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17is -H, and R18and R9taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring (i.e., pyrrolidinyl ring), then A is not substituted thiazolyl; (f) when V is -O-, Y is NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -CH3, then A is not phenyl or substituted thiazolyl; (g) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -H, then A is not substituted thiazolyl; (h) when V is -O-, Y is -NH2, X is -S-, n is 0, m is 0, l is 0, each of R9, R10, R19, R20, R21and R22is -H, Z is -H, then A is not phenyl or heterocycloalkyl; (i) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H or -NR17R18, R17and R18are both -H, then A is not substituted 4-pyridyl; (j) when V is -N(R16)-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R16, R19, R20, R21and R22is -H, Z is -H, then A is not substituted 4-pyridyl; (k) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted phenyl; (m) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 4-membered heterocyclyl ring substituted with one or more instances of -OH, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted 4-pyridyl; (n) when V is -O-, Y is -NH2, X is -S-, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not -OH; (o) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, R11is -H or-CH3, and Z is -H, then A is not -C(O)NH2; (p) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not optionally substituted aryl or optionally substituted heteroaryl;(q) when V is -O-, Y is -NH2, X is -S-, n is 3, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, each instance of R11independently is selected from -H and -OH, and Z is -H, then A is not -OH; (r) when V is -O-, Y is -NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, A is substituted thiazolyl, then R3is not cyclopropyl or cyclobutyl; and (s) when V is -O-, Y is NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R9, R10, R11, R12, R19, R20, R21and R22is -H, R7is -CH3, R8is -H or -CH3, A is substituted pyridyl, then R3is not cyclopropyl.

[0006] In some aspects, the present disclosure provides a pharmaceutical composition comprising (a) a compound as disclosed herein or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient.

[0007] In some aspects, the present disclosure provides a compound as disclosed herein (or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as disclosed herein (e.g., a pharmaceutical composition comprising (a) a compound provided herein or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient) for use as a medicament. DETAILED DESCRIPTION Definitions

[0008] The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0009] The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one carbon-carbon double bond.

[0010] As used herein, “aliphatic” or “aliphatic group” 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. 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.

[0011] An “alkyl” group is a straight chain or branched aliphatic group which is completely saturated. Typically, a straight chain or branched alkyl group has from 1 to about 20 carbon atoms,preferably from 1 to about 10 unless otherwise defined. Examples of straight chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-6straight chain or branched alkyl group is also referred to as a "lower alkyl" group.

[0012] The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one carbon-carbon triple bond.

[0013] The term “aryl” refers to monocyclic and bicyclic ring systems having a total offive to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like. 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 wherein the point of attachment is on the aryl ring. Such groups include, for example, indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.

[0014] The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon, and wherein the point of attachment is on the carbocyclic ring. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkyl rings, in which all carbon atoms are saturated, and cycloalkenyl rings, in which the ring contains at least one double bond. “Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]oct-3-enyl, naphthyl and adamantyl. Exemplary fused carbocycles include decalinyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, bicyclo[4.2.0]octanyl, 4,5,6,7-tetrahydro-1H- indenyl and bicyclo[4.1.0]hept-3-enyl.

[0015] A “cycloalkyl” group is a cyclic aliphatic group which is completely saturated, and wherein the point of attachment is on the cycloalkyl ring. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A “cycloalkenyl” group is a cyclic aliphatic that contains one or more double bonds.

[0016] The terms “halo” and “halogen” as used herein mean halogen and includes chloro,fluoro, bromo, and iodo.

[0017] The term “heteroaryl” refers to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, from one tofive heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, and sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized 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. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”.

[0018] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0019] The term “heterocyclyl” (also referred to herein as “heterocycloalkyl”, “heterocycle”, and “heterocyclic”) refer to a stable 3– 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 ofa 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 N–substituted pyrrolidinyl).

[0020] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbon atoms of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0021] As described herein, compounds provided herein may contain “optionally 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 are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0022] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R°, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(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)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR°, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; – C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 3–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur, which may be substituted as defined below.

[0023] 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)0–2R●, – (haloR●), –(CH2)0–2OH, –(CH2)0–2OR●, –(CH2)0–2CH(OR●)2; -O(haloR●), –CN, –N3, –(CH2)0–2C(O)R●, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR●, –(CH2)0–2SR●, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR●, –(CH2)0–2NR●2, –NO2, –SiR●3, –OSiR●3, -C(O)SR●,–(C1–4straight 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0024] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =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, C1-6aliphatic 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, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic 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, and sulfur.

[0025] 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0026] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, –S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6aliphatic 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, and 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, and sulfur.

[0027] 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0028] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and / or variables are permissible only if such combinations result in chemically stable compounds.

[0029] “Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rdEd., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and thelike. Representative hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

[0030] The term "healthcare providers" refers to individuals or organizations that provide healthcare services to a person, community, etc. Examples of "healthcare providers" include doctors, hospitals, continuing care retirement communities, skilled nursing facilities, subacute care facilities, clinics, multispecialty clinics, freestanding ambulatory centers, home health agencies, and HMOs.

[0031] Compounds of the present application containing one or multiple asymmetrically substituted atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or by synthesis using optically active reagents.

[0032] In certain embodiments, compounds of the application may be racemic. For example, in embodiments of the application wherein a compound (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof) is disclosed herein as a particular enantiomer, the application further contemplates the compound in its racemic form. In certain embodiments, a sample comprising a compound provided herein may be enriched in one enantiomer. For example, a sample comprising a compound provided herein may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater % ee.

[0033] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of afirst enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of thefirst enantiomer and only 2% of the second enantiomer.

[0034] In certain embodiments, compounds of the application may have more than one stereocenter. In certain such embodiments, compounds of the application may be enriched in one or more diastereomer. For example, a compound of the application may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

[0035] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (I), or a pharmaceutically acceptable salt thereof). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.

[0036] A variety of compounds in the present application may exist in particular geometric or stereoisomeric forms. The present application takes into account all such compounds, including tautomers, cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as being covered within the scope of this application. All tautomeric forms are encompassed in the present application. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this application, unless the stereochemistry or isomeric form is specifically indicated.

[0037] The present application further includes all pharmaceutically acceptable isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof). An "isotopically" or "radio-labelled" compound is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). For example, in certain embodiments, in compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof), hydrogen atoms are replaced or substituted by one or more deuterium or tritium (e.g., hydrogen atoms on a C1-6alkyl or a C1-6alkoxy are replaced with deuterium, such as d3-methoxy or 1,1,2,2-d4-3-methylbutyl).

[0038] Certain isotopically labelled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof), in the application, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon 14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0039] Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0040] Substitution with positron emi\ng isotopes, such as11C,18F,15O, and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0041] Isotopically labeled compounds (e.g., of formula (I), or pharmaceutically acceptable salts thereof) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically labelled reagent in place of the non-labelled reagent previously employed. Suitable isotopes that may be incorporated in compounds of the present application include but are not limited to2H (also written as D for deuterium),3H (also written as T for tritium),11C,13C,14C,13N,15N,15O,17O,18O,18F,35S,36Cl ,82B r,75Br,76B r,77Br,123I,124I,125I, and131I. Compounds

[0042] In certain embodiments, the present disclosure provides a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -N(R5)C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is -H, halo, -CN, -OR1, or -NR17R18;R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); R4is hydrogen or C1-6alkyl; each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C1-6alkyl, or C1-6haloalkyl; R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl; R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independentlyselected from alkyl (e.g., C1-6alkyl); or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that one or more of the following is true: (A) V is -(CR14R15)- or -N(R16)-; (B) Y is C1-6haloalkyl or C3-6heterocyclyl; (C) Z is -H, halo, -CN, or -NR17R18; (D) R1is C3-6cycloalkyl; (E) at least one of R2and R3is C3-6cycloalkyl; (F) R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; (G) R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; (H) R7is halo; (J) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; (K) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring; (L) R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 0 and l is 1; (M) R10is C1-6alkyl; (N) R19is halo, C1-6alkyl, or C1-6haloalkyl; (O) R20is halo, C1-6alkyl, or C1-6haloalkyl; (Q) R21is halo, C1-6alkyl, or C1-6haloalkyl; (R) R22is halo, C1-6alkyl, or C1-6haloalkyl; (S) l is 0; and (T) n is 3;and further provided that (a) when V is -O-, Y is -NH2, X is S, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, and R21is hydrogen, R22is -F, Z is -OR1, and R1and R9taken together with the atoms to which they are attached form a tetrahydrofuran, then A is not substituted phenyl or substituted thiazolyl; (b) when V is -O-, Y is -NH2, X is S, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -H, then A is not -OH; (c) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring (e.g., piperidinyl), X is -S-, n is 1, m is 0, l is 1, and each of R1, R7, R8, R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -OR1, then A is not substituted thiazolyl; (d) when V is -O-, Y is -NH2, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R7, R8, R9, R10, R11, R12, R19, R20, and R21is -H, R22is -F, then A is not substituted oxazolyl; (e) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17is -H, and R18and R9taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring (i.e., pyrrolidinyl ring), then A is not substituted thiazolyl; (f) when V is -O-, Y is NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -CH3, then A is not phenyl or substituted thiazolyl; (g) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -H, then A is not substituted thiazolyl; (h) when V is -O-, Y is -NH2, X is -S-, n is 0, m is 0, l is 0, each of R9, R10, R19, R20, R21and R22is -H, Z is -H, then A is not phenyl or heterocyclyl; (i) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H or -NR17R18, R17and R18are both -H, then A is not substituted 4-pyridyl; (j) when V is -N(R16)-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R16, R19, R20, R21and R22is -H, Z is -H, then A is not substituted 4-pyridyl; (k) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted phenyl; (m) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 4-membered heterocyclyl ring substituted with one or more instances of -OH, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted 4-pyridyl; (n) when V is -O-, Y is -NH2, X is -S-, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not -OH;(o) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, R11is -H or -CH3, and Z is -H, then A is not -C(O)NH2; (p) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not optionally substituted aryl or optionally substituted heteroaryl; (q) when V is -O-, Y is -NH2, X is -S-, n is 3, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, each instance of R11independently is selected from -H and -OH, and Z is -H, then A is not -OH; (r) when V is -O-, Y is -NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, A is substituted thiazolyl, then R3is not cyclopropyl or cyclobutyl; and (s) when V is -O-, Y is NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R9, R10, R11, R12, R19, R20, R21and R22is -H, R7is -CH3, R8is -H or -CH3, A is substituted pyridyl, then R3is not cyclopropyl.

[0043] In certain embodiments of formula (I), when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then l is not 0. In certain embodiments of formula (I), when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, and Z is -H, then l is not 0. In certain embodiments of formula (I), when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, and each of R9, R10, R11, R12, R19, R20, R21and R22is -H, then Z is not -H. In certain embodiments of formula (I), when V is -O-, m is 0, and l is 0, then Z is not -H.

[0044] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: V is -C(R14)(R15)- or -N(R16)-; and each of A, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0045] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Y is C1-6haloalkyl or C3-6heterocycloalkyl; and each of A, V, X, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0046] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Z is -H, halo, CN, -OR1, or -NR17R18; R1is C3-6cycloalkyl; andeach of A, V, X, Y, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0047] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, OR13, or -NR2R3; R2is -H, C1-6alkyl, or C3-C6cycloalkyl, and R3is C3-C6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; and each of A, V, X, Z, R1, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0048] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R7is halo; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0049] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: (i) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; and each of A, V, X, Y, Z, R2, R3, R4, R5, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I); or (ii) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0050] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:m is 0; l is 1; R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and n are as defined herein for formula (I).

[0051] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: R10is C1-6alkyl; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, m, and n are as defined herein for formula (I).

[0052] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: one of R19', R20', R21'and R22'is halo, C1-6alkyl, or C1-6haloalkyl, and each of the others independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, l, m, and n are as defined for herein formula (I).

[0053] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: l is 0; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, m, and n are as defined herein for formula (I).

[0054] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: n is 3; and each of A, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, l, and m are as defined herein for formula (I).

[0055] In certain embodiments of formula (I):A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)OC1-6alkyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein: optionally substituted aryl is optionally substituted naphthyl; optionally substituted heteroaryl is optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is halo, -CN, -OR1, or -NR17R18; R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; R4is hydrogen or C1-6alkyl; each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C2-6alkyl, or C1-6haloalkyl; R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl;R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -H; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0056] In certain such embodiments: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)OC1-6alkyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, wherein: optionally substituted heteroaryl is optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl; and R7is -H, halo, or C1-6haloalkyl.

[0057] In certain such embodiments: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)OC1-6alkyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl, wherein:optionally substituted heteroaryl is optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl; and R7is -H or halo.

[0058] In certain embodiments of formula (I), A is selected from -CN, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In certain embodiments of formula (I), A is selected from-CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl. In certain embodiments of formula (I), A is selected from-CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl. In certain embodiments of formula (I), A is selected from-CN, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, and optionally substituted heterocycloalkyl. In certain embodiments of formula (I), A is selected from-CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted pyridyl (e.g., optionally substituted 2-pyridyl or optionally substituted 3-pyridyl) or optionally substituted pyridazinyl. In certain embodiments of formula (I), A is selected from-CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, phenyl, pyridyl (e.g., 2-pyridyl or 3-pyridyl) or optionally substituted pyridazinyl. In certain embodiments of formula (I), A is selected from-CN, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, or optionally substituted pyridazinyl. In certain embodiments of formula (I), A is optionally substituted heteroaryl. In certain embodiments of formula (I), A is unsubstituted heteroaryl. In certain embodiments of formula (I), A is not substituted thiazolyl. In certain embodiment of formula (I), A is not substituted oxazolyl. In certain embodiments of formula (I), A is not -OH. In certain embodiments of formula (I), A is not substituted phenyl. In certain embodiments of formula (I), A is phenyl.

[0059] In certain embodiments of formula (I), A is optionally substituted 6-membered heteroaryl. In certain embodiments of formula (I), A is optionally substituted pyridyl, such as optionally substituted 2-pyridyl (e.g., 2-pyridyl), optionally substituted 3-pyridyl (e.g., 3-pyridyl), or optionally substituted pyridazinyl (e.g., pyridazin-3-yl). In certain embodiments of formula (I), A is pyridyl or pyridazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo and C1-3alkyl. In certain embodiments of formula (I), A is pyridyl or pyridazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from -F, -Cl, -CH3, and ethyl. In certain embodiments of formula (I), A is 2-pyridyl, 3-pyridyl or 3-pyridazinyl, each of which is optionally substituted once with -F, -Cl, -CH3, or ethyl. In certain embodiments of formula (I), A is 2-pyridyl, 3-pyridyl or 3-pyridazinyl, each of which is optionally substituted once with -F or -CH3. In certain embodiments of formula (I), A is 2-pyridyl, 3-pyridyl or 3-pyridazinyl, each of which is optionally substituted once with -CH3. In certain embodiments of formula (I), A is 2-pyridyl or 3-pyridyl. In certain embodiments of formula (I), A is 6-methyl-2-pyridyl. In certain embodiments of formula (I), A is 3-pyridyl. In certain embodiments of formula (I), A is 3-pyridazinyl.

[0060] In certain embodiments of formula (I), A is optionally substituted heterocycloalkyl (e.g., oxetanyl). In certain embodiments of formula (I), A is oxetanyl or tetrahydrofuranyl, each of which is optionally substituted. In certain embodiments of formula (I), A is oxetanyl or tetrahydrofuranyl. In certain embodiments of formula (I), A is oxetanyl.

[0061] In certain embodiments of formula (I), V is -(CR14R15)- or -N(R16)-. In certain embodiments of formula (I), V is -O-. In certain embodiments of formula (I), V is -N(R16)-. In certain such embodiments, R16is -H (i.e., V is -NH-). In certain embodiments of formula (I), V is -N(R16)- and R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring (e.g., substituted azetidinyl).

