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

Abstract

The present disclosure relates to compounds of formula I, such as la or lb, and their pharmaceutical compositions / preparations. This disclosure further relates to methods of treating or preventing 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, or 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).

Description

ADENOSINE LIGANDS FOR THE TREATMENT OF NEUROLOGICAL DISORDERS OR CHRONIC HEART FAILURE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The benefit of priority is claimed to the United States Provisional Application Number 63 / 532,763, 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

[0002] 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).

[0003] 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.

[0004] 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 after direct pre-stimulation of adenylate cyclase by forskolin). Correspondingly, A2A and A2B ARagonists (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). SUMMARY

[0005] In some embodiments, the present disclosure provides the recognition that the use of a brain penetrant A1, A2B and / or dual A1 / A2B AR agonists may produce a medication for treating Rett syndrome. In some embodiments, agonists of adenosine receptors, e.g., compounds provided herein, provide promising agents for the treatment of Rett Syndrome and its related disorders.

[0006] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from -H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen, or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, orR9and 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 selected from -H, halogen, and C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring;l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when L is -N=, each of J, M, and Q is -CH= (i.e., formula Ia), V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (B) when J is -N=, each of L, M, and Q is -CH=, (i.e., formula Ib) V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -N(H)-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is - H, then A is not optionally substituted thiazolyl; (D) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and(G) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0007] In some embodiments, the present disclosure provides a compound of formula I’:or a pharmaceutically acceptable salt thereof, wherein each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from -H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; orR2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and optionally substituted C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl;R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when L is -N=, each of J, M, and Q is -CH= (i.e., formula Ia), V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl;(B) when J is -N=, each of L, M, and Q is -CH=, (i.e., formula Ib) V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -N(H)-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is - H, then A is not optionally substituted thiazolyl; (D) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0008] In some embodiments, L is -N=. In certain embodiments, L is -N= and each of J, M, and Q is -CH=.

[0009] In some embodiments, a compound of formula I is represented by formula Ia:or a pharmaceutically acceptable salt thereof, wherein A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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;R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; orR17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

[0010] In some embodiments, a compound of formula I is represented by formula Ia’:or a pharmaceutically acceptable salt thereof, whereinA is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen, orR1and 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 selected from -H, halogen, and optionally substituted C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; orR17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

[0011]

[0012] In some embodiments, a compound of formula I is represented by formula Ib:or a pharmaceutically acceptable salt thereof, wherein A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-;X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from -H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6- membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and C1-6alkyl; R12and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; andn is 0, 1, 2, or 3, provided that (B) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when V is -NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0013] In some embodiments, a compound of formula I is represented by formula Ib’:or a pharmaceutically acceptable salt thereof, wherein A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from -H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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;R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6- membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and optionally substituted C1-6alkyl; R12and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocycyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; orR17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (B) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when V is -NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl;(E) when V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0014] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, A is optionally substituted heteroaryl. In certain such embodiments, A is selected from optionally substituted pyridyl, optionally substituted pyridizinyl, and optionally substituted pyrimidinyl. In certain embodiments, A is optionally substituted pyridyl. In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, A is optionally substituted heterocyclyl. In certain such embodiments, A is optionally substituted oxetanyl. In certain embodiments, A is 3-oxetanyl.

[0015] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, V is -O-.

[0016] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, n is 1.

[0017] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, R12is -H.

[0018] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, R11is -H.

[0019] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, X is -S-.

[0020] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, Y is - N(R2)(R3). In certain such embodiments, R2and R3each independently is selected from - H and C1-6alkyl. In other such embodiments, R2and R3are each -H. In certain embodiments, R2is -H and R3is C1-6alkyl.

[0021] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, Z is -OR1. In certain such embodiments, R1is C1-6alkyl. In other such embodiments, R1is -CH3. In certain embodiments, R1is -C(2H)3.In certain embodiments, R1is -H.

[0022] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, m is 0.

[0023] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, l is 1.

[0024] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, R7is -H.

[0025] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, R8is -H. In certain embodiments of the compound of formula I, such as the compound of formula Iaor Ib, or a pharmaceutically acceptable salt thereof, R8is C1-6alkyl. In certain such embodiments, R8is -CH3.

[0026] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, R9is -H.

[0027] In certain embodiments of the compound of formula I, such as the compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof, R10is -H.

[0028] In some embodiments, the present disclosure provides a compound selected from any one of compounds 1-294 or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) a compound as disclosed herein (e.g., a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, (such as a compound selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof); and (b) a pharmaceutically acceptable excipient.

[0030] In some embodiments, the present disclosure provides a compound of the disclosure (e.g., a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, such as a compound selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition of the disclosure for use as a medicament.

[0031] In some 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, or CHD8-related neurodevelopmental disorder (CHD8-NDD) and / or one or more symptoms associated with CHD8-NDD in a subject comprising administering to a subject in need thereof an effective amount of at least one compound of the disclosure (such as a compound of formula I, such as a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition of the disclosure. The present disclosure provides a method of treating Rett syndrome and / or one or more symptomsassociated with Rett syndrome. In certain embodiments, the method further comprises co-administering to the subject an additional therapeutic agent. In certain such embodiment, the additional therapeutic agent comprises trofinetide. In certain embodiments, the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism. In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. 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. 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.

[0032] In some embodiments, the present disclosure provides a method of treating chronic heart failure in a subject, the method comprising administering to a subject in need thereof an effective amount of at least one compound as disclosed herein (e.g., a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, such as a compound selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein (e.g., a pharmaceutical composition comprising (a) a compound as disclosed herein (b) a pharmaceutically acceptable excipient).

[0033] In some embodiments, the present disclosure provides a method of treating heart failure with preserved ejection fraction (HfpEF), the method comprising administering to a subject in need thereof an effective amount of at least one compound as disclosed herein (e.g., a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, such as a compound selected from any one of compounds 1-294,or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein (e.g., a pharmaceutical composition comprising (a) a compound as disclosed herein (b) a pharmaceutically acceptable excipient).

[0034] In some embodiments, the present disclosure provides a method of treating heart failure with reduced ejection fraction (HfrEF), the method comprising administering to a subject in need thereof an effective amount of at least one compound as disclosed herein (e.g., a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, such as a compound selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein (e.g., a pharmaceutical composition comprising (a) a compound as disclosed herein (b) a pharmaceutically acceptable excipient).