[0062] In certain embodiments of formula (I), V is -(CR14R15)-, Z is -OR1, and: R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring (e.g., tetrahydrofuranyl or tetrahydropyranyl). In certain such embodiments, R1and R15taken together with the atoms to which they are attached form tetrahydrofuranyl or tetrahydropyranyl. In certain such embodiments, R1and R15taken together with the atoms to which they are attached form tetrahydrofuranyl. In certain such embodiments, R1and R15taken together with the atoms to which they are attached form tetrahydropyranyl.

[0063] In certain embodiments of formula (I), V is -(CR14R15)- and each of R14and R15independently is selected from -H and -CH3. In certain such embodiments, V is -CH2-.

[0064] In certain embodiments of formula (I), X is -S-, -O-, or -N(R4)- wherein R4is -H or -CH3. In certain such embodiments, X is -S-, -O-, or -NH-. In certain such embodiments, X is -S- or -O-. In certain such embodiments, X is -S-.

[0065] In certain embodiments of formula (I), Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, or OR13. In certain embodiments of formula (I), Y is C1-6haloalkyl or C3-6heterocyclyl. In certain embodiments of formula (I), Y is C3-6cycloalkyl. In certain such embodiments, Y is cyclopropyl or cyclobutyl. In certain such embodiments, Y is cyclopropyl.

[0066] In certain embodiments of formula (I), Y is -NR2R3. In certain such embodiments, each of R2and R3independently is selected from -H and C1-6alkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6- membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl).

[0067] In certain embodiments of formula (I), Y is -NR2R3, and each of R2and R3independently is selected from -H, C1-6alkyl and C3-6cycloalkyl. In certain such embodiments, each of R2and R3independently is selected from -H and C1-6alkyl. In certain such embodiments, R2and R3are each -H (i.e., Y is -NH2). In certain such embodiments, each of R2and R3independently is selected from -H, C1-3alkyl and cyclopropyl. In certain such embodiments, each of R2and R3independently is selected from -H, -CH3and -CH2CH3.

[0068] In certain embodiments of formula (I), Y is C3-6heterocyclyl (e.g., azetidinyl or pyrrolidinyl).

[0069] In certain embodiments of formula (I), Y is -NR2R3, and R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring (e.g., azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperizinyl), wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo (e.g., -F) and - OH. In certain such embodiments, R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring (e.g., piperidinyl, morpholinyl, or piperizinyl), wherein the 6- membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo (e.g., -F) and -OH.

[0070] In certain embodiments of formula (I), Y is -NR2R3, and R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl).

[0071] In certain embodiments of formula (I), Y is -NR2R3, and R2and R3taken together with the nitrogen to which they are attached form an azetidinyl ring, wherein the azetidinyl ring is optionally substituted with one or more substituents independently selected from halo, -OH, C1-2alkyl, and C1-2haloalkyl, wherein the C1-2alkyl is optionally substituted with -OH or -OCH3. In certain such embodiments, the azetidinyl ring is optionally substituted with 1 or 2 substituents independently selected from -F, -Cl, -OH, and methyl, wherein the methyl is optionally substituted with -OH or -OCH3. In certain such embodiments, the azetidinyl ring is optionally substituted with -F, -OH, or methyl, wherein the methyl is optionally substituted with -OH or -OCH3. In certain such embodiments, the azetidinyl ring is optionally substituted with -F, -CH3OH or -CH3OCH3. In certain such embodiments, the azetidinyl ring is optionally substituted with -F. In certain such embodiments, the azetidinyl ring is substituted with -F.

[0072] In certain embodiments of formula (I), Z is selected from -H, halo, -CN, and -NR17R18. In certain embodiments of formula (I), Z is -OR1and R1is C3-6cycloalkyl. In certain embodiments of formula (I), Z is -OR1. In certain such embodiments, R1is hydrogen (i.e., Z is -OH). In certain embodiments of formula (I), Z is -OR1, and R1is C1-6alkyl, such as methyl (e.g., Z is -OCH3). In certain such embodiments of formula (I), the 4-, 5-, or 6-membered heterocycloalkyl ring is not substituted. In certain embodiments of formula (I), Z is OR1, and R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl ring (e.g., oxetanyl). In certain such embodiments, the 4-, 5-, or 6-membered heterocycloalkyl ring is not substituted. In certain embodiments of formula (I), Z is -OR1, and R1and R9taken together with the atoms to which they are attached form a 4-membered heterocycloalkyl ring (e.g., oxetanyl). In certain embodiments of formula (I), Z is -OR1, and R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl ring. In certain embodiments of formula (I) wherein Z is -OR1, and R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl ring, the 4-, 5-, or 6- membered heterocycloalkyl ring is not substituted (e.g., R1and R8taken together with the atoms to which they are attached do not form a 2,2-dimethyl-1,3-dioxolanyl ring). In certain embodiments of formula (I), Z is halo, such as -F. In certain embodiments of formula (I), Z is -NR17R18, and R17and R18each independently is selected from -H and C1-6alkyl (e.g., Z is -NH2, -NH(CH3), or -N(CH3)2). In certainembodiments of formula (I), Z is -NR17R18, and R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl ring (e.g., Z is an azetidinyl or morpholinyl ring), wherein the 4-, 5-, or 6-membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from halo (e.g., -F).

[0073] In certain embodiments of formula (I), each of R9and R10is -H. In certain embodiments of formula (I), R10is C1-6alkyl. In certain embodiments of formula (I), R9-H and R10is C1-6alkyl. In certain embodiments of formula (I), R10is -CH3. In certain embodiments of formula (I), R9-H and R10is -CH3. In certain embodiments of formula (I), each of R9and R10is -CH3.

[0074] In certain embodiments of formula (I), l is 0. In certain embodiments of formula (I), l is 1. In certain embodiments of formula (I), R7is -H. In certain embodiments of formula (I), R8is -H. In certain such embodiments, each of R7and R8is -H. In certain embodiments of formula (I), R7is halo. In other embodiments of formula (I), l is 1, R7is halo (e.g., -F), and R8is -H.

[0075] In certain embodiments of formula (I), R9is -H or halo, or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycloalkyl ring, or R9and R8taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1. In certain embodiments, R9and R8taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1.

[0076] In certain embodiments of formula (I), m is 0. In certain embodiments of formula (I), m is 1.

[0077] In certain embodiments of formula (I), n is 0. In certain embodiments of formula (I), n is 1. In certain embodiments of formula (I), n is 2. In certain embodiments of formula (I), n is 3. In certain such embodiments, each of R11and R12is hydrogen.

[0078] In certain embodiments of formula (I), R19is halo, C1-6alkyl, or C1-6haloalkyl. In certain embodiments of formula (I), R20is halo, C1-6alkyl, or C1-6haloalkyl. In certain embodiments of formula (I), R21is halo, C1-6alkyl, or C1-6haloalkyl. In certain embodiments of formula (I), R22is halo, C1-6alkyl, or C1-6haloalkyl. In certain embodiments of formula (I), each of R19, R20, R21, and R22independently is -H, -F, or -CH3. In certain embodiments of formula (I), each of R19, R20, R21, and R22is -H.

[0079] In certain embodiments of formula (I), R20is halo (e.g., -F). In certain such embodiments, R20is halo (e.g., -F), and each of R19, R21, and R22is -H.

[0080] In certain embodiments of formula (I), R21is C1-6alkyl (e.g., -CH3). In certain embodiments of formula (I), R19is C1-6alkyl (e.g., -CH3). In certain embodiments of formula (I), each of R19and R21independently is selected from C1-6alkyl (e.g., -CH3), and each of R20and R22is -H.

[0081] In certain embodiments, V is -O- and

[0082] In certain embodiments in which V is -N(R16)- and

[0083] In certain embodiments in which V is -C(R14R15)- and

[0084] In certain embodiments,

[0085] In certain embodiments, Y is -NH2

[0086] In certain embodiments, A is

[0087] In certain embodiments,

[0088] Each of the embodiments of formula (I) can be combined with one or more other embodiments of formula (I) to describe an embodiment of the disclosure. For example, as described above, in certain embodiments of formula (I): V is-N(R16)-; R16is -H; X is -S-; Y is -NR2R3; and each of R2and R3independently is selected from -H and C1-6alkyl.

[0089] In certain embodiments, the compound of formula (I) is not a compound of formula (X), or a pharmaceutically acceptable salt thereof, wherein:Y is selected from hydrogen, C1-6alkyl, C3-6cycloalkyl, OR13, and NR2R3, R2and R3each independently is selected from hydrogen and C1-6alkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocyclyl ring, wherein the 4-or 5-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halogen or hydroxyl; R1is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R7and R8each independently is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; R9is hydrogen or halogen, or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, or R9and R8taken together with the atoms to which they are attached form a cyclopropyl ring system when m is 0 or a cyclobutyl or cyclopentyl ring system when m is 1; R10and R11each independently is selected from hydrogen, hydroxyl, halogen, C1-6alkyl, and C1-6haloalkyl; R12is hydrogen or halogen; R13is selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; X is selected from a bond, S, O, and NR4, wherein R4is hydrogen or C1-6alkyl (e.g., methyl); A is selected from cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, hydroxycarbonyl, C1-6alkoxycarbonyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; R5and R6each independently is selected from hydrogen and C1-6alkyl; m is 0 or 1, provided that when m is 1, R8and R9are taken together with the carbons to which they are attached to form a cyclobutyl or cyclopentyl ring system; and n is 0, 1 or 2.

[0090] The present disclosure provides a compound selected from any one of the following, and pharmaceutically acceptable salts thereof:USE, FORMULATION AND ADMINISTRATION Uses

[0091] In certain embodiments, the present disclosure provides a method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome; FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome; CDKL5 deficiency disorder (CDD) and / or one or more symptoms associated with CDD; CHD8-related neurodevelopmental disorder (CHD8-NDD) and / or one or more symptoms associated with CHD8-NDD; or chronic heart failure, heart failure with preservedejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid- range ejection fraction (HFmrEF), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0092] Currently there is no cure for Rett Syndrome. Treatment for the disorder is symptomatic, i.e., focusing on the management of symptoms, and supportive, requiring a multidisciplinary approach. For example, medication may be used for breathing irregularities and motor difficulties, and anticonvulsant drugs may be used to control seizures. Also, occupational therapy is used to help children develop skills needed for performing self-directed activities (such as dressing, feeding, and practicing arts and craEs), while physical therapy and hydrotherapy may prolong mobility. There is a critical need for agents and methods for treating Rett Syndrome as well as related disorders.

[0093] CDLK5 deficiency disorder is a developmental disease that is generally characterized by seizures appearing during infancy, and typically leads to severe intellectual disability, impaired gross and fine motor function, and cortical visual impairment (Leonard H, Downs J, Benke TA, Swanson L, Olson H, Demarest S, Lancet Neurol.2022 Jun;21(6):563-576; ; doi: 10.1016 / S1474-4422(22)00035-7). Speech is also generally absent in individuals with CDLK5 deficiency disorder. Other common features include stereotypies (oEen involving the hands), sleep disruptions, gastrointestinal problems and may include breathing irregularities. The incidence of CDLK5 deficiency disorder is approximately 1 in 40,000-60,000 with approximately 90% of diagnosed individuals being girls. CDLK5 deficiency disorder had previously been described as an atypical version of Rett syndrome but is now recognized as a separate disorder. Clinical management has focused primarily on seizure management; however, most patients are refractory or exhibit only short term responses to treatment with seizure medications. There is a need for therapies to address the challenges faced by patients with CDLK5 deficiency disorder.

[0094] CDH8 encodes a chromodomain helicase DNA binding protein and mutations disrupting the CDH8 gene have been associated with autism spectrum disorder (ASD), leading to a specific subtype of ASD (Bernier, R, et al., Cell.2014 Jul 17;158(2):263-276; doi: 10.1016 / j.cell.2014.06.017). Individuals with disruptive mutations in CDH8 commonly show macrocephaly, intellectual disabilities, sleep dysfunction and gastrointestinal problems. There is a need for therapies to address the challenges faced by patients with CDH8 mutations.

[0095] FOXG1 syndrome is a developmental disorder which is characterized by structural malformations in the brain, including underdevelopment of the corpus callosum, reduced cortical gyri and white matter deficiencies (Hou P-S, Ó hAilín D, Vogel T and Hanashima C (2020) Front. Cell. Neurosci.14:35. doi: 10.3389 / fncel.2020.00035). Individuals with FOXG1 syndrome generally exhibit microcephaly and have severe intellectual disabilities, involuntary and repetitive movements, seizures, disrupted sleep, ASD and reduced speech and language. FOXG1 syndrome has been previously described as a variant of Rett syndrome, but clinicians generally consider FOXG1 syndrome as a distinct disorder. There remains a significant unmet need for therapies that could address the multiple symptoms afflicting patients with FOXG1 syndrome.

[0096] Heart failure (HF) is a complex cardiovascular syndrome which can involve impaired structure or function of the leE ventricle and is a leading cause of cardiovascular morbidity and mortality. The prevalence of HF is approximately 5.8-6.5 million patients in the U.S. and 26 million globally (Hajouli and Ludhwani, Heart Failure and Ejection Fraction, 2023 StatPearls Publishing, PMID: 31971755). Heart failure involving leE ventricular dysfunction is segregated into three subtypes based on leE ventricular ejection fraction (EF): heart failure with reduced ejection fraction (HFrEF), with EF less than or equal to 40%; heart failure with preserved ejection fraction (HFpEF), with EF greater than or equal to 50%; and heart failure with mid-range ejection fraction (HFmrEF), with EF from 41 to 49%. Symptoms of HFpEF, HFmrEF and HFrEF are similar and increase with physical exertion. These symptoms can include fatigue, weakness,fluid accumulation, wheezing, loss of appetite and palpitations, and can progress to tachycardia and peripheral edema. Recommended treatment approaches for HFrEF include nonpharmacologic therapies such as lifestyle, diet, exercise, weight management and smoking cessation, as well as a range of pharmacologic therapeutic approaches. These pharmacologic therapeutic treatments include Class IA angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, Class IB beta blockers, mineralocorticoid receptor antagonists, nitrates with hydralazine, digoxin, aspirin with statin, ivabradine, sodium-glucose cotransporter 2 inhibitors, and dobutamine or milrinone. Disease-modifying therapies for HFpEF or HFmrEF have not been identified, and therapies that have been effective for HFrEF have not shown similar benefits for HFpEF or HFmrEF. There is a need for therapies to address the challenges faced by patients with HFrEF, HFpEF or HFmrEF.

[0097] Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator. The MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which is needed for brain development and acts as one of the many biochemical switches that can regulate gene expression. Because the MECP2 gene does not function properly in individuals with Rett syndrome, insufficient amounts or structurally abnormal forms of the MeCP2 protein are producedand can cause other genes to be abnormally expressed (Rett Syndrome Fact Sheet; www.ninds.nih.gov / Disorders / Patient-Caregiver-Education / Fact-Sheets / Rett-Syndrome-Fact-Sheet). The prevalence of RTT is high (1 in 10,000 births), and it is one of the most common causes of intellectual and developmental disabilities (IDD) in females. Lifespan and disease severity vary greatly.

[0098] RTT is characterized by progressive development of motor and neurological dysfunction. Girls affected with RTT acquire speech and movement skills on a normal timeline aEer birth but develop symptoms between 6 months and 2 years of age. Neurological manifestations of disease include loss of speech and motor skills, stereotypic hand movements, difficulty walking, sporadic rapid respiration and apnea, and seizures. Apraxia, the inability to perform motor functions, is perhaps the most severely disabling feature of RTT, interfering with every body movement, including eye gaze and speech. Children with Rett syndrome oEen exhibit autistic-like behaviors in the early stages. Other symptoms may include walking on the toes, sleep problems, a wide-based gait, teeth grinding and difficulty chewing, slowed growth, seizures, cognitive disabilities, and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing (Rett Syndrome Fact Sheet; www.ninds.nih.gov / Disorders / Patient-Caregiver-Education / Fact-Sheets / Rett-Syndrome-Fact-Sheet).