[0035] In some embodiments, the present disclosure provides a method of treating heart failure with mid-range ejection fraction (HfmrEF), the method comprising administering to a subject in need thereof an effective amount of at least one compound as disclosed herein (e.g., a compound of formula I, Ia or Ib, or a pharmaceutically acceptable salt thereof, such as a compound selected from any one of compounds 1-294, and pharmaceutically acceptable salts thereof) or a pharmaceutical composition as disclosed herein (e.g., a pharmaceutical composition comprising (a) a compound as disclosed herein (b) a pharmaceutically acceptable excipient).

[0036] In some embodiments of the methods disclosed herein, the compound is selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the present disclosure provides a compound as disclosed herein (such as a compound of formula I, such as a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein, in the preparation of a medicament for 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, or CHD8-NDD and / or one or more symptomsassociated with CHD8-NDD. In certain embodiments, the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism. In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. 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. 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.

[0038] In some embodiments, the present disclosure provides use of a compound as disclosed herein (such as a compound of formula I, such as a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein, in the preparation of a medicament for the treatment of chronic heart failure.

[0039] In some embodiments, the present disclosure provides use of a compound as disclosed herein (such as a compound of formula I, such as a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein, in the preparation of a medicament for the treatment of heart failure with preserved ejection fraction (HfpEF).

[0040] In some embodiments, the present disclosure provides use of a compound as disclosed herein (such as a compound of formula I, such as a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition asdisclosed herein, in the preparation of a medicament for the treatment of heart failure with reduced ejection fraction (HFrEF).

[0041] In some embodiments, the present disclosure provides use of a compound as disclosed herein (such as a compound of formula I, such as a compound of formula Ia or Ib, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as disclosed herein, in the preparation of a medicament for the treatment of heart failure with mid-range ejection fraction (HFmrEF).

[0042] In some embodiments of the uses as disclosed herein, the compound is selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION Definitions

[0043] 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.

[0044] The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one carbon-carbon double bond.

[0045] 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.

[0046] 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.

[0047] The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one carbon-carbon triple bond

[0048] The term “aryl” refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 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. 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 thedefinition 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.

[0049] 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.

[0050] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0051] 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 to five 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 ofattachment 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”.

[0052] The term “heteroatom” as used herein means an atom of any element other than carbon or -H. Exemplary heteroatoms are nitrogen, oxygen, and sulfur.

[0053] 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 of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0054] 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.

[0055] 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 “optionallysubstituted” 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.

[0056] 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 –(C1–4straight 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 independentlyselected 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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 substituentsand / or variables are permissible only if such combinations result in chemically stable compounds.

[0063] 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.

[0064] 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.

[0065] 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, Ia, or Ib, 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.

[0066] 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 ofthe other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.

[0067] 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.

[0068] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of formula I, Ia, or Ib, 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.

[0069] 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.

[0070] The present application further includes all pharmaceutically acceptable isotopically labelled compounds (e.g., of formula I, Ia, or Ib, or a pharmaceutically acceptable salt 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).

[0071] Certain isotopically labelled compounds (e.g., of formula I, Ia, or Ib, or a pharmaceutically acceptable salt 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.

[0072] 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.

[0073] Substitution with positron emitting isotopes, such as11C,18F,15O, and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0074] 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

[0075] In some embodiments, the present disclosure provides a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: each of J, L, M, and Q is independently selected -N=, and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6-N(R4)-haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; orR2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl(e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when L is -N=, each of J, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (B) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4- pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when J is -N=, each of L, M, and Q is -CH=, V is -NH-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl;(E) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0076] In some embodiments, the present disclosure provides a method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome (such as 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) comprising administering to a subject in need thereof a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:each of J, L, M, and Q is independently selected -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from -H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring;R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring;l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0077] In some embodiments, the present disclosure provides a method of treating FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying) comprising administering to a subject in need thereof a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; orR2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl(e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring;R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0078] In some embodiments, the present disclosure provides a method of treating 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 (gastroesophageal reflux); and irregular breathing) comprising administering to a subject in need thereof a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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;R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl(e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-memberedspiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0079] In some embodiments, the present disclosure provides a method of treating 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) comprising administering to a subject in need thereof a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl);R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0080] In some embodiments, the present application provides a method of treating 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), the method comprising administering to a subject in need thereof a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein: each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-memberedspiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl(e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; orR17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0081] In some embodiments of the foregoing methods, (A) when L is -N=, each of J, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (B) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin- 2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when J is -N=, each of L, M, and Q is -CH=, V is -N(H)-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl;(E) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and / or (G) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0082] In certain embodiments of formula I, L is -N=. In certain such embodiments, L is -N= and each of J, M, and Q is -CH=.

[0083] In certain embodiments of formula I, R11and R12each independently is selected from -H and C1-6alkyl.

[0084] In certain embodiments of formula I, R17and R18each independently is selected from -H and C1-6alkyl.

[0085] In some embodiments, the present disclosure provides a compound of formula Ia:or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen (e.g., F), -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen (e.g., F), C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

[0086] The present application provides a method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome (such as 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); FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying); 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 (gastroesophageal reflux); and irregular breathing); 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, HFpEF, HFrEF, or HFmrEF comprising administering to a subject in need thereof a compound of formula Ia,or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6) - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen (e.g., F), -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen (e.g., F), C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), or R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, orR9and 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0087] In certain embodiments of the foregoing methods, when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

[0088] The present application provides a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen (e.g., F), -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; orR2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen (e.g., F), C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (B) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when V is -NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0089] The present application provides a method of treating Rett syndrome and / or one or more symptoms associated with Rett syndrome (such as 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); FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying); 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 (gastroesophageal reflux); and irregular breathing); 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, HFpEF, HFrEF, or HFmrEF comprising administering to a subject in need thereof a compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen (e.g., F), -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl;R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen (e.g., F), C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-memberedspiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3.

[0090] In certain embodiments of the foregoing methods, (B) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when V is -NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0091] In certain embodiments of formula I, Ia, or Ib, A is optionally substituted heteroaryl. In certain embodiments of formula I, Ia, or Ib, A is optionally substituted heteroaryl, provided that A is not optionally substituted thiazolyl (e.g., A is not substituted thiazolyl). In certain embodiments of formula I, Ia, or Ib, A is optionally substituted heteroaryl, provided that A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, imidazolyl, or substituted triazolyl. In certain embodiments of formula I, Ia, or Ib, A is optionally substituted heteroaryl, provided that A is not optionally substituted pyridyl, optionally substituted pyridin- 2(1H)-one-4-yl, optionally substituted thiazolyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted oxazolyl, optionally substituted oxadiazolyl, optionally substituted thiophenyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, or optionally substituted triazolyl.

[0092] In certain embodiments of formula I, Ia, or Ib, A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)C16alkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl.

[0093] As defined generally above, each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=.

[0094] In some embodiments, J is -N=. In some embodiments, J is -CH=.

[0095] In some embodiments, L is -N=. In some embodiments, L is -CH=.

[0096] In some embodiments, M is -N=. In some embodiments, M is -CH=.

[0097] In some embodiments, Q is -N=. In some embodiments, Q is -CH=.

[0098] In some embodiments, J is -N= and L, M, and Q are -CH=.

[0099] In some embodiments, L is -N= and -N=, M, and Q are -CH=.

[0100] In some embodiments, M is -N= and J, L, and Q are -CH=.

[0101] In some embodiments, Q is -N= and J, L, and M are -CH=.

[0102] In some embodiments,

[0103] In some embodiments,is selected from, , ,

[0104] In some embodiments,is selected fromIn some embodiments,In some embodiments,

[0105] As defined genereally above, A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, - C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. In some embodiments, A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), N(R5)C(O)C1-6alkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0106] In some embodiments, A is -CN.

[0107] In some embodiments, A is -OH.

[0108] In some embodiments, A is optionally substituted C1-6alkyl. In some embodiments, A is optionally substituted C1-2alkyl. In some embodiments, A is C1-2alkyl optionally substituted with halogen. In some embodiments, A is C1-2alkyl optionally substituted with fluoro. In some embodiments, A is -CF3. In some embodiments, A is C1-2alkyl optionally substituted with –(CH2)0–4OR°. In some embodiments, A is C1-2alkyl optionally substituted with OR°. In some embodiments, A is C1-2alkyl optionally substituted with OH. In some embodiments, A is C1-2alkyl optionally substituted with O(C1–6aliphatic). In some embodiments, A is C1-2alkyl optionally substituted with - OCH3.

[0109] In some embodiments, A is unsubstituted C1-6alkyl (e.g., C1-6alkyl).

[0110] In some embodiments, A is substituted C1-6alkyl. In some embodiments, A is substituted C1-2alkyl. In some embodiments, A is C1-2alkyl substituted with halogen. In some embodiments, A is C1-2alkyl substituted with fluoro. In some embodiments, A is C1-2alkyl substituted with –(CH2)0–4OR°. In some embodiments, A is C1-2alkyl substituted with OR°. In some embodiments, A is C1-2alkyl substituted with OH. In some embodiments, A is C1-2alkyl substituted with O(C1–6aliphatic). In some embodiments, A is C1-2alkyl substituted with -OCH3.

[0111] In some embodiments, A is optionally substituted C1-6alkoxy. In some embodiments, A is optionally substituted C1-2alkoxy. In some embodiments, A is C1-2alkoxy, optionally substituted with halogen. In some embodiments, A is -OCF3.

[0112] In some embodiments, A is unstubstituted C1-6alkoxy (e.g., C1-6alkoxy). In some embodiments, A is unsubstituted C1-2alkoxy (e.g., C1-2alkoxy). In some embodiments, A is -OCH3.

[0113] In some embodiments, A is substituted C1-6alkoxy. In some embodiments, A is substituted C1-2alkoxy. In some embodiments, A is C1-2alkoxy, substituted with halogen.

[0114] In some embodiments, A is -C(O)OH.

[0115] In some embodiments, A is -C(O)C1-6alkoxy,.

[0116] In some embodiments, A is -C(O)N(R5)(R6). In some embodiments, A is - C(O)N(CH3)2. In some embodiments, A is -C(O)NH(CH3). In some embodiments, A is - C(O)NH2.

[0117] In some embodiments, A is -N(R5)(R6). In some embodiments, A is - N(CH3)2.

[0118] In some embodiments, A is -N(R5)C(O)(C1-6alkyl). In some embodiments, A is -N(R5)C(O)C1-2alkyl. In some embodiments, A is -NHC(O)C1-2alkyl. In some embodiments, A is -N(R5)C(O)CH3. In some embodiments, A is -NHC(O)CH3.

[0119] In some embodiments, A is optionally substituted heterocyclyl. In some embodiments, A is a 3- to 6-membered optionally substituted heterocyclyl. In some embodiments, A is a 4-membered optionally substituted heterocyclyl. In some embodiments, A is a 5-membered optionally substituted heterocyclyl. In some embodiments, A is optionally substituted oxetanyl. In some embodiments, A is optionally substituted tetrahydrofuranyl.

[0120] In some embodiments, A is unsubstituted heterocyclyl (e.g., heterocyclyl). In some embodiments, A is a 3- to 6-membered usubstituted heterocyclyl. In some embodiments, A is a 4-membered usubstituted heterocyclyl. In some embodiments, A is a 5-membered usubstituted heterocyclyl. In some embodiments, A is unsubstituted oxetanyl (e.g., oxetanyl). In some embodiments, A is unsubstituted tetrahydrofuranyl (e.g., tetrahydrofuranyl).

[0121] In some embodiments, A is substituted heterocyclyl. In some embodiments, A is a 3- to 6-membered substituted heterocyclyl. In some embodiments, A is a 4-membered substituted heterocyclyl. In some embodiments, A is a 5-membered substituted heterocyclyl. In some embodiments, A is substituted oxetanyl. In some embodiments, A is substituted tetrahydrofuranyl.

[0122] In some embodiments, A is a 3- to 6-membered optionally substituted heterocyclyl, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A is a 4- to 5-membered optionally substituted heterocyclyl, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A is a 4- to 5-membered optionally substituted heterocyclyl, having 1 oxygen atom.

[0123] In some embodiments, A is optionally substituted aryl. In some embodiments, A is optionally substituted phenyl.

[0124] In some embodiments, A is unsubstituted aryl (e.g., aryl). In some embodiments, A is unsubstituted phenyl (e.g., phenyl).

[0125] In some embodiments, A is substituted aryl.