[0099] RTT was initially thought to be an entirely neurological disorder, and RTT research focused on the role of MeCP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients also implicate important roles for MeCP2 in peripheral systems (Kyle SM, Vashi N, Justice MJ, Open Biol.2018 Feb;8(2):170216; doi: 10.1098 / rsob.170216). More than 95% of RTT patients carry a mutation in the MECP2 gene. Mechanistically, MECP2 binds to methylated DNA to regulate gene transcription through repression or activation. When MECP2 represses gene transcription, it associates with chromatin-remodeling complexes that contain Type I histone deacetylases (HDACs) (Bienvenu T, Chelly J, Nat Rev Genet.2006 Jun;7(6):415-26; doi: 10.1038 / nrg1878; erratum in: Nat Rev Genet.2006 Jul;7(7):583). Therefore, the elimination of MECP2 may result in the upregulation of genes that would normally be repressed. Notably, the severity of MECP2 mutation does not always correlate with disease severity, due at least in part to favorable patterns of X-chromosome inactivation in heterozygous females.

[0100] Many children diagnosed with RTT have reduced brain volume compared with healthy individuals, consistent with a smaller head circumference. Reduced brain volume is largely due to small neuronal body size and a denser packing of cells, particularly in layers III and V of the cerebral cortex, thalamus, substantia nigra, basal ganglia, amygdala, cerebellum and hippocampus. Patients also havereduced dendritic arborization, indicative of a delay in neuronal maturation. Furthermore, hypopigmentation of the substantia nigra suggests a dysfunction of dopaminergic neurons. RTT patients show evidence of dysregulated neurotransmitters, neuromodulators and transporters, indicating an important role in synaptic function (Kyle SM, Vashi N, Justice MJ, Open Biol.2018 Feb;8(2):170216; doi: 10.1098 / rsob.170216).

[0101] Mouse models that carry Mecp2 mutations and recapitulate most of the symptoms of RTT are available. Mecp2 / Ymale mutant mice are normal at birth and weaning, but develop symptoms that include hypo-activity, limb clasping, tremors, motor impairment and abnormal breathing as early as 4 weeks of age. Such symptoms progressively worsen, leading to their death at 6-16 weeks. Pronounced neuronal deficits are observed in Mecp2 / Ynull mice, including delayed transition into mature stages, altered expression of presynaptic proteins and reduced dendritic spine density.

[0102] Remarkably, re-expression of Mecp2 in mutant male and female mice aEer the onset of symptoms rescues neurological deficits and mice recover normal movements to live a long life (Guy J, Gan J, Selfridge J, Cobb S, Bird A, Science, 2007 Feb 23;315(5815):1143-7; doi: 10.1126 / science.1138389). Thesefindings show that RTT is not caused by a permanent abnormal development of neurons during embryogenesis; instead, MECP2 is required for the maintenance of neurons aEer birth. Thus, RTT may be ameliorated or even reversed by genetic or pharmacological means aEer the onset of symptoms, providing tremendous hope for patients and families. Unfortunately, gene therapy using MECP2 is challenging, because brain function is exquisitely sensitive to levels of MECP2: increased MECP2 causes a progressive neurological disorder that leads to death as well (Bienvenu T, Chelly J, Nat Rev Genet.2006 Jun;7(6):415-26; doi: 10.1038 / nrg1878; erratum in: Nat Rev Genet.2006 Jul;7(7):583).

[0103] In certain embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0104] In certain embodiments, the present disclosure provides a method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome; FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying); CDKL5 deficiency disorder (CDD) and / or one or more symptoms associated with CDD (e.g., repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophagealreflux); and irregular breathing); CHD8-related neurodevelopmental disorder (CHD8-NDD) and / or one or more symptoms associated with CHD8-NDD (e.g., generalized overgrowth, developmental delay / intellectual disability (DD / ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions); or chronic heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), or heart failure with mid- range ejection fraction (HFmrEF) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the present disclosure provides: (i) a method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject (e.g. a mammal, such as a human being), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject (e.g. a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject (e.g. a mammal, such as a human being).

[0106] In certain embodiments, the one or more symptoms associated with Rett syndrome is selected from sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath- holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism.

[0107] In certain embodiments in which the method comprises treating Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject, the method further comprises co- administering to the subject an additional therapeutic agent. In certain such embodiments, the additional therapeutic agent comprises trofinetide.

[0108] In certain embodiments, the present disclosure provides:(i) a method of treating or preventing FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject (e.g., a mammal, such as a human being), comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject (e.g., a mammal, such as a human being).

[0109] In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.

[0110] In certain embodiments, the present disclosure provides: (i) a method of treating or preventing CDD and / or one or more symptoms associated with CDD in a subject (e.g., a mammal, such as a human being), comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of CDD and / or one or more symptoms associated with CDD in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of CDD and / or one or more symptoms associated with CDD in a subject (e.g., a mammal, such as a human being).

[0111] In certain embodiments, the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.

[0112] In certain embodiments, the present disclosure provides: (i) a method of treating or preventing CHD8-NDD and / or one or more symptoms associated with CHD8- NDD in a subject (e.g., a mammal, such as a human being), comprising administering to said subject atherapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of CHD8-NDD and / or one or more symptoms associated with CHD8-NDD in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of CHD8-NDD and / or one or more symptoms associated with CHD8-NDD in a subject (e.g., a mammal, such as a human being).

[0113] In certain embodiments, the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay / intellectual disability (DD / ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.

[0114] In certain embodiments, the present disclosure provides: (i) a method of treating or preventing chronic heart failure in a subject (e.g., a mammal, such as a human being), comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic heart failure in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of chronic heart failure in a subject (e.g., a mammal, such as a human being).

[0115] In certain embodiments, the present disclosure provides: (i) a method of treating or preventing heart failure with preserved ejection fraction (HFpEF) in a subject (e.g., a mammal, such as a human being), comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with preserved ejection fraction (HFpEF) in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of heart failure with preserved ejection fraction (HFpEF) in a subject (e.g., a mammal, such as a human being).

[0116] In certain embodiments, the present disclosure provides: (i) a method of treating or preventing heart failure with reduced ejection fraction (HFrEF) in a subject (e.g., a mammal, such as a human being), comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with reduced ejection fraction (HFrEF) in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of heart failure with reduced ejection fraction (HFrEF) in a subject (e.g., a mammal, such as a human being).

[0117] In certain embodiments, the present disclosure provides: (i) a method of treating or preventing heart failure with mid-range ejection fraction (HFmrEF) in a subject (e.g., a mammal, such as a human being), comprising administering to said subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; (ii) a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with mid-range ejection fraction (HFmrEF) in a subject (e.g., a mammal, such as a human being); or (iii) the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of heart failure with mid-range ejection fraction (HFmrEF) in a subject (e.g., a mammal, such as a human being).

[0118] In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is a brain penetrant. In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is capable of crossing the blood brain barrier. In certain such embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is useful in methods of: (i) treating or preventing Rett syndrome and / or one or more symptoms associated with Rett syndrome (e.g., symptoms described herein); (ii) treating or preventing FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome (e.g., symptoms described herein); (iii) treating or preventing CDD and / or one or more symptoms associated with CDD (e.g., symptoms described herein); or(iv) treating or preventing CHD8-NDD and / or one or more symptoms associated with CHD8-NDD (e.g., symptoms described herein).

[0119] In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is not brain penetrant. In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is not capable of crossing the blood brain barrier (i.e., is peripherally restricted). In certain such embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is useful in methods of treating or preventing chronic heart failure, HFpEF, HFrEF, or HFmrEF. Administration

[0120] Compounds provided herein may be administered orally, parenterally, buccally, vaginally, rectally, via inhalation, via insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly or by injection into the joints. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. The quantity of the compound to be administered will vary for the patient being treated and will vary from about 100 ng / kg of body weight to 100 mg / kg of body weight per day. For instance, dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art. Thus, one skilled in the art can readily determine the amount of compound and optional additives, vehicles, and / or carrier in compositions and to be administered in methods of the application.

[0121] In the treatment of any of the disorders disclosed herein, different compounds of the present disclosure may be administered (e.g., conjointly)with one or more other compounds of the present disclosure. Moreover, compounds of formula (I), or a pharmaceutically acceptable salt thereof, or certain combinations thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein.

[0122] In certain embodiments, compounds of the present disclosure may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeuticcompound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either simultaneously, sequentially, or by separate dosing of the individual components of the treatment. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds. In certain embodiments, conjoint administration of compounds of the present disclosure with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the application (e.g., compound of formula (I), or a pharmaceutically acceptable salt thereof the compound) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the present disclosure and the one or more additional therapeutic agent(s).

[0123] Such conventional therapeutics may include one or more of the following categories of agents: anticonvulsants including, for example, carbamazepine, clonazepam, ethosuximide, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrogine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabaline, rufinamide, topiramate, valproate, vigabatrine, zonisamide and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; insomnia therapies including, for example, agomelatine, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ramelteon, roletamide, triclofos, secobarbital, zaleplon, zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; Rett syndrome therapies including, for example, trofinetide; agents that lower blood pressure by widening blood vessels, such as angiotensin-converting enzyme (ACE) inhibitors (including, for example captopril (Capoten) enalapril (Vasotec), fosinopril(Monopril), lisinopril (Prinivil, Zestril), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), trandolapril (Mavik), benazepril, and moexipril) and angiotensin receptor blockers (ARBs) (including, for example, candesartan (Atacand), losartan (Cozaar), and valsartan (Diovan)); agents that improve artery opening and bloodflow, reduce sodium retention and decreases strain on the heart, such as angiotensin-receptor neprilysin inhibitors (ARNIs) (e.g., a drug combination of a neprilysin inhibitor and an ARB) including, for example, sacubitril / valsartan (Entresto); agents that reduce heart rate, such as I(f) channel blockers including, for example, ivabradine (Corlanor); beta-adrenergic blocking agents (“beta blockers”) including, for example, acebutolol, atenolol (Tenormin), betaxolol (Bisoprolol), carvedilol (Coreg), carvedilol phosphate (Coreg CR), labetalol (Trandate), metoprolol succinate (Toprol XL and Kapspargo Sprinkle), metoprolol tartrate (Lopressor), nadolol (Corgard), nebivolol (Bystolic), pindolol (Visken), and propranolol (Inderal, Inderal LA, and InnoPran XL); agents that improve blood glucose control and decrease body weight and blood pressure, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors including, for example, empagliflozin (Jardiance), and dapagliflozin (Farxiga); aldosterone antagonists including, for example, spironolactone (Aldactone), and eplerenone (Inspra); vasodilators including, for example, hydralazine and nitrates (e.g., nitroglycerin or isosorbide dinitrate) and combinations thereof; diuretics including, for example, furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), chlorothiazide (Diuril), amiloride (Midamor Chlorthalidone, Hygroton), hydrochlorothiazide or HCTZ (Esidrix, Hydrodiuril), indapamide (Lozol), metolazone (Zaroxolyn), and triamterene (Dyrenium); anticoagulants; cholesterol-lowering drugs (e.g., statins); digoxin;calcium channel blockers (CCBs); potassium; and oxygen therapy.

[0124] In certain embodiments, the present disclosure provides conjoint administration of compounds of the application with trofinetide, providing improved efficacy relative to each individual administration of the compound of the present disclosure (e.g., compound of formula (I), or a pharmaceutically acceptable salt thereof or the trofinetide. In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the application and the trofinetide.

[0125] Such combination products employ the compounds of the present disclosure within the dosage range described herein and the other pharmaceutically active compound or compounds within approved dosage ranges and / or the dosage described in the publication reference. PHARMACEUTICAL COMPOSITIONS

[0126] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising as active ingredient a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain such embodiments, the pharmaceutical composition is for treating a disease or disorder in a patient in need thereof, such as a disease or disorder as disclosed herein.

[0127] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising (1) a compound according to formula (I), or a pharmaceutically acceptable salt thereof, (2) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (3) a pharmaceutically acceptable carrier.

[0128] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the application and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment when such pharmaceutical compositions are forhuman administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0129] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the application. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the application. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0130] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0131] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solidfiller, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose andsucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0132] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0133] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of ac5ve ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0134] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the application, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present application with liquid carriers, orfinely divided solid carriers, or both, and then, if necessary, shaping the product.

[0135] Formulations of the present disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes and the like, each containing a predetermined amount of a compound of the present application as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0136] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) we\ng agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed asfillers in soE and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0137] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0138] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example,filtration through a bacteria-retainingfilter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0139] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0140] Besides inert diluents, the oral compositions can also include adjuvants such as we\ng agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

[0141] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0142] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0143] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0144] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0145] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0146] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0147] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0148] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0149] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of suchflux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0150] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present disclosure. Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No.6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimalfluids, aqueous humor or vitreous humor or are compatible with suchfluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0151] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0152] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0153] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Properfluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0154] These compositions may also contain adjuvants such as preservatives, we\ng agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0155] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0156] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0157] For use in the methods of the present disclosure, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0158] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0159] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0160] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0161] A physician having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the application. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0162] In general, a suitable daily dose of an active compound used in the compositions and methods of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0163] If desired, the effective daily dose of the active compound may be administered as one, two, three, four,five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0164] The patient receiving this treatment is any animal in need, including primates, in particular humans.

[0165] This present disclosure includes the use of pharmaceutically acceptable salts of compounds of the application in the compositions and methods of the present disclosure. The term “pharmaceutically acceptable salts” includes salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, such as an amine, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, trifluoroacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzensulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, camphorsulfonic and the like. In certain embodiments, the pharmaceutically acceptable salt is a hydrochloride salt. In certain embodiments, the pharmaceutically acceptable salt is a camsylate salt. In certain embodiments, contemplated salts of the compounds include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of compounds include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)- morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of compounds include, but are not limited to, Li, Na, Ca, K, Mg, Zn or other metal salts. Also included are the salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0166] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. The compounds of the present disclosure, including their pharmaceutically acceptable salts, can also exist as various solvates, such as with water (also known as hydrates), methanol, ethanol, dimethylformamide, diethyl ether, acetamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0167] We\ng agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0168] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. EXAMPLES

[0169] As described 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. Table of AbbreviationsExample 1: Synthetic Protocols

[0170] Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room temperature (about 18 °C to about 25 °C) under nitrogen atmosphere. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure. The course of a reaction was followed by thin layer chromatography (TLC), high- performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC-MS), and reaction times are given for illustration only. The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercriticalfluid chromatography (SFC). Silica gel chromatography was performed on silica gel 60 (230-400 mesh). Chromatography columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, Waters Xbridge Prep OBD®, Waters Xbridge BEH®, Kromasil®, Phenomenex Luna®, etc.

[0171] The structure and purity of allfinal products was assured by at least one of the following analytical methods: nuclear magnetic resonance (NMR) and LC-MS. NMR spectra was recorded on a Bruker 400 MHz NMR Spectrometer using the indicated solvent. Chemical shiE (δ) is given in parts permillion (ppm) relative to tetramethylsilane (TMS) as an internal standard. Coupling constants (J) are expressed in hertz (Hz), and conventional abbreviations used for signal shape are: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad; etc. General synthetic methods for the preparation of the compounds of the present disclosure

[0172] The general synthetic routes to prepare diversely substituted amino-3,5-dicyanopyridine derivatives are depicted in the schemes below. Compounds were synthesized starting from the suitable commercially available 4-hydroxybenzaldehyde properly alkylated, followed by a one-pot cyclization with cyanothioacetamide in the presence of a base such as triethylamine or piperidine. Upon treatment with alkylating agents, the thiolate gave new 2-(alkylthio)pyridines (Matrosova, S. V.; Zav'yalova, V. K.; Litvinov, V. P.; Sharanin, Yu. A. Izvestiya Akademii Nauk SSSR, Seriya Chimucheka (1991), (7), 1643-6. Scheme 1

[0173] Preparation of 6-amino-3,5-dicyanopyridines diversely substituted on C-6 with mono- or dialkylamino groups may then be carried out by reaction with t-butyl nitrite and a copper salt in a solvent such as acetonitrile, followed by nucleophilic substitution of the halogen by a mono- or dialkyl- substituted amine (Scheme 2).Scheme 2

[0174] Compounds wherein the 6-position of the pyridine ring (Y) is hydrogen, alkyl or cycloalkyl, can be prepared by reacting an appropriately substitute aldehyde with a 1:1 mixture of cyanothioacetamide and a 3-substituted-3-oxo-propanenitrile in the in the presence of a base such as triethylamine or piperidine (Scheme 3). Treatment with alkylating agents gives new 2-(alkylthio)pyridines where Y is H, alkyl or cycloalkyl. Scheme 3

[0175] Compounds of formula Ii.e., compounds of Formula I where X is Sand Y = NH2and V is CR14R15, O or NR16are prepared by treatment of an appropriately substituted aromatic aldehyde with 2-cyanothio- acetamide in the presence of a base such as N-methylmorpholine or K2CO3in a solvent such as ethanol to give a biaryl 2-mercaptopyridine.

[0176] The 2-mercaptopyridine can be reacted with an alkylating agent containing a leaving group commonly used in the art such as chloride, bromide, or mesylate in the presence of base in a solvent such as DMF to give a compound of Formula I where A is cyano, hydroxyl, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocycloalkyl, aryl, or optionally substituted heteroaryl.

[0177] A compound of Formula I where R2and R3are H can be further modified to give a compound of Formula I where R2and R3each independently can be C1-6alkyl or R2and R3taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocycloalkyl ring by conversion of the amine to a chloride or bromide using a t-butyl nitrite and a copper salt in a solvent such as acetonitrile. The resulting 2-halopyridine can be treated with an amine such as pyrrolidine or azetidine in a solvent such as methanol or dichloromethane to give a compound of Formula I where R2and R3are each independently C1-6alkyl or R2and R3taken together with the nitrogen to which they are attached form a 4- or 5-membered heterocycloalkyl ring.

[0178] Example 1.1. (R*)-2-(3-fluoroazetidin-1-yl)-6-((oxetan-3-ylmethyl)thio)-4-(4- (tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (49(g))

[0179] As used herein, the designations R* and S* indicate relative the stereochemistry of enantiomers and compounds synthesized therefrom whose absolute configuration has not beendetermined. For example, as described below, compounds 49-G and 49-H are identified by their retention times following separation by SFC. The stereocenter of 49-G is labeled R* above, and 49-I, 49-J and 49(g) are labeled similarly in order to indicate that 49-I, 49-J and 49(g) have the same absolute configuration at the indicated stereocenter as 49-G (be it R or S). Compounds listed in Table E-1 having "(g)" appended to their number similarly have the same absolute configuration at the indicated stereocenter as 49-G. Similarly, compound 50(h) and other compounds listed in Table E-1 having "(h)" appended to their number have the same absolute configuration at the indicated stereocenter as 49-H (be it R or S).

[0180] Step 1.4-(2,5-dihydrofuran-3-yl)benzaldehyde (49-B). To a solution of 4-bromobenzaldehyde (4.00 g, 21.62 mmol, 1 eq) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.66 g, 23.78 mmol, 1.1 eq) in dioxane (50 mL) and H2O (25 mL) was added Pd(dtbpf)Cl2(1.41 g, 2.16 mmol, 0.1 eq) and K2CO3(8.96 g, 64.86 mmol, 3 eq). The mixture was stirred at 60°C for 2 hrs under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70mm,15 um); mobile phase: [H2O (0.2%FA)- ACN]; gradient: 30%-60% B over 24.0 min) to give 4-(2,5-dihydrofuran-3-yl)benzaldehyde (2.2 g, 12.63 mmol, 58.42% yield) as a yellow solid. [M+H]=175.4

[0181] Step 2.4-(Tetrahydrofuran-3-yl)benzaldehyde (49-C). To a solution of 4-(2,5-dihydrofuran-3- yl)benzaldehyde (1.9 g, 10.91 mmol, 1 eq) in MeOH (20 mL) was added Pd / C (11.61 g, 10% Pd on carbon) under N2. The mixture was stirred at 25 °C for 1hr under H2(15 Psi). The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give 4-(tetrahydrofuran-3-yl)benzaldehyde (700 mg, 3.97 mmol, 36.42% yield) as a colorless oil. [M+H]=177.3

[0182] Step 3.2-Amino-6-mercapto-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (49-D). To a solution of 4-(tetrahydrofuran-3-yl)benzaldehyde (700 mg, 3.97 mmol, 1 eq) in EtOH (10 mL) was added piperidine (338.25 mg, 3.97 mmol, 392.31 μL, 1 eq) and 2-cyanothioacetamide (994.54 mg, 9.93 mmol, 2.5 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure to give 2-amino-6-mercapto-4-(4-(tetrahydrofuran-3- yl)phenyl)pyridine-3,5-dicarbonitrile (2 g, crude) as a yellow oil. [M+H]=323.1

[0183] Step 4.2-Amino-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (49-E). To a mixture of 2-amino-6-mercapto-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbo- nitrile (400 mg, 1.24 mmol, 1 eq) in NaOH (0.833 M in H2O, 2.46 mL, 1.65 eq) and MeI (187.99 mg, 1.32 mmol, 82.45 μL, 1.07 eq) at 0°C, the reaction mixture was stirred at 25°C for 1 hr. The reaction mixturewasfiltered and thefilter cake was concentrated under reduced pressure to give 2-amino-6- (methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (400 mg, crude) as a yellow solid. [M+H]=337.3

[0184] Step 5.2-Chloro-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (49-F). To a mixture of 2-amino-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5- dicarbonitrile (380 mg, 1.13 mmol, 1 eq) in ACN (2 mL) was added CuCl2(303.75 mg, 2.26 mmol, 2 eq) and t-BuONO (232.96 mg, 2.26 mmol, 268.70 μL, 2 eq) at 0°C, the reaction mixture was stirred at 40°C for 1 hr. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give 2-chloro-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (400 mg, 1.12 mmol, 99.52% yield) as a yellow solid.

[0185] Step 6. (R*)-2-(3-fluoroazetidin-1-yl)-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)- phenyl)pyridine-3,5-dicarbonitrile (49-G) and (S*)-2-(3-fluoroazetidin-1-yl)-6-(methylthio)-4-(4-(tetra- hydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (49-H). To a mixture of 2-chloro-6-(methylthio)-4-(4- (tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (400 mg, 1.12 mmol, 1 eq) in THF (2 mL) was added DIEA (435.85 mg, 3.37 mmol, 587.39 μL, 3 eq) and 3-fluoroazetidine (150.47 mg, 1.35 mmol, 1.2 eq, HCl) at 0°C, the reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 0:1 to 1:1) and then purified by SFC: (Instrument: Waters SFC80Q Preparative SFC System; Column: DAICEL CHIRALCEL OZ 250*25 mm I.D. 10um;Mobile phase: A for CO2and B for EtOH(0.1% NH3H2O) Gradient: B%=70.00% isocratic elution mode; Flow rate: 80.00g / min; Monitor wavelength: 220&254nmColumn temperature: 40℃ System back pressure: 100 bar) to give peak 1(Rt = 1.418 min), assigned without verification as (R*)-2-(3-fluoro- azetidin-1-yl)-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (150 mg, 380.26 μmol, 33.83% yield) as a yellow solid and peak 2 (Rt = 2.653 min) assigned without verification as (S*)-2-(3-fluoroazetidin-1-yl)-6-(methylthio)-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (120 mg, 304.21 μmol, 27.06% yield) as a yellow solid. [M+H]=395.2

[0186] Step 7.2-(3-Fluoroazetidin-1-yl)-6-(methylsulfinyl)-4-(4-((R*)-tetrahydrofuran-3-yl)phenyl)- pyridine-3,5-dicarbonitrile (49-I). To a solution of 2-(3-fluoroazetidin-1-yl)-6-methylsulfanyl-4-[4-[(3R*)- tetrahydrofuran-3-yl]phenyl]pyridine-3,5-dicarbonitrile (90.00 mg, 228.16 μmol, 1 eq) in DCM (4 mL) was added m-CPBA (46.32 mg, 228.16 μmol, 85% purity, 1 eq) at 0°C. The mixture was stirred at 25°C for 1hr. The reaction mixture wasfiltered, thefilter cake was washed with DCM (10 mL×3). The combinedorganic phase was quenched by sat.aq. Na2SO3(10x 3mL) slowly at 0°C until potassium iodide-starch test paper was negative, washed with brine (10 mL×3), dried over Na2SO4,filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether: Ethyl acetate = 0:1) to give 2-(3- fluoroazetidin-1-yl)-6-(methylsulfinyl)-4-(4-((R*)-tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (90 mg, 219.26 μmol, 96.10% yield) as a white solid. [M+H]=411.3

[0187] Step 8. (R*)-2-(3-fluoroazetidin-1-yl)-6-mercapto-4-(4-(tetrahydrofuran-3-yl)phenyl)pyridine- 3,5-dicarbonitrile (49-J). To a 2-(3-fluoroazetidin-1-yl)-6-(methylsulfinyl)-4-(4-((R)-tetrahydrofuran-3- yl)phenyl)pyridine-3,5-dicarbonitrile (90.00 mg, 219.26 μmol, 1 eq) in DMF (5 mL) was added potassium;ethanethioate (250.42 mg, 2.19 mmol, 10 eq) at 0°C. The mixture was stirred at 25°C for 1hr. The reaction mixture was partitioned between EtOAc (15 mL) and H2O (10 mL), the water phase was extracted with EtOAc (15 mL*3), the combined organic phase was dried over Na2SO4,filtered and concentrated under reduced pressure to give (R)-2-(3-fluoroazetidin-1-yl)-6-mercapto-4-(4-(tetra- hydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (80 mg, crude) as a brown solid. [M+H]=381.3

[0188] Step 9. (R*)-2-(3-fluoroazetidin-1-yl)-6-((oxetan-3-ylmethyl)thio)-4-(4-(tetrahydrofuran-3- yl)phenyl)pyridine-3,5-dicarbonitrile (49(g)). To a solution of (R*)-2-(3-fluoroazetidin-1-yl)-6-mercapto-4- (4-(tetrahydrofuran-3-yl)phenyl)pyridine-3,5-dicarbonitrile (63.51 mg, 420.57 μmol, 2 eq) in DMF (5 mL) was added K2CO3(58.12 mg, 420.57 μmol, 2 eq) and 3-(bromomethyl)oxetane (80 mg, 210.28 μmol, 1 eq). The mixture was stirred at 25 °C for 1hr. The reaction mixture was diluted with H2O (5 mL), filtered and thefilter cake was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18(100 × 30 mm, 10 um);flow rate: 25 mL / min; gradient: 35% – 65% B over 8 min; mobile phase A:10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give (R*)-2-(3-fluoroazetidin-1-yl)-6-((oxetan-3-ylmethyl)thio)-4-(4-(tetrahydrofuran-3- yl)phenyl)pyridine-3,5-dicarbonitrile (49(g)) (24.6 mg, 54.44 μmol, 25.89% yield, 99.7% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 7.48 (s, 4H), 5.64 - 5.38 (m, 1H), 4.84 - 4.69 (m, 2H), 4.67 (dd, J = 7.6, 6.0 Hz, 2H), 4.54 - 4.39 (m, 2H), 4.35 (t, J = 6.4 Hz, 2H), 4.08 (t, J = 7.6 Hz, 1H), 3.98 (dt, J = 8.4, 4.8 Hz, 1H), 3.82 (q, J = 8.0 Hz, 1H), 3.64 - 3.54 (m, 3H), 3.53 - 3.43 (m, 1H), 3.43 - 3.34 (m, 1H), 2.44 - 2.29 (m, 1H), 1.98 (m, 1H). ESI [M+H]=451.1

[0189] Compounds synthesized in a manner similar to that described in Example 1.1 are listed in Table E-1.Table E-1

[0190] Example 1.2. 2-amino-4-(4-(2,2-difluoroethoxy)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (25)

[0191] Step 1.4-(2,2-Difluoroethoxy)benzaldehyde (25-B). A mixture of 4-hydroxybenzaldehyde (5 g, 40.94 mmol, 1 eq), 2-bromo-1,1-difluoroethane (8.90 g, 61.41 mmol, 1.5 eq), Cs2CO3(26.68 g, 81.89 mmol, 2 eq) in DMF (100 mL) was stirred at 50 °C for 12hrs. The reaction mixture was diluted with H2O200 mL and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with sat.aq.NaCl (100 mL), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 1:0) to give 4-(2,2-difluoroethoxy)benzaldehyde (6.8 g, 36.53 mmol, 89.22% yield) as a white solid. [M+H]=187.1

[0192] Step 2.2-Amino-4-(4-(2,2-difluoroethoxy)phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (25- C). A mixture of 4-(2,2-difluoroethoxy)benzaldehyde (3 g, 16.12 mmol, 1 eq), 2-cyanoethanethioamide (3.55 g, 35.45 mmol, 2.2 eq), NMM (3.26 g, 32.23 mmol, 3.54 mL, 2 eq) in EtOH (30 mL) was stirred at 25 °C for 72hrs. The reaction mixture was added H2O (50 mL), then the reaction was mixturefiltered and thefilter cake was concentrated under reduced pressure to give a 2-amino-4-(4-(2,2-difluoro- ethoxy)phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (4.6 g, crude) as a white solid without further purification. [M+H]=331.2

[0193] Step 3.2-Amino-4-(4-(2,2-difluoroethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (25). A mixture of 2-amino-4-(4-(2,2-difluoroethoxy)phenyl)-6-mercaptopyridine-3,5- dicarbonitrile (100 mg, 300.91 μmol, 1 eq), 3-(chloromethyl)pyridine;hydrochloride (74.04 mg, 451.36 μmol, 1.5 eq), K2CO3(83.17 mg, 601.82 μmol, 2 eq) in DMF (2 mL) was stirred at 25 °C for 1hr. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875 × 30mm × 3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:20%-55% B over 8.0 min) to give 2-amino-4-(4-(2,2-difluoroethoxy)phenyl)- 6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (32.6 mg, 68.19 μmol, 22.66% yield, 98.2% purity, FA salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 1.9 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 7.95 (td, J = 8.0, 2.0 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.35 (dd, J = 7.6, 4.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.60 - 6.27 (m, 1H), 4.50 (s, 2H), 4.42 (dt, J = 14.4, 3.6 Hz, 2H). [M+H]=424.2

[0194] Compounds synthesized in a manner similar to that described in Example 1.2 are listed in Table E-2.Table E-2

[0195] Example 1.3. 4-(4-(2,2-difluoroethoxy)phenyl)-2-(3-fluoroazetidin-1-yl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (9)

[0196] Step 1.2-Chloro-4-(4-(2,2-difluoroethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (9-B). To a solution of 2-amino-4-(4-(2,2-difluoroethoxy)phenyl)-6-((pyridin-3-ylmethyl)-thio)pyridine-3,5-dicarbonitrile (150 mg, 354.24 μmol, 1 eq) in ACN (2 mL) was added tert-butyl nitrite (73.06 mg, 708.49 μmol, 84.27 μL, 2 eq) and CuCl (70.14 mg, 708.49 μmol, 16.94 μL, 2 eq). The mixture was stirred at 60 °C for 1hr under N2. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give 2-chloro-4-(4-(2,2-difluoroethoxy)phenyl)-6-((pyridin-3-yl- methyl)thio)pyridine-3,5-dicarbonitrile (140 mg, crude) as a white solid without further purification. [M+H] = 443.0

[0197] Step 2.4-(4-(2,2-Difluoroethoxy)phenyl)-2-(3-fluoroazetidin-1-yl)-6-((pyridin-3-ylmethyl)- thio)pyridine-3,5-dicarbonitrile (9). To a solution of 2-chloro-4-(4-(2,2-difluoroethoxy)phenyl)-6-((pyridin- 3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (140 mg, 316.12 μmol, 1 eq) in THF (2 mL) was added TEA (63.98 mg, 632.24 μmol, 88.00 μL, 2 eq) and 3-fluoroazetidine;hydrochloride (52.89 mg, 474.18 μmol, 1.5 eq). The mixture was stirred at 25 °C for 1hr. The reaction mixture wasfiltered. Thefiltrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100 × 30mm × 10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35% - 65% B over 8.0 min) to give 4-(4-(2,2-difluoroethoxy)phenyl)-2-(3-fluoroazetidin-1-yl)-6-((pyridin-3-yl- methyl)thio)pyridine-3,5-dicarbonitrile (3.2 mg, 6.61 μmol, 2.09% yield, 99.5% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.69 (d, J = 1.2 Hz, 1H), 8.50 (d, J = 3.6 Hz, 1H), 7.88 (br d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.40 (dd, J = 7.6, 4.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 6.45 (tt, J = 54.4, 3.6 Hz, 1H), 5.67 - 5.42 (m, 1H), 4.87 - 4.69 (m, 2H), 4.59 (s, 2H), 4.53 - 4.40 (m, 4H) [M+H]=482.0.