[0126] In some emblodiments, A is optionally substituted heteroaryl. In some embodiments, A is a 5- to 6-membered optionally substituted heteroaryl. In some embodiments, A is optionally substituted pyridyl. In some embodiments, A is pyridyl optionally substituted with halogen. In some embodiments, A is pyridyl optionally substituted with fluoro. In some embodiments, A is pyridyl optionally substituted with chloro. In some embodiments, A is pyridyl optionally substituted with –(CH2)0–4R°. In some embodiments, A is pyridyl optionally substituted with R°. In some embodiments, A is pyridyl optionally substituted with C1–6aliphatic. In some embodiments, A is pyridyl optionally substituted with -CH3. In some embodiments, A is pyridyl optionally substituted with –(CH2)0–4OR°. In some embodiments, A is pyridyl optionally substituted with OR°. In some embodiments, A is pyridyl optionally substituted with O(C1–6aliphatic). In some embodiments, A is pyridyl optionally substituted with -OCH3.

[0127] In some embodiments, A is optionally substituted 2-pyridyl.

[0128] In some embodiments, A is optionally substituted 3-pyridyl. In some embodiments, A is 3-pyridyl optionally substituted with halogen. In some embodiments, A is 3-pyridyl optionally substituted with fluoro. In some embodiments, A is 3-pyridyl optionally substituted with chloro. In some embodiments, A is 3-pyridyl optionally substituted with –(CH2)0–4R°. In some embodiments, A is 3-pyridyl optionally substituted with R°. In some embodiments, A is 3-pyridyl optionally substituted with C1–6aliphatic. In some embodiments, A is 3-pyridyl optionally substituted with -CH3. In some embodiments, A is 3-pyridyl optionally substituted with –(CH2)0–4OR°. In some embodiments, A is 3-pyridyl optionally substituted with OR°. In some embodiments, A is 3-pyridyl optionally substituted with O(C1–6aliphatic). In some embodiments, A is 3- pyridyl optionally substituted with -OCH3.

[0129] In some embodiments, A is optionally substituted 4-pyridyl. In some embodiments, A is optionally substituted pyridazinyl. In some embodiments, A isoptionally substituted pyrimidinyl. In some embodiments, A is optionally substituted thiazolyl.

[0130] In some embodiments, A is unsubstituted heteroaryl (e.g., heteroaryl). In some embodiments, A is a 5- to 6-membered unsubstituted heteroaryl. In some embodiments, A is unsubstituted pyridyl (e.g., pyridyl). In some embodiments, A is unsubstituted 2-pyridyl (e.g., 2-pyridyl). In some embodiments, A is unsubstituted (e.g., 3-pyridyl). In some embodiments, A is unsubstituted 4-pyridyl (e.g., 4-pyridyl). In some embodiments, A is unsubstituted pyridazinyl(e.g., pyridazinyl). In some embodiments, A is unsubstituted pyrimidinyl (e.g., pyrimidinyl). In some embodiments, A is unsubstituted thiazolyl (e.g., thiazolyl).

[0131] In some embodiments, A is substituted heteroaryl. In some embodiments, A is a 5- to 6-membered substituted heteroaryl. In some embodiments, A is substituted pyridyl. In some embodiments, A is pyridyl substituted with halogen. In some embodiments, A is pyridyl substituted with fluoro. In some embodiments, A is pyridyl substituted with chloro. In some embodiments, A is pyridyl substituted with –(CH2)0–4R°. In some embodiments, A is pyridyl substituted with R°. In some embodiments, A is pyridyl substituted with C1–6aliphatic. In some embodiments, A is pyridyl substituted with -CH3. In some embodiments, A is pyridyl substituted with –(CH2)0–4OR°. In some embodiments, A is pyridyl substituted with OR°. In some embodiments, A is pyridyl substituted with O(C1–6aliphatic). In some embodiments, A is pyridyl substituted with - OCH3.

[0132] In some embodiments, A is substituted 2-pyridyl.

[0133] In some embodiments, A is substituted 3-pyridyl. In some embodiments, A is 3-pyridyl substituted with halogen. In some embodiments, A is 3-pyridyl substituted with fluoro. In some embodiments, A is 3-pyridyl substituted with chloro. In some embodiments, A is 3-pyridyl substituted with –(CH2)0–4R°. In some embodiments, A is 3- pyridyl substituted with R°. In some embodiments, A is 3-pyridyl substituted with C1–6aliphatic. In some embodiments, A is 3-pyridyl substituted with -CH3. In someembodiments, A is 3-pyridyl substituted with –(CH2)0–4OR°. In some embodiments, A is 3-pyridyl substituted with OR°. In some embodiments, A is 3-pyridyl substituted with O(C1–6aliphatic). In some embodiments, A is 3-pyridyl substituted with -OCH3.

[0134] In some embodiments, A is substituted 4-pyridyl. In some embodiments, A is substituted pyridazinyl. In some embodiments, A is substituted pyrimidinyl. In some embodiments, A is substituted thiazolyl.

[0135] In some embodiments, A is selected from:

[0136] In certain embodiments of formula I, Ia, or Ib, A is optionally substituted pyridyl, such as optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, or optionally substituted 4-pyridyl. In certain embodiments of formula I, Ia, or Ib, A is selected from optionally substituted pyridyl, optionally substituted pyridizinyl, optionally substituted pyrimidinyl, and thiazolyl. In certain embodiments of formula I, Ia, or Ib, A is selected from optionally substituted pyridyl, optionally substituted pyridizinyl, and optionally substituted pyrimidinyl. In certain embodiments of formula I, Ia, or Ib, A is optionally substituted aryl, such as optionally substituted phenyl. In certain embodiments of formula I, Ia, or Ib, A is optionally substituted heterocycloalkyl (e.g., oxetanyl or tetrahydrofuranyl). In certain embodiments of formula I, Ia, or Ib, A is optionally substituted oxetanyl. In certain embodiments of formula I, Ia, or Ib, A is optionally substituted C1-6alkyl (e.g., haloalkyl).

[0137] As defined generally above, V is selected from -C(R14)(R15)-, -O-, and - N(R16)-.

[0138] In some embodiments, V is -C(R14)(R15)-. In some embodiments, V is - CH2-. In some mebodiments, V is -C(H)(C1-6alkyl)-. In some embodiments, V is - C(H)(CH2)-. In some embodiments, V is -C(H)(CH2CH2)-

[0139] In some embodiments, V is -C(R14)(R15)- and R1and R15taken together with the atoms to which they are attached form a tetrahydrofuranyl ring. In some embodiments, V is -C(R14)(R15)- and R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring.

[0140] In some embodiments, V is -O-.

[0141] In some embodiments, V is -N(R16)-. In some embodiments, V is -N(H)-. In some embodiments, V is -N(C1-6alkyl)-. In some embodiments, V is -N(CH2)-. In some embodiments, V is -N(CH2CH2)-.

[0142] In some embodiments, 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. In some embodiments, V is -N(R16)- and R8and R16taken together with the atoms to which they are attached form an azetidinyl ring.

[0143] In certain embodiments of formula I, Ia, or Ib, V is -O-. In certain embodiments of formula I, Ia, or Ib, V is -N(R16)- and R16is -H (e.g., V is -NH-). In certain embodiments of formula I, Ia, or Ib, 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). In certain embodiments of formula I, Ia, or Ib, V is - C(R14)(R15)-, 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). In certain embodiments of formula I, Ia, or Ib,V is -C(R14)(R15)-, such as CH2.

[0144] As defined generally above, X is selected from a bond, -S-, -O-, and - N(R4)-.

[0145] In some embodiments, X is a bond.

[0146] In some embodiments, X is -S-.

[0147] In some embodiments, X is -O-.

[0148] In some embodiments, X is -N(R4)-.

[0149] In certain embodiments of formula I, Ia, or Ib, X is -S-. In certain embodiments of formula I, Ia, or Ib, X is a bond. In certain embodiments of formula I, Ia, or Ib, X is -O-. In certain embodiments of formula I, Ia, or Ib, X is -N(R4)-.

[0150] As defined generally above, Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3).

[0151] In some embodiments, Y is -H.

[0152] In some embodiments, Y is C1-6alkyl. In some embodiments, Y is C1-2alkyl. In some embodiments, Y is -CH3.

[0153] In some embodiments, Y is C1-6haloalkyl. In some embodiments, Y is C1-2haloalkyl. In some embodiments, Y is -CHF2.

[0154] In some embodiments, Y is C3-6cycloalkyl. In some embodiments, Y is cyclopropyl.

[0155] In some embodiments, Y is -OR13. In some embodiments, R is -O(C1-6alkyl). In some embodiments, R is -O(C1-2alkyl). In some embodiments, Y is -OCH3.

[0156] In some embodiments, Y is -N(R2)(R3). In some embodiments, Y is -NH2. In some embodiments, Y is -NH(C1-6alkyl). In some embodiments, Y is -NH(C3-6cycloalkyl).

[0157] In certain embodiments of formula I, Ia,or Ib, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom 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 halogen (e.g., fluoro) or -OH.

[0158] In certain embodiments of formula I, Ia, or Ib, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring (e.g., diazaspiro[3.3]heptane or oxa-azaspiro[3.3]heptane), wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., methyl). In certain embodiments of formula I, Ia, or Ib, Y is -OR13, such as -OCH3. In certain embodiments of formula I, Ia, or Ib, Y is C3-6cycloalkyl (e.g., cyclopropyl). In certain embodiments of formula I, Ia, or Ib, Y is C1-6alkyl (e.g., -CH3). In certain embodiments of formula I, Ia, or Ib, Y is C1-6haloalkyl (e.g., -CHF2). In certain embodiments of formula I, Ia, or Ib, Y is -H.

[0159] In certain embodiments of formula I, Ia, or Ib, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a 7-membered heterocyclyl ring (e.g., diazaspiro[3.3]heptane or oxa-azaspiro[3.3]heptane), wherein the 7-membered heterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl (e.g., methyl). In certain embodiments of formula I, Ia, or Ib, Y is -OR13, such as -OCH3. In certain embodiments of formula I, Ia, or Ib, Y is C3-6cycloalkyl (e.g., cyclopropyl). In certain embodiments of formula I, Ia, or Ib, Y is C1-6alkyl (e.g., -CH3). In certain embodiments of formula I, Ia, or Ib, Y is C1-6haloalkyl (e.g., -CHF2). In certain embodiments of formula I, Ia, or Ib, Y is -H.

[0160] In some embodiments, Y is selected from:

[0161] In certain embodiments of formula I, Ia, or Ib, Y is -N(R2)(R3). In certain such embodiments, R2and R3are each -H (i.e., Y is -NH2). In other embodiments of formula I, Ia, or Ib, Y is -N(R2)(R3) , R2is -H and R3is C1-6alkyl (e.g., Y is -NH(CH3)). In other embodiments of formula I, Ia, or Ib, Y is -N(R2)(R3) and R2and R3are each C1-6alkyl (e.g., Y is N(CH3)2).

[0162] As defined generally above, Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18).

[0163] In some embodiments, Z is selected from H, fluoro, -CN, -OR1, and - NH(CH3).

[0164] In some embodiments, Z is -H.

[0165] In some embodiments, Z is halogen. In some embodiments Z is fluoro.

[0166] In some embodiments, Z is -CN.

[0167] In some embodiments, Z is -OR1. In some embodiments, Z is -OH. In some embodiments, Z is -O(C1-6alkyl). In some embodiments, Z is -O(C1-3alkyl). In some embodiments, Z is -O(CH2CH2CH3). In some embodiments, Z is -O(C1-2alkyl). In some embodiments, Z is -OCH3. In some embodiments, Z is -O(CH2CH3). In some embodiments, Z is -OCD3. In some embodiments, Z is -O(CH2)-. In some embodiments, Z is -O(C1-6haloalkyl). In some embodiments, Z is -O(C1-2haloalkyl). In some embodiments, Z is -O(CHF2). In some embodiments, Z is -O(CF3). In some embodiments, Z is -O(C3-6cycloalkyl is -O(cyclopropyl).

[0168] In some embodiments, Z is OR1and R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In someembodiments, Z is OR1and R1and R15taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0169] In some embodiments, Z is OR1and R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, Z is OR1and R1and R8taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0170] In some embodiments, Z is -N(R17)(R18). In some embodiments, Z is - NH(CH3).