[0198] Compounds synthesized in a manner similar to that described in Example 1.3 are listed in Table E-3 Table E-3

[0199] Example 1.4. 4-(4-(2,2-difluoroethoxy)phenyl)-2-(3-fluoroazetidin-1-yl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (23)

[0200] Step 1. tert-Butyl 3-(2-cyanoacetyl)pyrrolidine-1-carboxylate (23-B). To a mixture of 1-(tert- butyl) 3-methyl pyrrolidine-1,3-dicarboxylate (5 g, 21.81 mmol, 1 eq) and ACN (4.48 g, 109.04 mmol, 5.74 mL, 5 eq) in THF (50 mL) was added t-BuOK (7.34 g, 65.42 mmol, 3 eq) at 0°C, the reaction mixture was stirred at 25°C for 12 hrs. The reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL), the water phase was extracted with EtOAc (50 mL*3), the combined organic phase was dried over Na2SO4,filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl acetate = 1:0 to 3:1) to give tert-butyl 3-(2- cyanoacetyl)pyrrolidine-1-carboxylate (1.2 g, 5.04 mmol, 23.09% yield) as a yellow oil. [M+H-56] =183.0.

[0201] Step 2. tert-Butyl 3-(3,5-dicyano-6-mercapto-4-(4-(2-methoxyethoxy)phenyl)pyridin-2- yl)pyrrolidine-1-carboxylate (23-E). To a mixture of 4-(2-methoxyethoxy)benzaldehyde (100 mg, 554.94 μmol, 1 eq), tert-butyl 3-(2-cyanoacetyl)pyrrolidine-1-carboxylate (145.46 mg, 610.43 μmol, 1.1 eq) and 2-cyanoethanethioamide (61.13 mg, 610.43 μmol, 1.1 eq) in EtOH (3 mL) was added NMM (168.39 mg, 1.66 mmol, 183.03 μL, 3 eq) at 25°C, the reaction mixture was stirred at 80°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give tert-butyl 3-(3,5-dicyano-6-mercapto-4-(4-(2- methoxyethoxy)phenyl)pyridin-2-yl)pyrrolidine-1-carboxylate (250 mg, crude) as a yellow oil. [M+H-56] = 425.0.

[0202] Step 3. tert-Butyl 3-(3,5-dicyano-4-(4-(2-methoxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)- thio)pyridin-2-yl)pyrrolidine-1-carboxylate (23-F). To a mixture of tert-butyl 3-(3,5-dicyano-6-mercapto- 4-(4-(2-methoxyethoxy)phenyl)pyridin-2-yl)pyrrolidine-1-carboxylate (250 mg, 520.21 μmol, 1 eq) and 3-(chloromethyl)pyridine (85.33 mg, 520.21 μmol, 1 eq, HCl) in DMF (1 mL) was added K2CO3(143.79 mg, 1.04 mmol, 2 eq) at 25°C, the reaction mixture was stirred at 25°C for 2 hrs. The reaction mixture was partitioned between EtOAc (15 mL) and H2O (15 mL), the water phase was extracted with EtOAc (15 mL*3), the combined organic phase was dried over Na2SO4,filtered and concentrated to give a crude product. The crude product was purified by prep-TLC (Petroleum ether : Ethyl acetate = 0:1) to give tert- butyl 3-(3,5-dicyano-4-(4-(2-methoxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridin-2-yl)pyrrolidine- 1-carboxylate (100 mg, 174.92 μmol, 33.63% yield) as a yellow oil. [M+H] = 572.2.

[0203] Step 4.4-(4-(2-Methoxyethoxy)phenyl)-2-((pyridin-3-ylmethyl)thio)-6-(pyrrolidin-3-yl)- pyridine-3,5-dicarbonitrile (23). A mixture of tert-butyl 3-(3,5-dicyano-4-(4-(2-methoxyethoxy)phenyl)-6- ((pyridin-3-ylmethyl)thio)pyridin-2-yl)pyrrolidine-1-carboxylate (100 mg, 174.92 μmol, 1 eq) in TFA (0.3 mL) and DCM (1 mL) was stirred at 25°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex luna C18 (100 × 40 mm, 3 um);flow rate: 25 mL / min; gradient: 10% – 40% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 4-(4-(2-methoxyethoxy)phenyl)-2-((pyridin-3-ylmethyl)- thio)-6-(pyrrolidin-3-yl)pyridine-3,5-dicarbonitrile (26.4 mg, 48.59 μmol, 27.78% yield, 95.267% purity, FA salt) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.68 (s, 1H), 8.49 (d, J = 3.8 Hz, 1H), 8.38 - 8.19 (m, 1H), 7.87 (br d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.39 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 4.70 (s, 2H), 4.24 - 4.18 (m, 2H), 3.84 - 3.81 (m, 1H), 3.73 - 3.68 (m, 2H), 3.38 (br d, J = 8.0 Hz, 1H), 3.33 (s, 3H), 3.20 - 3.04 (m, 3H), 2.28 - 2.17 (m, 1H), 2.07 - 1.93 (m, 1H). [M+H] = 472.2.

[0204] Compounds synthesized in a manner similar to that described in Example 1.4 are listed in Table E-4.Table E-4

[0205] Example 1.5. 4-(4-(2,2-difluoroethoxy)phenyl)-2-(3-fluoroazetidin-1-yl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (26)

[0206] Step 1.4,4,5,5-Tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane (26-B). To a solution of 2,2,6,6-tetramethylpiperidine (2 g, 14.16 mmol, 2.40 mL, 1 eq) in THF (5 mL), n-BuLi (2.5 M,5.66 mL, 1 eq) was added dropwise at -30°C under N2, and the mixture was stirred at -30°C for 30 min. Then the reaction was cooled to -78°C, and a solution of bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methane (3.22 g, 12.04 mmol, 0.85 eq) in THF (3 mL) was added drop-wise to the mixture. AEer stirring for 30 min at -78°C, another solution of oxetan-3-one (3.06 g, 42.48 mmol, 3 eq) in THF (3 mL) was added drop-wise at -78°C. The reaction mixture was allowed to slowly warm up to 15°C and stirred for 10 hrs. The reaction mixture was quenched by addition saturated aqueous NH4Cl (10 mL) at 0°C slowly under N2and stirred at 25°C for 15 mins. Then THF was removed under vacuum. The resulting solution was extracted with Ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (2 mL × 2), dried over Na2SO4,filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 10:1 to 1:1) to give 4,4,5,5-tetra- methyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxaborolane (2.5 g, 12.75 mmol, 90.06% yield) as a white oil. [M+H] =197.1.

[0207] Step 2.4-(Oxetan-3-ylidenemethyl)benzaldehyde (26-D). To a mixture of 4-bromobenz- aldehyde (1.8 g, 9.73 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(oxetan-3-ylidenemethyl)-1,3,2-dioxa- borolane (1.91 g, 9.73 mmol, 1 eq) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)Cl2(711.86 mg, 972.88 μmol, 0.1 eq) and KOAc (1.91 g, 19.46 mmol, 2 eq) at 25°C, the reaction mixture was stirred at 80°C for 1hr under N2. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate = 1:0 to 3:1) to give 4-(oxetan-3-ylidenemethyl)benzaldehyde (1.6 g, 9.19 mmol, 94.41% yield) as a white solid. [M+H] = 178.1

[0208] Step 3.4-(Oxetan-3-ylmethyl)benzaldehyde (26-E). To a mixture of 4-(oxetan-3-ylidene- methyl)benzaldehyde (1.5 g, 8.61 mmol, 1 eq) in MeOH (10 mL) was added Pd / C (17.22 mmol, 50% purity) at 25°C, the reaction mixture was stirred at 25°C for 1 hr under the H2(15 Psi). The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give 4-(oxetan-3-yl- methyl)benzaldehyde (1 g, 5.68 mmol, 65.90% yield) as a white solid.

[0209] Step 4.2-Amino-6-mercapto-4-(4-(oxetan-3-ylmethyl)phenyl)pyridine-3,5-dicarbonitrile (26- F). To a solution of 4-(oxetan-3-ylmethyl)benzaldehyde (600 mg, 3.41 mmol, 1 eq) in EtOH (8 mL) was added NMM (1.03 g, 10.22 mmol, 1.12 mL, 3 eq) and 2-cyanothioacetamide (750.17 mg, 7.49 mmol, 2.2 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture wasfiltered andfilter cake was concentrated under reduced pressure to give 2-amino-6-mercapto-4-(4-(oxetan-3-ylmethyl)phenyl)-pyridine-3,5-dicarbonitrile (600 mg, crude) as a white solid and used directly into the next step without further purification. [M+H] = 323.2

[0210] Step 5.2-Amino-4-(4-(oxetan-3-ylmethyl)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (26). To a solution of 2-amino-6-mercapto-4-(4-(oxetan-3-ylmethyl)phenyl)pyridine-3,5- dicarbonitrile (150 mg, 465.28 μmol, 1 eq) in DMF (2 mL) was added K2CO3(128.61 mg, 930.57 μmol, 2 eq) and 3- (chloromethyl)pyridine;hydrochloride (91.59 mg, 558.34 μmol, 1.2 eq). The mixture was stirred at 45°C for 1 hr. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 (100 × 40 mm × 5 um );flow rate: 25 mL / min; gradient: 15% –55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-amino-4-(4-(oxetan-3-ylmethyl)phenyl)-6- ((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (43.1 mg, 93.42 μmol, 20.08% yield, 99.6% purity, FA salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.78 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (td, J =8.0, 2.0 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.37 - 7.31 (m, 3H), 4.67 (dd, J = 7.6, 6.0 Hz, 2H), 4.49 (s, 2H), 4.37 (t, J = 6.0 Hz, 2H), 3.32 - 3.25 (m, 1H), 3.05 (d, J = 8.0 Hz, 2H). [M+H] = 323.2

[0211] Example 1.6. 2-Amino-4-(4-(2-fluoroethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine- 3,5-dicarbonitrile (20)

[0212] Step 1.2-Amino-4-(4-(2-hydroxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (20-B). To a solution of 2-amino-4-(4-(2-hydroxyethoxy)phenyl)-6-mercaptopyridine-3,5- dicarbonitrile (500 mg, 1.60 mmol, 1 eq) in DMF (5 mL) was added K2CO3(442.48 mg, 3.20 mmol, 2 eq) and 3-(chloromethyl)pyridine hydrochloride (315.10 mg, 1.92 mmol, 1.2 eq). The mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O 10mL and extracted with Ethyl acetate 60 mL (20 mL × 3). The combined organic layerswere washed with brine 60 mL (10 mL × 3), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 (100 × 40 mm × 5 um);flow rate: 25 mL / min; gradient: 10% –50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-amino-4-(4-(2-hydroxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)- thio)pyridine-3,5-dicarbonitrile (350 mg, 756.09 μmol, 47.23% yield, 97.1% purity, FA salt) as a white solid. [M+H] = 404.1

[0213] Step 2.2-Amino-4-(4-(2-fluoroethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (20). To a solution of 2-amino-4-(4-(2-hydroxyethoxy)phenyl)-6-((pyridin-3-ylmethyl)- thio)pyridine-3,5-dicarbonitrile (70 mg, 173.50 μmol, 1 eq) in DCM (3 mL) was added DAST (83.90 mg, 520.50 μmol, 68.77 μL, 3 eq) at -78°C. The mixture was stirred at 20°C for 1 hr under N2. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 (100 × 40 mm × 5 um );flow rate: 25 mL / min; gradient: 15% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-amino-4-(4-(2-fluoroethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-di- carbonitrile (2.2 mg, 4.84 μmol, 2.79% yield, 99.3% purity, FA salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.78 (d, J = 1.6 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.35 (dd, J =7.6, 4.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.85 - 4.69 (m, 2H), 4.49 (s, 2H), 4.38 - 4.27 (m, 2H). [M+H] = 406.1

[0214] Example 1.7. 2-amino-4-(4-(2-aminoethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine- 3,5-dicarbonitrile (16)

[0215] Step 1. tert-Butyl (2-(4-(2-amino-3,5-dicyano-6-mercaptopyridin-4-yl)phenoxy)ethyl)- carbamate (16-B). To a solution of tert-butyl (2-(4-formylphenoxy)ethyl)carbamate (1 g, 3.77 mmol, 1 eq) in EtOH (5 mL) was added NMM (1.14 g 1131 mmol 124 mL 3 eq) and 2-cyanoethanethioamide(943.65 mg, 9.42 mmol, 2.5 eq). The mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give tert-butyl (2-(4-(2-amino-3,5-dicyano-6-mercapto- pyridin-4-yl)phenoxy)ethyl)carbamate (1.3 g, crude) as a yellow solid. [M+H] = 412.2

[0216] Step 2. tert-Butyl (2-(4-(2-amino-3,5-dicyano-6-((pyridin-3-ylmethyl)thio)pyridin-4-yl)- phenoxy)ethyl)carbamate (16-C). To a solution of tert-butyl(2-(4-(2-amino-3,5-dicyano-6-mercapto- pyridin-4-yl)phenoxy)ethyl)carbamate (300 mg, 729.08 μmol, 1 eq) in DMF (3 mL) was added K2CO3(201.53 mg, 1.46 mmol, 2 eq) and 3-(chloromethyl)pyridine (143.51 mg, 874.90 μmol, 1.2 eq). The mixture was stirred at 20°C for 1 hr. The residue was diluted with H2O 20 mL and extracted with Ethyl acetate 60 mL (20mL × 3). The combined organic layers were washed with brine 40 mL (20 mL × 2), dried over Na2SO4,filtered and concentrated under reduced pressure to give tert-butyl (2-(4-(2-amino-3,5-di- cyano-6-((pyridin-3-ylmethyl)thio)pyridin-4-yl)phenoxy)ethyl)carbamate (300 mg, crude) as a black solid. [M+H]=503.2

[0217] Step 3.2-Amino-4-(4-(2-aminoethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (16). To a solution of tert-butyl (2-(4-(2-amino-3,5-dicyano-6-((pyridin-3-ylmethyl)thio)- pyridin-4-yl)phenoxy)ethyl)carbamate (250 mg, 497.43 μmol, 1 eq) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25°C for 1 hr. The reaction mixture wasfiltered and thefiltrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18150 × 40 mm × 10 um );flow rate: 25 mL / min; gradient: 20% –50% B over 8 min; mobile phase A:10 mM aqueous NH4HCO3,mobile phase B: acetonitrile) to give 2-amino-4-(4-(2- aminoethoxy)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (28.5 mg, 70.81 μmol, 14.24% yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.77 (s, 1H), 8.45 (d, J = 4.4 Hz, 1H), 7.94 (br d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 4.49 (s, 2H), 4.00 (t, J = 5.6 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.20 - 1.90 (m, 2H). [M+H] = 403.0

[0218] Compounds synthesized in a manner similar to that described in Example 1.7 are listed in Table E-5.Table E-5

[0219] Example 1.8. 2-amino-4-(4-(3-methoxyazetidin-1-yl)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (27) and 2-amino-4-(4-(3-hydroxyazetidin-1-yl)phenyl)-6- ((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (24)