[0171] In certain embodiments of formula I, Ia, or Ib, Z is -OR1. In certain such embodiments, R1is -H (i.e., Z is -OH). In certain embodiments of formula I, Ia, or Ib, Z is -OR1, and R1is C1-6alkyl, such as -CH3(e.g., -CH3or -C(2H)3). In certain embodiments of formula I, Ia, or Ib, Z is -OR1, and R1is C1-6haloalkyl (e.g., -CHF2). In certain embodiments of formula I, Ia, or Ib, Z is -OR1, and R1is C3-6cycloalkyl, such as cyclopropyl. In certain embodiments of formula I, Ia, or Ib, Z is -OR1, and R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring (e.g., tetrahydrofuranyl). In certain embodiments of formula I, Ia, or Ib wherein Z is -OR1, and R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, the 4-, 5-, or 6-membered heterocyclyl ring is not substituted. In certain embodiments of formula I, Ia, or Ib, Z is - OR1, and R1and R9taken together with the atoms to which they are attached form a 4-, 5- , or 6-membered heterocyclyl ring (e.g., oxetanyl). In certain embodiments of formula I, Ia, or Ib, Z is halogen, such as F. In certain embodiments of formula I, Ia, or Ib, Z is - N(R17)(R18), and R17and R18each independently is selected from -H and C1-6alkyl (e.g., Z is -NH2or -NHCH3). In certain embodiments of formula I, Ia, or Ib, Z is -CN. In certain embodiments of formula I, Ia, or Ib, Z is -H.

[0172] As defined generally above, R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl.

[0173] In some embodiments, R1is selected from -H, -CH3,-CH2CH3,- CH2CH2CH3,-CD3,-CH2-, -CH2CH2-, -CH2CH2CH2-, -CHF2, -CF3, cyclopropyl, and / or R1and R15taken together with the atoms to which they are attached form a tetrahydrofuranyl ring, and / or R1and R8taken together with the atoms to which they are attached form a tetrahydrofuranyl ring, and / or R1and R9taken together with the atoms to which they are attached form an oxetanyl ring.

[0174] In some embodiments, R1is -H.

[0175] In some embodiments, R1is C1-6alkyl. In some embodiments, R1is C1-3alkyl. In some embodiments, R1is -CH2CH2CH3. In some embodiments, R1is C1-2alkyl. In some embodiments, R1is -CH3. In some embodiments, R1is -CH2CH3. In some embodiments, R1is -CD3. In some embodiments, R1is -CH2-. In some embodiments, R1is -CH2CH2-. In some embodiments, R1is -CH2CH2CH2-.

[0176] In some embodiments, R1is C1-6haloalkyl. In some embodiments, R1is C1-2haloalkyl. In some embodiments, R1is -CHF2. In some embodiments, R1is -CF3.

[0177] In some embodiments, R1is C3-6cycloalkyl. In some embodiments, R1is cyclopropyl.

[0178] In some embodiments, R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R1and R15taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0179] In some embodiments, R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R1and R8taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0180] In some embodiments, R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R1and R9taken together with the atoms to which they are attached form an oxetanyl ring.

[0181] As defined generally above, R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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.

[0182] In some embodiments, R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl. In some embodiments, R2and R3each independently is selected from -H, C1-3alkyl, and C3-C5cycloalkyl. In some embodiments, R2and R3each independently is selected from -H, C1-3alkyl, and C3-6cycloalkyl.

[0183] In some embodiments, R2and R3are -H. In some embodiments, R2is -H. In some embodiments, R3is -H.

[0184] In some embodiments, R2and R3are each independently selected from C1-6alkyl. In some embodiments, R2is C1-6alkyl. In some embodiments, R3is C1-6alkyl. In some embodiments, R2and R3are each independently selected from C1-3alkyl. In some embodiments, R2is C1-3alkyl. In some embodiments, R3is C1-3alkyl. In some embodiments, R2is -CH3. In some embodiments, R3is -CH3. In some embodiments, R2is -CD3. In some embodiments, R3is -CD3. In some embodiments, R2is -CH2CH3. In some embodiments, R3is -CH2CH3. In some embodiments, R2is -CH2CH2CH3. In some embodiments, R3is -CH2CH2CH3.

[0185] In some embodiments, R2and R3are each independently selected from C3-6cycloalkyl. In some embodiments, R2is C3-6cycloalkyl. In some embodiments, R3is C3-6cycloalkyl. In some embodiments, R2is cyclopropyl. In some embodiments, R3is cyclopropyl.

[0186] In some embodiments, R2and R3each independently is selected from -H, - CH3, -CD3, -CH2CH3, -CH2CH2CH3, and cyclopropyl.

[0187] In some embodiments, R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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.

[0188] In some embodiments, R2and R3taken together with the nitrogen atom 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 halogen or -OH. In some embodiments, R2and R3taken together with the nitrogen atom 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 halogen (e.g., fluoro) or -OH.

[0189] In some embodiments, R2and R3taken together with the nitrogen atom 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. In some embodiments, R2and R3taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring (e.g., diazaspiro[3.3]heptanyl or oxa-azaspiro[3.3]heptanyl), wherein the 7-membered spiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl.

[0190] In some embodiments, R2and R3taken together with the nitrogen atom to which they are attached form an unsubstituted 4-, 5-, or 6-membered heterocyclyl ring (e.g., azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperizinyl); or R2and R3taken together with the nitrogen atom to which they are attached form an unsubstituted 7-membered spiroheterocyclyl ring (e.g., diazaspiro[3.3]heptanyl or oxa- azaspiro[3.3]heptanyl).

[0191] In some embodiments, R2and R3taken together with the nitrogen atom 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 substituted with one or more substituents independently selected from halogen (e.g., fluoro) or -OH; or R2and R3taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring(e.g., diazaspiro[3.3]heptane or oxa-azaspiro[3.3]heptane), wherein the 7-membered spiroheterocyclyl ring is substituted with one or more substituents independently selected from alkyl.

[0192] As defined generally above, R4is -H or C1-6alkyl.

[0193] In some embodiments, R4is -H.

[0194] In some embodiments, R4is C1-6alkyl. In some embodiments, R4is C1-2alkyl.

[0195] As defined generally above, R5and R6each independently is selected from -H and C1-6alkyl. In some embodiments, R5and R6each independently is selected from - H and -CH3.

[0196] In some embodiments R5is -H. In some embodiments R6is -H.

[0197] In some embodiments, R5and R6each independently is selected from C1-6alkyl. In some embodiments, R5is C1-6alkyl. In some embodiments, R6is C1-6alkyl. In some embodiments, R5and R6each independently is selected from C1-2alkyl. In some embodiments, R5is C1-2alkyl. In some embodiments, R6is C1-2alkyl. In some embodiments, R5is -CH3. In some embodiments, R6is -CH3.

[0198] As defined generally above, R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl.

[0199] In some embodiments, R7is selected from -H, fluoro, -CH3, and -CH2CH3.

[0200] In some embodiments, R7is -H.

[0201] In some embodiments, R7is halogen. In some embodiments, R7is fluoro.

[0202] In some embodiments, R7is C1-6alkyl. In some embodiments, R7is C1-3alkyl. In some embodiments, R7is C1-2alkyl. In some embodiments, R7is -CH3. In some embodiments, R7is -CH2CH3.

[0203] In some embodiments, R7is C1-6haloalkyl. In some embodiments, R7is C1-3haloalkyl.

[0204] As defined generally above, R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring.

[0205] In some embodiments, R8is selected from -H, -CH3, -CH2CH3, -CH2-,- CH2CH2-, -CH2CH2CH2-, and / or R1and R8taken together with the atoms to which they are attached form a tetrahydrofuranyl ring, or R8and R16taken together with the atoms to which they are attached form an azetidinyl ring.

[0206] In some embodiments, R8is selected from -H, C1-6alkyl, and C1-6haloalkyl.

[0207] In some embodiments, R8is -H.

[0208] In some embodiments, R8is C1-6alkyl. In some embodiments, R8is C1-3alkyl. In some embodiments, R8is C1-2alkyl. In some embodiments, R8is -CH3. In some embodiments, R8is -CH2CH3. In some embodiments, R8is -CH2-. In some embodiments, R8is -CH2CH2-.In some embodiments, R8is -CH2CH2CH2-.

[0209] In some embodiments, R8is C1-6haloalkyl. In some embodiments, R8is C1-3haloalkyl.

[0210] In some embodiments, R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments,R1and R8taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0211] In some embodiments, R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R8and R16taken together with the atoms to which they are attached form an azetidinyl ring.

[0212] As defined generally above, R9is -H 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, 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.

[0213] In some embodiments, R9is -H or fluoro, and / or R1and R9taken together with the atoms to which they are attached form an oxetanyl ring.

[0214] In some embodiments, R9is -H or halogen.

[0215] In some embodiments, R9is -H.

[0216] In some embodiments, R9is halogen. In some embodiments, R9is fluoro.

[0217] In some embodiments, R1and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R1and R9taken together with the atoms to which they are attached form an oxetanyl ring.

[0218] In some embodiments, 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. In some 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.

[0219] In some embodiments, 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.

[0220] In some embodiments, R9and R8taken together with the atoms to which they are attached form a cyclobutyl or cyclopentyl ring system when m is 1 and l is 1.

[0221] As defined generally above for formula I, Ia, and Ib, R10is selected from - H, halogen, and C1-6alkyl.

[0222] In some embodiments, R10is selected from -H, fluoro, and -CH3.

[0223] In some embodiments, R10is -H.

[0224] In some embodiments, R10is halogen. In some embodiments, R10is fluoro.

[0225] In some embodiments, R10is C1-6alkyl. In some embodiments, R10is C1-3alkyl. In some embodiments, R10is C1-2alkyl. In some embodiments, R10is -CH3.

[0226] As defined generally above for formula I’, Ia’, and Ib’, R10is selected from -H, halogen, and optionally substituted C1-6alkyl. In some embodiments of I’, Ia’, and Ib’, R10is optionally substituted C1-6alkyl. In some embodiments of I’, Ia’, and Ib’, R10is C1-6alkyl optionally substituted with halogen. In some such embodiments, R10is fluoro. In some embodiments of I’, Ia’, and Ib’, R10is -CH2F.

[0227] In certain embodiments of formula I, Ia, or Ib, each of R9and R10is -H. In certain embodiments of formula I, Ia, or Ib, each of R9and R10is halogen (e.g., F).

[0228] As defined generally above, R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments R11and R12each independently is selected from -H and C1-6alkyl.

[0229] In some embodiments, R11and R12are -H. In some embodiments, R11is - H. In some embodiments, R12is -H.

[0230] In some embodiments, R11and R12are -OH. In some embodiments, R11is - OH. In some embodiments, R12is -OH.

[0231] In some embodiments, R11and R12are each independently selected from halogen. In some embodiments, R11and R12are fluoro. In some embodiments, R11is halogen. In some embodiments, R11is fluoro. In some embodiments, R12is halogen. In some embodiments, R12is fluoro.

[0232] In some embodiments, R11and R12each independently is selected from C1-6alkyl. In some embodiments, R11is C1-6alkyl. In some embodiments, R12is C1-6alkyl. In some embodiments, R11and R12each independently is selected from C1-2alkyl. In some embodiments, R11is C1-2alkyl. In some embodiments, R12is C1-2alkyl.

[0233] In some embodiments, R11and R12each independently is selected from C1-6haloalkyl. In some embodiments, R11is C1-6haloalkyl. In some embodiments, R12is C1-6haloalkyl. In some embodiments, R11and R12each independently is selected from C1-2haloalkyl. In some embodiments, R11is C1-2haloalkyl. In some embodiments, R12is C1-2haloalkyl.

[0234] As defined generally above, R13is selected from -H, C1-6alkyl, and C1-6haloalkyl.

[0235] In some embodiments, R13is -H.

[0236] In some embodiments, R13is C1-6alkyl. In some embodiments, R13is C1-2alkyl. In some embodiments, R13is -CH3.

[0237] In some embodiments, R13is C1-6haloalkyl. In some embodiments, R13is C1-2haloalkyl.

[0238] As defined generally above, R14is selected from -H, C1-6alkyl, and C1-6haloalkyl.

[0239] In some embodiments, R14is selected from -H and -CH3.

[0240] In some embodiments, R14is -H.

[0241] In some embodiments, R14is C1-6alkyl. In some embodiments, R14is C1-2alkyl. In some embodiments, R14is -CH3.

[0242] In some embodiments, R14is C1-6haloalkyl. In some embodiments, R14is C1-2haloalkyl.

[0243] As defined generally above, R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring.

[0244] In some embodiments, R15is selected from -H, -CH3, -CH2-, -CH2CH2-, and / or R1and R15taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0245] In some embodiments, R15is selected from -H, C1-6alkyl, and C1-6haloalkyl.

[0246] In some embodiments, R15is -H.

[0247] In some embodiments, R15is C1-6alkyl. In some embodiments, R15is C1-2alkyl. In some embodiments, R15is -CH3. In some embodiments, R15is -CH2-. In some embodiments, R15is -CH2CH2-.

[0248] In some embodiments, R15is C1-6haloalkyl. In some embodiments, R15is C1-2haloalkyl.