[0220] Step 1.2-Amino-6-mercapto-4-(4-(3-methoxyazetidin-1-yl)phenyl)pyridine-3,5-dicarbonitrile (24-B). To a solution of 4-(3-methoxyazetidin-1-yl)benzaldehyde (1.5 g, 7.84 mmol, 1 eq) in EtOH (30 mL) was added piperidine (3.34 g, 39.22 mmol, 3.87 mL, 5 eq) and 2-cyanoethanethioamide (3.93 g, 39.22 mmol, 5 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture wasfiltered and thefilter cake was concentrated under reduced pressure to give 2-amino-6-mercapto-4-(4-(3-methoxyazetidin-1- yl)phenyl)pyridine-3,5-dicarbonitrile (2.4 g, crude) as a brown solid and used directly into the next step without further purification. [M+H] = 337.9

[0221] Step 2.2-Amino-4-(4-(3-methoxyazetidin-1-yl)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine- 3,5-dicarbonitrile (27). To a solution of 2-amino-6-mercapto-4-(4-(3-methoxyazetidin-1-yl)-phenyl)pyridine-3,5-dicarbonitrile (500 mg, 1.48 mmol, 1 eq) and 3-(chloromethyl)pyridine hydrochloride (364.63 mg, 2.22 mmol, 1.5 eq) in DMF (5 mL) was added K2CO3(409.62 mg, 2.96 mmol, 2 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture wasfiltered. H2O (10 mL) was added to thefiltrate andfiltered again, then thefilter cake was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (Waters Xbridge Prep OBD C18 column (150 × 40 mm, 10 mm);flow rate: 60 mL / min; gradient: 35% – 75% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-amino-4-(4-(3-methoxy- azetidin-1-yl)phenyl)-6-((pyridin-3-ylmethyl)thio)-pyridine-3,5-dicarbonitrile (380.4 mg, 887.73 μmol, 59.90% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.78 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (td, J = 8.0, 2.0 Hz, 1H), 7.39 - 7.33 (m, 3H), 6.56 - 6.51 (m, 2H), 4.49 (s, 2H), 4.35 (tt, J = 6.0, 4.0 Hz, 1H), 4.13 (dd, J = 8.0, 6.4 Hz, 2H), 3.73 (dd, J = 8.8, 4.0 Hz, 2H), 3.26 (s, 3H). [M+H] = 429.0

[0222] Step 3.2-Amino-4-(4-(3-hydroxyazetidin-1-yl)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (24). To a solution of 2-amino-4-(4-(3-methoxyazetidin-1-yl)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (60 mg, 140.02 μmol, 1 eq) in DCM (3 mL) was added BBr3(175.39 mg, 700.10 μmol, 67.46 μL, 5 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 column (100 × 30 mm, 3 mm);flow rate: 25 mL / min; gradient: 10% – 40% B over 8 min; mobile phase A: 0.2% aqueous FA , mobile phase B: acetonitrile) to give 2-amino-4-(4-(3- hydroxyazetidin-1-yl)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (19.6 mg, 41.54 μmol, 29.67% yield, 97.6% purity, FA salt) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.78 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (td, J = 8.0, 2.0 Hz, 1H), 7.39 - 7.32 (m, 3H), 6.52 (d, J = 8.8 Hz, 2H), 5.68 (d, J = 6.8 Hz, 1H), 4.64 - 4.55 (m, 1H), 4.49 (s, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.63 (dd, J = 8.4, 4.8 Hz, 2H). [M+H] = 415.1

[0223] Example 1.9. 2-Amino-4-(4-((2-methoxyethyl)amino)phenyl)-6-((pyridin-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (3)

[0224] Step 1. tert-Butyl (2-methoxyethyl)(4-vinylphenyl)carbamate (3-B). To a solution of N-(2- methoxyethyl)-4-vinylaniline (2.6 g, 14.67 mmol, 1 eq) in dioxane (30 mL) was added di-tert-butyl dicarbonate (3.52 g, 16.14 mmol, 3.71 mL, 1.1 eq). The mixture was stirred at 85°C for 1hr under N2. The reaction mixture was concentrated under reduced pressure to give tert-butyl (2-methoxyethyl)(4-vinyl- phenyl)carbamate (4 g, crude) as a white solid and used directly into the next step without further purification. [M+H] = 278.4

[0225] Step 2. tert-Butyl (4-formylphenyl)(2-methoxyethyl)carbamate (3-C). Ozone (692.25 mg, 14.42 mmol, 1 eq) was bubbled into a solution of tert-butyl (2-methoxyethyl)(4-vinylphenyl)carbamate (4 g, 14.42 mmol, 1 eq) in DCM (40 mL) and MeOH (20 mL) at -78°C for 4 hr. AEer excess O3was purged by N2, the reaction mixture was poured into (300 mL) of H2O and extracted with EtOAc (600 mL). The combined organic phase was extracted with H2O (300 mL), then dried with anhydrous Na2SO4,filtered and concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether : Ethyl acetate = 1:0 to 3:1) to give tert-butyl (4-formylphenyl)(2-methoxyethyl)carbamate (1.3 g, 4.65 mmol, 32.27% yield) as a white oil. [M+H]=280.1

[0226] Step 3. tert-Butyl (4-(2-amino-3,5-dicyano-6-mercaptopyridin-4-yl)phenyl)(2-methoxy- ethyl)carbamate (3-D). To a solution of tert-butyl (4-formylphenyl)(2-methoxyethyl)carbamate (100 mg, 358.00 μmol, 1 eq) in EtOH (2 mL) was added NMM (72.42 mg, 716.00 μmol, 78.72 μL, 2 eq) and 2-cyanoethanethioamide (89.63 mg, 895.00 μmol, 2.5 eq). The mixture was stirred at 80 °C for 1hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (4-(2-amino-3,5-dicyano-6- mercaptopyridin-4-yl)phenyl)(2-methoxyethyl)carbamate (100 mg, crude) as a white solid without further purification. [M+H]=426.3

[0227] Step 4. tert-Butyl (4-(2-amino-3,5-dicyano-6-((pyridin-3-ylmethyl)thio)pyridin-4-yl)phenyl)(2- methoxyethyl)carbamate (3-E). To a solution of tert-butyl (4-(2-amino-3,5-dicyano-6-mercaptopyridin-4- yl)phenyl)(2-methoxyethyl)carbamate (70 mg, 164.51 μmol, 1 eq) in DMF (1 mL) was added K2CO3(68.21 mg, 493.53 μmol, 3 eq) and 3-(chloromethyl)pyridine (20.99 mg, 164.51 μmol, 1 eq). The mixture was stirred at 25 °C for 1hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (4-(2-amino-3,5-dicyano-6-((pyridin-3-ylmethyl)thio)pyridin-4-yl)phenyl)(2-methoxyethyl)carbamate (100 mg, crude) as a red oil. [M+H] = 517.5

[0228] Step 5.2-Amino-4-(4-((2-methoxyethyl)amino)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine- 3,5-dicarbonitrile (3). To a solution of tert-butyl (4-(2-amino-3,5-dicyano-6-((pyridin-3-yl- methyl)thio)pyridin-4-yl)phenyl)(2-methoxyethyl)carbamate (100 mg, 193.57 μmol, 1 eq) in TFA (0.1 mL) and DCM (1 mL). The mixture was stirred at 25 °C for 1hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (100 × 40 mm, 5 um);flow rate: 25 mL / min; gradient: 15% – 55% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-amino-4-(4-((2-methoxyethyl)amino)phenyl)- 6-((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (13.3 mg, 28.76 μmol, 14.86% yield, 100% purity, FA salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.77 (s, 1H), 8.44 (br d, J = 4.0 Hz, 1H), 7.93 (br d, J = 8.0 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.34 (t, J = 5.6 Hz, 1H), 4.47 (s, 2H), 3.50 (t, J = 5.6 Hz, 2H), 3.29 (s, 3H), 3.26 (br d, J = 5.6 Hz, 2H). [M+H]=417.1

[0229] Example 1.10. 2-amino-4-[4-(2-hydroxyethylamino)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (2)

[0230] To a solution of tert-butyl N-[4-[2-amino-3,5-dicyano-6-(3-pyridylmethylsulfanyl)-4- pyridyl]phenyl]-N-(2-methoxyethyl)carbamate (250 mg, 483.92 μmol, 1 eq) in DCM (3 mL) and BBr3 (1 M, 9.68 mL, 20 eq) at 0°C. The mixture was stirred at 25°C for 1hr. The reaction mixture was added to warm water and neutralized with sodium bicarbonate to pH 6-8. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O 20 mL and extracted with DCM 90 mL. The combined organic layers were washed with brine 60 mL, dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column (100 × 40 mm, 5 um);flow rate: 25 mL / min; gradient: 10% – 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2-amino-4-[4-(2-hydroxyethyl- amino)phenyl]-6-(3-pyridylmethylsulfanyl)-pyridine-3,5-dicarbonitrile (5.9 mg, 12.55 μmol, 2.59% yield, 95.4% purity, FA salt) as a white solid.1H NMR (400 MHz, CD3OD) δ = 8.73 – 8.67 (m, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.99 (br d, J = 8.0 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 4.54 (s, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.29 (br s, 2H). [M+H]=403.5

[0231] Example 1.11. 2-amino-4-[4-(3-methoxypropyl)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (29), 2-amino-4-[4-(3-hydroxypropyl)phenyl]-6-(3- pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (28) and 2-amino-4-(4-(3-fluoropropyl)phenyl)-6- ((pyridin-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (21)

[0232] Step 1.4-(3-Methoxypropyl)benzaldehyde (21-B). To a solution of 1-bromo-4-(3- methoxypropyl)benzene (1 g, 4.36 mmol, 1 eq) in THF (10 mL) was added n-BuLi (2.5 M, 5.24 mL, 3 eq), the mixture was stirred at -78 °C for 1 hr , then DMF (638.06 mg, 8.73 mmol, 671.64 μL, 2 eq) was added and the mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition saturated aqueous NH4Cl (20 mL) at 0°C slowly under N2 and stirred at 25°C for 15 mins. Then THF was removed under vacuum. The resulting solution was extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL×3), dried over Na2SO4,filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 100:1 to 10:1) to give 4-(3-methoxypropyl)benzaldehyde (370 mg, 2.08 mmol, 47.56% yield) as a yellow oil.

[0233] Step 2.2-Amino-4-[4-(3-methoxypropyl)phenyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (21-C). To a solution of 4-(3-methoxypropyl)benzaldehyde (370 mg, 2.08 mmol, 1 eq) and 2-cyanothioacetamide (519.74 mg, 5.19 mmol, 2.5 eq) in EtOH (3 mL) was added NMM (629.94 mg, 6.23 mmol, 684.72 μL, 3 eq). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue to give 2-amino-4-[4-(3-methoxypropyl)phenyl]-6-sulfanyl-pyridine-3,5- dicarbonitrile (350 mg, crude) as a yellow solid. [M+H]=325.2

[0234] Step 3.2-Amino-4-[4-(3-methoxypropyl)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5- dicarbonitrile (29). To a mixture of 2-amino-4-[4-(3-methoxypropyl)phenyl]-6-sulfanyl-pyridine-3,5-di- carbonitrile (200 mg, 616.52 μmol, 1 eq) and 3-(chloromethyl)pyridine;hydrochloride (202.26 mg, 1.23 mmol, 2 eq) in DMF (2 mL),was added K2CO3(255.62 mg, 1.85 mmol, 3 eq), the mixture was stirred at 20°C for 1 hr. The residue was diluted with H2O 5 mL, then the reaction mixture wasfiltered and the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex LunaC18 column (100×30 mm, 3µm);flow rate: 25 mL / min; gradient: 15% –55% B over 8 min; mobile phase A: H2O(0.2% FA), mobile phase B: acetonitrile) to give 2-amino-4-[4-(3-methoxypropyl)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5-dicarbonitrile (175 mg, 371.12 μmol, 60.19% yield, 97.876% purity, FA salt) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 1.2 Hz, 1H), 8.46 (br d, J = 3.6 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.46 - 7.42 (m, 2H), 7.39 - 7.35 (m, 3H), 4.50 (s, 2H), 3.37 - 3.35 (m, 2H), 3.25 (s, 3H), 2.72 - 2.67 (m, 2H), 1.88 - 1.81 (m, 2H). [M+H] = 416.2

[0235] Step 4.2-Amino-4-[4-(3-hydroxypropyl)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine-3,5- dicarbonitrile (28). To a solution of 2-amino-4-[4-(3-methoxypropyl)phenyl]-6-(3-pyridylmethyl- sulfanyl)-pyridine-3,5-dicarbonitrile (120 mg, 288.80 μmol, 1 eq) in DCM (2 mL) was added BBr3 (1 mL), and the mixture was stirred at 20°C for 1 hr. The reaction mixture was quenched by addition of saturated aqueous NaHCO3(5 mL) at 0°C, and then extracted with DCM (5 mL ×3). The combined organic layers were dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex LunaC18 column (75×30 mm, 3µm);flow rate: 25 mL / min; gradient: 10% –45% B over 8 min; mobile phase A:H2O(0.2% FA), mobile phase B: acetonitrile) to give 2-amino-4-[4-(3-hydroxypropyl)phenyl]-6-(3-pyridylmethylsulfanyl)pyridine- 3,5-dicarbonitrile (12.3 mg, 25.63 μmol, 8.88% yield, 93.261% purity, FA salt) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 1.2, 4.8 Hz, 1H), 7.95 (td, J = 1.6, 7.6 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.39 - 7.34 (m, 3H), 4.50 (s, 2H), 3.44 (br s, 2H), 2.73 - 2.67 (m, 2H), 1.81 - 1.73 (m, 2H). [M+H]=402.1

[0236] Step 5.2-Amino-4-(4-(3-fluoropropyl)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5- dicarbonitrile (21). To a mixture of 2-amino-4-(4-(3-hydroxypropyl)phenyl)-6-((pyridin-3-ylmethyl)- thio)pyridine-3,5-dicarbonitrile (10 mg, 24.91 μmol, 1 eq) in DCM (1 mL) was added DAST (8.45 mg, 49.82 μmol, 6.93 μL, 95% purity, 2 eq) at -78°C, the reaction mixture was stirred at 25°C for 1 hr under N2. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 × 30 mm, 10 um);flow rate:25 mL / min; gradient: 45% – 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2-amino-4-(4-(3-fluoropropyl)phenyl)-6-((pyridin-3-ylmethyl)thio)pyridine-3,5-di- carbonitrile (0.9 mg, 2.13 μmol, 8.57% yield, 95.665% purity) as a white solid.1H-NMR (400 MHz,CD3OD) δ = 8.74 (s, 1 H), 8.45 (d, J = 3.6 Hz, 1 H), 8.03 (br d, J = 8.4 Hz, 1 H), 7.48 - 7.41 (m, 5 H), 4.61 - 4.57 (m, 2 H), 4.55 (t, J = 6.0 Hz, 1 H), 4.43 (t, J = 6.0 Hz, 1 H), 2.90 - 2.84 (m, 2 H), 2.12 - 2.02 (m, 2 H) [M+H] = 404.0.

[0237] Compounds synthesized in a manner similar to that described in Example 1.11 are listed in Table E-6. Table E-6

[0238] Example 1.12.2-methylamino-4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-6-((oxetan-3- ylmethyl)thio)pyridine-3,5-dicarbonitrile (101)

[0239] Step 1: 4-((cis)-3-fluorocyclobutoxy)benzaldehyde (101-B). To a solution of 4-hydroxy- benzaldehyde (1.3 g, 10.65 mmol, 1 eq), 3-fluorocyclobutanol (978.27 mg, 10.86 mmol, 1.02 eq) and PPh3 (4.19 g, 15.97 mmol, 1.5 eq) in THF (15 mL) was added dropwise DIAD (3.23 g, 15.97 mmol, 3.10 mL, 1.5 eq) under N2 at 0°C, aEer the addition, the reaction was allowed to 50 °C and stirred at 50°C for 3 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE:EtOAc = 1:0 to 1:1) to give 4-((cis)-3-fluorocyclo- butoxy)benzaldehyde (300 mg, 1.54 mmol, 14.51% yield) as a yellow solid.1H NMR (400 MHz, CD3OD) δ = 9.83 (s, 1H), 7.96 - 7.75 (m, 2H), 7.12 - 6.90 (m, 2H), 4.93 (t, J = 6.4 Hz, 1H), 4.82 - 4.74 (m, 1H), 4.54 - 4.35 (m, 1H), 3.15 - 2.96 (m, 2H), 2.41 - 2.27 (m, 2H).

[0240] Step 2: 2-amino-4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-6-mercaptopyridine-3,5-di- carbonitrile (101-C). To a mixture of 4-((cis)-3-fluorocyclobutoxy)benzaldehyde (250 mg, 1.29 mmol, 1 eq) and 2-cyanothioacetamide (283.61 mg, 2.83 mmol, 2.2 eq) in EtOH (5 mL) was added NMM (195.31 mg, 1.93 mmol, 212.30 μL, 1.5 eq), the reaction mixture was stirred at 60°C for 3 hrs under air. The reaction mixture was concentrated under reduced pressure to give 2-amino-4-(4-((cis)-3-fluorocyclo- butoxy)phenyl)-6-mercaptopyridine-3,5-dicarbonitrile (300 mg, crude) as a yellow solid. ESI [M+H] = 341.1.

[0241] Step 3: 2-amino-4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-6-((oxetan-3-ylmethyl)thio)pyridine- 3,5-dicarbonitrile (95). To a solution of 2-amino-4-[4-(3-fluorocyclobutoxy)phenyl]-6-sulfanyl-pyridine- 3,5-dicarbonitrile (300 mg, 880 μmol, 1 eq) and (oxetan-3-yl) methyl 4-methylbenzenesulfonate (230 mg, 925 μmol, 1.1 eq) in DMF (3 mL) was added K2CO3(305 mg, 2.20 mmol, 2.5 eq). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100×30mm×10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 40%-70% B over 8.0 min ) to give to give 2-amino-4-(4- ((cis)-3-fluorocyclobutoxy)phenyl)-6-((oxetan-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (95) (60 mg, 16% yield, 96.3% purity) as a yellow solid. ESI [M+H] = 411.2.1H NMR (400 MHz, DMSO-d6) δ = 8.30 - 7.86 (m, 2H), 7.59 - 7.50 (m, 2H), 7.12 - 7.06 (m, 2H), 5.08 - 4.84 (m, 1H), 4.71 (dd, J = 8.0, 6.4 Hz, 2H), 4.54 - 4.39 (m, 3H), 3.61 (d, J = 7.2 Hz, 2H), 3.46 - 3.41 (m, 0.5H), 3.37 (s, 0.5H), 3.14 (m, 2H), 2.42 - 2.27 (m, 2H).

[0242] Step 4: 2-chloro-4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-6-(((-2-oxetan-3-yl)methyl)thio)- pyridine-3,5-dicarbonitrile (101-E). To a solution of 2-amino-4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-6- ((oxetan-3-ylmethyl)thio)pyridine-3,5-dicarbonitrile (20 mg, 47 μmol, 1 eq) in ACN (1 mL) was added t-BuONO (24 mg, 235 μmol, 28 μL, 5 eq) and CuCl2(25 mg, 188 μmol, 4 eq) and CuCl (23 mg, 235 μmol, 5.6 μL, 5 eq). The mixture was stirred at 60°C for 0.5 hr. The reaction mixture was diluted with EtOAc (2 mL), washed with NH3.H2O (3 × 2 mL), than washed with brine (3 × 2 mL), dried over Na2SO4, filtered, and thefiltrate was concentrated under reduced pressure to give 2-chloro-4-(4-((cis)-3-fluoro- cyclobutoxy)phenyl)-6-(((oxetan-3-yl)methyl)thio)pyridine-3,5-dicarbonitrile (20 mg, crude) as a yellow solid. ESI [M+H] = 444.2.

[0243] Step 5: 4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-2-(methylamino)-6-(((oxetan-3-yl)methyl)- thio)pyridine-3,5-dicarbonitrile (101). To a solution of 2-chloro-4-(4-((cis)-3-fluorocyclobutoxy)phenyl)-6- (((-2-oxetan-3-yl)methyl)thio)pyridine-3,5-dicarbonitrile (20 mg, 45 μmol, 1 eq) and methanamine;hydrochloride (4.6 mg, 68 μmol, 1.5 eq) in ACN (2 mL) was added TEA (23 mg, 225 μmol, 31 μL, 5 eq). The mixture was stirred at 25°C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 column (100 × 30 mm, 3 mm);flow rate: 25 mL / min; gradient: 40% – 70% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 4-(4-((cis)-3-fluorocyclo- butoxy)phenyl)-2-(methylamino)-6-(((oxetan-3-yl)methyl)thio)pyridine-3,5-dicarbonitrile (101). (9 mg, 20.20 μmol, 44% yield, 98.4% purity) as a white solid. ESI [M+H] = 424.1.1H NMR (400 MHz,DMSO-d6) δ = 8.16 (br d, J = 4.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 5.03 - 4.82 (m, 1H), 4.67 (dd, J = 8.8, 6.0 Hz, 2H), 4.48 - 4.40 (m, 1H), 4.37 (t, J = 6.0 Hz, 2H), 3.61 (d, J = 7.2 Hz, 2H), 3.45 - 3.35 (m, 1H), 3.13 - 3.04 (m, 2H), 2.99 (d, J = 4.4 Hz, 3H), 2.37 - 2.22 (m, 2H).

[0244] Compounds synthesized in a manner similar to that described in Example 1.12 are listed in Table E-7. Table E-7Example 2: Biological Activity

[0245] Example 2.1. Adenosine Agonist Activity

[0246] Material and Methods: Biological materials

[0247] SPA35S-GTPγS experiments were conducted with Epics Therapeutics membrane preparations. cAMP HTRF assays were conducted with recombinant cell lines. Receptor accession numbers and cellular backgrounds are shown in Table 2.1. Table 2.1. Cell lines used for in vitro assays

[0248] Conditions for the GTPγS scintillation proximity assay are shown in Table 2.2. Table 2.2. GTPγS scintillation proximity assay (96 w)RT = room temperatureAssay buffer: 20 mM HEPES pH 7.4; 100 mM NaCl, 10 µg / mL saponin, MgCl2at optimized concentration for the specific receptor. Membranes: membrane extracts prepared from CHO-K1 cells expressing recombinant human Adenosine A1 receptor, thawed on ice, diluted in assay buffer and kept on ice. GDP: diluted in assay buffer at the optimized concentration for the specific receptor Beads: PVT-WGA (Perkin Elmer, RPNQ001), diluted in assay buffer at 50 mg / mL (0.5mg / 10 µL) GTPγ35S: (Perkin Elmer, NEG030X), diluted in assay buffer for afinal 0.1 nM assay concentration

[0249] Protocol for agonist testing: membranes are mixed with GDP (volume:volume). In parallel, GTPγ[35S] is mixed with the beads (volume:volume) just before starting the reaction. The following reagents are successively added in the wells of an Optiplate (Perkin Elmer): 50 µL of test or reference ligand, 25 µL of the membranes:GDP mix, and 25 µL of the GTPγ[35S]:beads mix. The plates are covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated for 1 hour at room temperature. Then the plates are centrifuged for 10 min at 2000 rpm, incubated at room temperature and counted for 30 sec / well with a PerkinElmer TopCountTMreader.

[0250] Conditions for the GTPγS scintillation proximity assay are shown in Table 2.3. Table 2.3. cAMP HTRF assays

[0251] cAMP HTRF assay for Gs coupled receptor (A2A and A2B): HEK293 cells expressing recombinant receptor grown prior to the test in media without antibiotic are detached by gentleflushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / L BSA, supplemented with 1 mM IBMX or 25 µM rolipram).

[0252] cAMP HTRF assay for Gi coupled receptor (A1): Cells expressing recombinant receptor grown prior to the test in media without antibiotic are detached by gentleflushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA, supplemented with 1mM IBMX or 25μM Rolipram).

[0253] Dose response curves are performed in parallel with the reference compounds.

[0254] For agonist test (96 well): 12 µL of cells are mixed with 12 µL of the test compound at increasing concentrations and then incubated 30 min at room temperature. AEer addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates are incubated 1 hour incubation at room temperature, andfluorescence ratios are measured according to the manufacturer specification, with the HTRF kit.

[0255] Results are provided in Table 2.3 below, in which the following notation is used:Table 2.3: Adenosine Agonist Activity

[0256] Example 2.2. BCRP permeability assay

[0257] Material and Methods: Biological materials

[0258] MDCK cell lines transfected with the BCRP gene were grown in 75 cm2tissue cultureflasks and split (passed) two times per week to maintain desired confluence. MDCK assay plates were seeded 4 days prior to running the assay. The 24-well plates were seeded at a cell density of 0.88×105 / well in a 400 µL apical chamber volume (2.2×105 / mL) with 25 mL of growth medium added to the 24-well basal chamber. The plates contain an apical side (A or donor chamber) and a basolateral side (B or receiver chamber). Movement or permeability of compound is measured in both directions (A to B and B to A) for 90 minutes at 37 °C. Dosing solutions were prepared as shown in Table 2.4. Teriflunomide, Metoprolol and Atenolol were included as reference standards.Table 2.4. Summary of donor solution and compound preparation

[0259] Dosing solutions were added to the plate as outlined in Table 2.5. Table 2.5. Outline of how dosing solutions were added to the plate

[0260] The plates were warmed to 37 °C and the transport was initiated by placing the apical plate onto the basolateral plate. The plates were incubated for 90 minutes and then separated and the concentration of compounds in the donor and receiver compartments for both A to B and B to A plates were measured by LC-MS / MS. The measurements were performed in duplicate. Lucifer yellow (LY) was included to confirm the cell monolayers had tight junctions based on TEER values. The permeability calculations are as follows: Transepithelial electrical resistance (TEER) = (Resistance sample – Resistance blank) × Effective Membrane Area Drug permeability: Papp = (VA / (Area × Time)) × ([drug]accepter, 90-min / (([drug]donor, 0-min) × Dilution Factor) where:VA is the volume in the acceptor well, the Area is the surface area of the membrane and the Time is the total transport time in seconds; [drug]donor, 0-minand [RFU]donor, 0-minare the donor drug concentration or Lucifer Yellow count measured at 0-min; [drug]acceptor, 90-minand [RFU]acceptor, 90-minare the acceptor drug concentration or Lucifer Yellow count measured at 90-min; and the Dilution Factor is the fold of dilution of the donor sample before loaded to LC-MS / MS.

[0261] Permeability Papp A to B values of < 3 x 10-6cm / sec are low, values between 3 and 10 x 10-6cm / sec are moderate, and values > 10 x 10-6cm / sec are considered high.

[0262] Efflux ratios > 10-fold are considered high and could significantly limit brain penetration, values between 3 and 10 are moderate and could limit brain penetration, and values < 3 are low and would be consistent with good brain penetration.

[0263] Results are provided in Table 2.6. Table 2.6: BCRP Permeability and efflux ratio data

[0264] In some aspects, the present disclosure provides the following enumerated embodiments.

[0265] 1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -N(R5)C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is -H, halo, -CN, -OR1, or -NR17R18; R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with thenitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); R4is hydrogen or C1-6alkyl; each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C1-6alkyl, or C1-6haloalkyl; R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl; R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; l is 0 or 1; m is 0 or 1; andn is 0, 1, 2, or 3; provided that one or more of the following is true: (A) V is -(CR14R15)- or -N(R16)-; (B) Y is C1-6haloalkyl or C3-6heterocyclyl; (C) Z is -H, halo, -CN, or -NR17R18; (D) R1is C3-6cycloalkyl; (E) at least one of R2and R3is C3-6cycloalkyl; (F) R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; (G) R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; (H) R7is halo; (J) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; (K) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring; (L) R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 0 and l is 1; (M) R10is C1-6alkyl; (N) R19is halo, C1-6alkyl, or C1-6haloalkyl; (O) R20is halo, C1-6alkyl, or C1-6haloalkyl; (Q) R21is halo, C1-6alkyl, or C1-6haloalkyl; (R) R22is halo, C1-6alkyl, or C1-6haloalkyl; (S) l is 0; and (T) n is 3; and further provided that (a) when V is -O-, Y is -NH2, X is S, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, and R21is hydrogen, R22is -F, Z is -OR1, and R1and R9taken together with the atoms to which they are attached form a tetrahydrofuran, then A is not substituted phenyl or substituted thiazolyl;(b) when V is -O-, Y is -NH2, X is S, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -H, then A is not -OH; (c) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring (e.g., piperidinyl), X is -S-, n is 1, m is 0, l is 1, and each of R1, R7, R8, R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -OR1, then A is not substituted thiazolyl; (d) when V is -O-, Y is -NH2, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R7, R8, R9, R10, R11, R12, R19, R20, and R21is -H, R22is -F, then A is not substituted oxazolyl; (e) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17is -H, and R18and R9taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring (i.e., pyrrolidinyl ring), then A is not substituted thiazolyl; (f) when V is -O-, Y is NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -CH3, then A is not phenyl or substituted thiazolyl; (g) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -H, then A is not substituted thiazolyl; (h) when V is -O-, Y is -NH2, X is -S-, n is 0, m is 0, l is 0, each of R9, R10, R19, R20, R21and R22is -H, Z is -H, then A is not phenyl or heterocyclyl; (i) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H or -NR17R18, R17and R18are both -H, then A is not substituted 4-pyridyl; (j) when V is -N(R16)-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R16, R19, R20, R21and R22is -H, Z is -H, then A is not substituted 4-pyridyl; (k) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted phenyl; (m) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 4-membered heterocyclyl ring substituted with one or more instances of -OH, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted 4-pyridyl; (n) when V is -O-, Y is -NH2, X is -S-, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not -OH; (o) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, R11is -H or -CH3, and Z is -H, then A is not -C(O)NH2; (p) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not optionally substituted aryl or optionally substituted heteroaryl;(q) when V is -O-, Y is -NH2, X is -S-, n is 3, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, each instance of R11independently is selected from -H and -OH, and Z is -H, then A is not -OH; (r) when V is -O-, Y is -NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, A is substituted thiazolyl, then R3is not cyclopropyl or cyclobutyl; and (s) when V is -O-, Y is NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R9, R10, R11, R12, R19, R20, R21and R22is -H, R7is -CH3, R8is -H or -CH3, A is substituted pyridyl, then R3is not cyclopropyl.

[0266] 2. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)OC1-6alkyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein: optionally substituted aryl is optionally substituted naphthyl; optionally substituted heteroaryl is optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally subs5tuted pyrazinyl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is halo, -CN, -OR1, or -NR17R18; R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclylring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; R4is hydrogen or C1-6alkyl; each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C2-6alkyl, or C1-6haloalkyl; R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl; R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -H; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl;l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3; provided that one or more of the following is true: (A) V is -(CR14R15)- or -N(R16)-; (B) Y is C1-6haloalkyl or C3-6heterocyclyl; (C) Z is -H, halo, -CN, or -NR17R18; (D) R1is C3-6cycloalkyl; (E) at least one of R2and R3is C3-6cycloalkyl; (F) R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; (G) R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; (H) R7is halo; (J) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; (K) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring; (L) R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 0 and l is 1; (M) R10is C1-6alkyl; (N) R19is halo, C1-6alkyl, or C1-6haloalkyl; (O) R20is halo, C1-6alkyl, or C1-6haloalkyl; (Q) R21is halo, C1-6alkyl, or C1-6haloalkyl; (R) R22is halo, C1-6alkyl, or C1-6haloalkyl; (S) l is 0; and (T) n is 3.

[0267] 3. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein V is -C(R14)(R15)- or -N(R16)-.

[0268] 4. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is C1-6haloalkyl or C3-6heterocycloalkyl.

[0269] 5. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: Z is -H, halo, CN, -OR1, or -NR17R18; and R1is C3-6cycloalkyl.

[0270] 6. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R2is -H, C1-6alkyl, or C3-C6cycloalkyl, and R3is C3-C6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl.

[0271] 7. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R7is halo.

[0272] 8. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: (i) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or (ii) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring.

[0273] 9. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: m is 0; l is 1; and R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system.

[0274] 10. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R10is C1-6alkyl.

[0275] 11. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein one of R19', R20', R21'and R22'is halo, C1-6alkyl, or C1-6haloalkyl, and each of the others independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl.

[0276] 12. The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0277] 13. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 6-membered heteroaryl.

[0278] 14. The compound of embodiment 13, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl or pyridazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo and C1-3alkyl.

[0279] 15. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted oxetanyl or optionally substituted tetrahydrofuranyl.

[0280] 16. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein A is.

[0281] 17. The compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein

[0282] 18. The compound of any one of embodiments 1, 2 or 4-17, or a pharmaceutically acceptable salt thereof, wherein V is -O-.

[0283] 19. The compound of embodiments 18, or a pharmaceutically acceptable salt thereof, wherein.

[0284] 20. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein V is -N(R16)-.

[0285] 21. The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, whereinis..

[0286] 22. The compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein R16is -H.

[0287] 23. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein V is -(CR14R15)-.

[0288] 24. The compound of embodiment 23, or a pharmaceutically acceptable salt thereof, wherein,

[0289] 25. The compound of embodiment 23, or a pharmaceutically acceptable salt thereof, wherein each of R14and R15independently is selected from -H and -CH3.

[0290] 26. The compound of any one of embodiments 1-3 or 5-25, or a pharmaceutically acceptable salt thereof, wherein Y is -NR2R3.

[0291] 27. The compound of embodiment 26, or a pharmaceutically acceptable salt thereof, wherein each of R2and R3independently is selected from -H, C1-6alkyl and C3-6cycloalkyl.

[0292] 28. The compound of embodiment 27, or a pharmaceutically acceptable salt thereof, wherein Y is

[0293] 29. The compound of embodiment 26, or a pharmaceutically acceptable salt thereof, wherein R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6- membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH.

[0294] 30. The compound of embodiment 29, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl ring is azetidinyl optionally substituted with one or more substituents independently selected from halo and -OH.

[0295] 31. The compound of embodiment 29, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl ring is.

[0296] 32. The compound of any one of embodiments 1-5 or 7-25, or a pharmaceutically acceptable salt thereof, wherein Y is C3-6heterocyclyl.

[0297] 33. The compound of embodiment 32, or a pharmaceutically acceptable salt thereof, wherein Y is.

[0298] 34. The compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, wherein each of R19, R20, R21, and R22independently is -H, -F, or -CH3.

[0299] 35. The compound of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein

[0300] 36. The compound of any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein: X is -S-, -O-, or -N(R4)-; and R4is -H or -CH3.

[0301] 37. The compound of embodiment 36, or a pharmaceutically acceptable salt thereof, wherein X is -S-.

[0302] 38. A pharmaceutical composition, comprising the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0303] 39. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0304] 40. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject.

[0305] 41. A method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0306] 42. The method of embodiment 41, further comprising administering to the subject an additional therapeutic agent.

[0307] 43. The method of embodiment 42, wherein the additional therapeutic agent comprises trofinetide.

[0308] 44. The use of a compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject.

[0309] 45. The compound or pharmaceutically acceptable salt of embodiment 40, the method of any one of embodiments 41-43, or the use of embodiment 44, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances, including irregular sleep times, falling asleep during the day and being awake at night, or waking in the night with crying or screaming; sleep apnea; seizures, including those accompanied by an abnormal electroencephalogram (EEG); breathing disorders, including breath-holding, abnormally rapid breathing (hyperventilation), forceful exhalation of air or saliva, and swallowing air; irregular heartbeat, including problems with heart rhythm such as abnormally long pauses between heartbeats (e.g., as measured by an electrocardiogram), and other types of arrhythmia; intellectual disabilities; and autism.

[0310] 46. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject.

[0311] 47. A method of treating FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0312] 48. The use of a compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject.

[0313] 49. The compound or pharmaceutically acceptable salt of embodiment 46, the method of embodiment 47, or the use of embodiment 48, wherein the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.

[0314] 50. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of CDD and / or one or more symptoms associated with CDD in a subject.

[0315] 51. A method of treating CDD and / or one or more symptoms associated with CDD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0316] 52. The use of a compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of CDD and / or one or more symptoms associated with CDD in a subject.

[0317] 53. The compound or pharmaceutically acceptable salt of embodiment 50, the method of embodiment 52, or the use of embodiment 53, wherein the one or more symptoms associated with CDD is selected from repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing.

[0318] 54. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of CHD8-NDD and / or one or more symptoms associated with CHD8- NDD in a subject.

[0319] 55. A method of treating CHD8-NDD and / or one or more symptoms associated with CHD8- NDD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0320] 56. The use of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of CHD8-NDD and / or one or more symptoms associated with CHD8-NDD in a subject.

[0321] 57. The compound or pharmaceutically acceptable salt of embodiment 54, the method of embodiment 55, or the use of embodiment 56, wherein the one or more symptoms associated with CHD8-NDD is selected from generalized overgrowth, developmental delay / intellectual disability (DD / ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, gastrointestinal and sleep dysfunctions.

[0322] 58. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic heart failure in a subject.

[0323] 59. A method of treating chronic heart failure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0324] 60. The use of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of chronic heart failure in a subject.

[0325] 61. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with preserved ejection fraction (HFpEF) in a subject.

[0326] 62. A method of treating heart failure with preserved ejection fraction (HFpEF) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0327] 63. The use of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of heart failure with preserved ejection fraction (HFpEF) in a subject.

[0328] 64. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with reduced ejection fraction (HFrEF) in a subject.

[0329] 65. A method of treating heart failure with reduced ejection fraction (HFrEF) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0330] 66. The use of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of heart failure with reduced ejection fraction (HFrEF) in a subject.

[0331] 67. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of heart failure with mid-range ejection fraction (HFmrEF) in a subject.

[0332] 68. A method of treating heart failure with mid-range ejection fraction (HFmrEF) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof.

[0333] 69. The use of the compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of heart failure with mid- range ejection fraction (HFmrEF) in a subject. Incorporation by Reference

[0334] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.Equivalents

[0335] While specific embodiments of the subject application have been discussed, the above specification is illustrative and not restrictive. Many variations of the subject of the application will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the application should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS 1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)NR5R6, -NR5R6, -N(R5)C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is -H, halo, -CN, -OR1, or -NR17R18; R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); R4is hydrogen or C1-6alkyl; each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C1-6alkyl, or C1-6haloalkyl;R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl; R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., C1-6alkyl); or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3; provided that one or more of the following is true: (A) V is -(CR14R15)- or -N(R16)-; (B) Y is C1-6haloalkyl or C3-6heterocyclyl; (C) Z is -H, halo, -CN, or -NR17R18; (D) R1is C3-6cycloalkyl;(E) at least one of R2and R3is C3-6cycloalkyl; (F) R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; (G) R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; (H) R7is halo; (J) R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; (K) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered saturated carbocyclic ring; (L) R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 0 and l is 1; (M) R10is C1-6alkyl; (N) R19is halo, C1-6alkyl, or C1-6haloalkyl; (O) R20is halo, C1-6alkyl, or C1-6haloalkyl; (Q) R21is halo, C1-6alkyl, or C1-6haloalkyl; (R) R22is halo, C1-6alkyl, or C1-6haloalkyl; (S) l is 0; and (T) n is 3; and further provided that (a) when V is -O-, Y is -NH2, X is S, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, and R21is hydrogen, R22is -F, Z is -OR1, and R1and R9taken together with the atoms to which they are attached form a tetrahydrofuran, then A is not substituted phenyl or substituted thiazolyl; (b) when V is -O-, Y is -NH2, X is S, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -H, then A is not -OH; (c) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring (e.g., piperidinyl), X is -S-, n is 1, m is 0, l is 1, and each of R1, R7, R8, R9, R10, R11, R12, R19, R20, R21, and R22is -H, and Z is -OR1, then A is not substituted thiazolyl; (d) when V is -O-, Y is -NH2, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R7, R8, R9, R10, R11, R12, R19, R20, and R21is -H, R22is -F, then A is not substituted oxazolyl;(e) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17is -H, and R18and R9taken together with the atoms to which they are attached form a 5-membered heterocyclyl ring (i.e., pyrrolidinyl ring), then A is not substituted thiazolyl; (f) when V is -O-, Y is NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -CH3, then A is not phenyl or substituted thiazolyl; (g) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, Z is -NR17R18, R17and R18are both -H, then A is not substituted thiazolyl; (h) when V is -O-, Y is -NH2, X is -S-, n is 0, m is 0, l is 0, each of R9, R10, R19, R20, R21and R22is -H, Z is -H, then A is not phenyl or heterocyclyl; (i) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H or -NR17R18, R17and R18are both -H, then A is not substituted 4-pyridyl; (j) when V is -N(R16)-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R16, R19, R20, R21and R22is -H, Z is -H, then A is not substituted 4-pyridyl; (k) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 1, each of R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted phenyl; (m) when V is -O-, Y is -NR2R3, R2and R3taken together with the nitrogen to which they are attached form a 4-membered heterocyclyl ring substituted with one or more instances of -OH, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not substituted 4-pyridyl; (n) when V is -O-, Y is -NH2, X is -S-, n is 2, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not -OH; (o) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, R11is -H or -CH3, and Z is -H, then A is not -C(O)NH2; (p) when V is -O-, Y is -NH2, X is -S-, n is 1, m is 0, l is 0, each of R9, R10, R11, R12, R19, R20, R21and R22is -H, and Z is -H, then A is not optionally substituted aryl or optionally substituted heteroaryl; (q) when V is -O-, Y is -NH2, X is -S-, n is 3, m is 0, l is 0, each of R9, R10, R12, R19, R20, R21and R22is -H, each instance of R11independently is selected from -H and -OH, and Z is -H, then A is not -OH; (r) when V is -O-, Y is -NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R7, R8, R9, R10, R11, R12, R19, R20, R21and R22is -H, A is substituted thiazolyl, then R3is not cyclopropyl or cyclobutyl; and (s) when V is -O-, Y is NR2R3, X is -S-, Z is -OR1, n is 1, m is 0, l is 1, each of R1, R2, R9, R10, R11, R12, R19, R20, R21and R22is -H, R7is -CH3, R8is -H or -CH3, A is substituted pyridyl, then R3is not cyclopropyl.

2. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: A is -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)OC1-6alkyl, -C(O)NR5R6, -NR5R6, -NR5C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, wherein: optionally substituted aryl is optionally substituted naphthyl; optionally substituted heteroaryl is optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, or optionally substituted pyrazinyl; V is -C(R14R15)-, -O-, or -N(R16)-; X is a bond, -S-, -O-, or -N(R4)-; Y is -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6heterocyclyl, -OR13, or -NR2R3; Z is halo, -CN, -OR1, or -NR17R18; R1is -H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; each of R2and R3independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4-, 5-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; R4is hydrogen or C1-6alkyl;each of R5and R6independently is selected from -H and C1-6alkyl; R7is -H, halo, C2-6alkyl, or C1-6haloalkyl; R8is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R8taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; or R7and R8taken together with the carbon to which they are attached form a 3-, 4-, ti-, or 6-membered saturated carbocyclic ring; R9is -H or halo; or R1and R9taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; or R9and R8taken together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl ring system when m is 0 and l is 1 or a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1; R10is -H, halo, or C1-6alkyl; each instance of R11and R12independently is selected from -H, -OH, halo, C1-6alkyl, and C1-6haloalkyl; R13is -H, C1-6alkyl, or C1-6haloalkyl; R14is -H, C1-6alkyl, or C1-6haloalkyl; R15is -H, C1-6alkyl, or C1-6haloalkyl; or R1and R15taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; R16is-H or C1-6alkyl; or R8and R16taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; each of R17and R18independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring, wherein the 4-, ti-, or 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -H; or R17and R18taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl; or R17is -H or C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; each of R19, R20, R21, and R22independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3; provided that one or more of the following is true: (A) V is -(CR14R15)- or -N(R16)-; (B) Y is C1-6haloalkyl or C3-6heterocyclyl;(C) Z is -H, halo, -CN, or -NR17R18; (D) R1is C3-6cycloalkyl; (E) at least one of R2and R3is C3-6cycloalkyl; (F) R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; (G) R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; (H) R7is halo; (J) R1and R8taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; (K) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, ti-, or 6- membered saturated carbocyclic ring; (L) R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 0 and l is 1; (M) R10is C1-6alkyl; (N) R19is halo, C1-6alkyl, or C1-6haloalkyl; (O) R20is halo, C1-6alkyl, or C1-6haloalkyl; (Q) R21is halo, C1-6alkyl, or C1-6haloalkyl; (R) R22is halo, C1-6alkyl, or C1-6haloalkyl; (S) l is 0; and (T) n is 3.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein V is -C(R14)(R15)- or -N(R16)-.

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is C1- 6 haloalkyl or C3-6heterocycloalkyl.

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: Z is -H, halo, CN, -OR1, or -NR17R18; and R1is C3-6cycloalkyl.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: R2is -H, C1-6alkyl, or C3-C6cycloalkyl, and R3is C3-C6cycloalkyl; or R2and R3taken together with the nitrogen to which they are attached form a 6-membered heterocyclyl ring, wherein the 6-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH; or R2and R3taken together with the nitrogen to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from C1-6alkyl.

7. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R7is halo.

8. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: (i) R1and R8taken together with the atoms to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring; or (ii) R7and R8taken together with the carbon to which they are attached form a 3-, 4-, ti-, or 6- membered saturated carbocyclic ring.

9. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: m is 0; l is 1; and R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system.

10. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R10is C1-6alkyl.

11. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein one of R19', R20', R21'and R22'is halo, C1-6alkyl, or C1-6haloalkyl, and each of the others independently is selected from -H, halo, C1-6alkyl, and C1-6haloalkyl.

12. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein n is 3.

13. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 6-membered heteroaryl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl or pyridazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo and C1-3alkyl.

15. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted oxetanyl or optionally substituted tetrahydrofuranyl.

16. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein A is.

17. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein ,18. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein V is - O-.

19. The compound of claims 18, or a pharmaceutically acceptable salt thereof, wherein20. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein V is - N(R16)-.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein.

22. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R16is -H.

23. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein V is -(CR14R15)-.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein25. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein each of R14and R15independently is selected from -H and -CH3.

26. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is - NR2R3.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein each of R2and R3independently is selected from -H, C1-6alkyl and C3-6cycloalkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein Y is.

29. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R2and R3taken together with the nitrogen to which they are attached form a 4-, ti-, or 6-membered heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo and -OH.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl ring is azetidinyl optionally substituted with one or more substituents independently selected from halo and -OH.

31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the heterocyclyl ring is32. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is C3-6heterocyclyl.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein Y is.

34. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein each of R19, R20, R21, and R22independently is -H, -F, or -CH3.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein.

36. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: X is -S-, -O-, or -N(R4)-; and R4is -H or -CH3.

37. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein X is -S-.

38. A pharmaceutical composition, comprising the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, for use as a medicament.

40. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, for use in the treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome; in the treatment of FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome; in the treatment of CDD and / or one or more symptoms associated with CDD; in the treatment of CHD8-NDD and / or one or more symptoms associated with CHD8-NDD; in the treatment of chronic heart failure; in the treatment of heart failure with preserved ejection fraction (HFpEF); in the treatment of heart failure with reduced ejection fraction (HFrEF); or in the treatment of heart failure with mid- range ejection fraction (HFmrEF); in a subject.

41. A method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome; treating FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome; treating CDD and / or one or more symptoms associated with CDD; treating CHD8-NDD and / or one or more symptoms associated with CHD8-NDD; treating chronic heart failure; treating heart failure with preserved ejection fraction (HFpEF); treating heart failure with reduced ejection fraction (HFrEF); or treating heart failure with mid-range ejection fraction (HFmrEF); in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof.

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