[0249] In some embodiments, R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R1and R15taken together with the atoms to which they are attached form a tetrahydrofuranyl ring.

[0250] As defined generally above, R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6- membered heterocyclyl ring.

[0251] In some embodiments, R16is selected from -H, -CH2-, -CH2CH2-, and / or R8and R16taken together with the atoms to which they are attached form an azetidinyl ring.

[0252] In some embodiments, R16is selected from -H and C1-6alkyl.

[0253] In some embodiments, R16is -H.

[0254] In some embodiments, R16is C1-6alkyl. In some embodiments, R16is C1-2alkyl. In some embodiments, R16is -CH2-. In some embodiments, R16is -CH2CH2-.

[0255] In some embodiments, R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R8and R16taken together with the atoms to which they are attached form an azetidinyl ring.

[0256] As defined generally above, R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring.

[0257] In some embodiments, R17and R18each independently is selected from -H and C1-6alkyl. In some embodiments, R17and R18each independently is selected from -H and C1-2alkyl. In some embodiments, R17and R18each independently is selected from -H and -CH3.

[0258] In some embodimentsformula IIaIb, R17and R18each independently is selected from -H and C1-6alkyl.

[0259] In some embodiments, R17and R18are -H. In some embodiments, R17is - H. In some embodiments, R18is -H.

[0260] In some embodiments, R17and R18each independently is selected from C1-6 alkyl. In some embodiments, R17is selected from C1-6alkyl. In some embodiments, R18is selected from C1-6alkyl. In some embodiments, R17and R18each independently is selected from C1-2alkyl. In some embodiments, R17is selected from C1-2alkyl. In some embodiments, R18is selected from C1-2alkyl. In some embodiments, R17and R18are - CH3. In some embodiments, R17is -CH3. In some embodiments, R18is -CH3.

[0261] In some embodiments, R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH.

[0262] In some embodiments, R17and R18taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4- , 5-, or 6-membered heterocyclyl ring is substituted with one or more substituents independently selected from halogen (e.g., F) or -OH.

[0263] In some embodiments, R17and R18taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring, wherein the 4- , 5-, or 6-membered heterocyclyl ring is unsubstituted.

[0264] In some embodiments, R17and R18taken together with the nitrogen atom 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.

[0265] In some embodiments, R17and R18taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is substituted with one or more substituents independently selected from alkyl.

[0266] In some embodiments, R17and R18taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7- membered spiroheterocyclyl ring is unsubstituted.

[0267] In some embodiments, R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R17is -H and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring. In some embodiments, R17is selected from C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring.

[0268] As defined generally above, l is 0 or 1. In some embodiments, l is 0. In some embodiments, l is 1.

[0269] As defined generally above, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0270] As defined generally above, n is 0, 1, 2, or 3. In some embodiments, n is 1, 2 or 3.

[0271] In some embodiments, n is 0.

[0272] In some embodiments, n is 1.

[0273] In some embodiments, n is 2.

[0274] In some embodiments, n is 3.

[0275] In some embodimentsof formula I, Ia, or Ib, l is 0. In some embodimentsformula I, Ia, or Ib, l is 1. In some such embodiments, each of R7and R8is -H.

[0276] In some embodiments of formula I, Ia,or Ib, l is 1, R7is -H, and R8is C1-6alkyl (e.g., -CH3). In someembodimentsformula I, Ia, or Ib, l is 1, R7is halogen (e.g., F), and R8is -H.

[0277]

[0278] In certain embodiments of formula I, Ia, or Ib, R11and R12each independently is selected from -H and C1-6alkyl. In certain such embodiments, each of R11and R12is -H.

[0279] In some embodiments, when L is -N=, each of J, M, and Q is -CH=, V is - O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

[0280] In some embodiments, when J is -N=, each of L, M, and Q is -CH=, V is - O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridazi-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl.

[0281] In some embodiments, when J is -N=, each of L, M, and Q is -CH=, V is - NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl.

[0282] In some embodiments, when J is -N=, each of L, M, and Q is -CH=, V is - O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl.

[0283] In some embodiments, when J is -N=, each of L, M, and Q is -CH=, V is - O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

[0284] In some embodiments, when J is -N=, each of L, M, and Q is -CH=, V is - O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl.

[0285] In some embodiments, when J is -N=, each of L, M, and Q is -CH=, V is - O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

[0286] In some embodiments,is selected from:

[0287] In some embodiments,is selected from:

[0288] The present application provides a compound selected from any one of the following, or a pharmaceutically acceptable salt thereof:

[0289] In certain embodiments, the present application provides a pharmaceutical preparation suitable for use in a human patient comprising any of the compounds shown above (e.g., a compound of formula I, such as a compound of formula Ia or Ib, or pharmaceutically acceptable salts thereof) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use intreating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.

[0290] Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein. Uses of the compounds

[0291] Compounds of the present application may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

[0292] 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. This, the skilled artisan 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. In certain embodiments, the application relates to a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, for use as a medicament, e.g., for treatment of any of the disorders disclosed herein.

[0293] In certain embodiments, the application relates to a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, for use as a medicament.

[0294] In certain embodiments, the application relates to the use of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in the manufacture of a medicamentfor treatment of Rett syndrome and / or one or more symptoms associated with Rett syndrome in a subject. In certain such 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.

[0295] In certain embodiments, the application relates to the use of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in the manufacture of a medicament for treatment of FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome in a subject. In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.

[0296] In certain embodiments, the application relates to the use of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in the manufacture of a medicament for treatment of CDD and / or one or more symptoms associated with CDD in a subject. 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.

[0297] In certain embodiments, the application relates to the use of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in the manufacture of a medicamentfor treatment of CHD8-NDD and / or one or more symptoms associated with CHD8-NDD in a subject. 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.

[0298] In certain embodiments, the application relates to the use of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in the manufacture of a medicament for treatment of chronic heart failure in a subject. In certain embodiments, the application relates to the use of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in the manufacture of a medicament for treatment of HfpEF, HfrEF, and HfmrEF in a subject.

[0299] In certain embodiments, the application relates to a method of treating or preventing Rett syndrome and / or one or more symptoms associated with Rett syndrome in a mammal, such as a human being, the method comprising administering to said patient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib. In certain such 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.

[0300] In certain embodiments, the application relates to a method of treating or preventing FOXG1 syndrome and / or one or more symptoms associated with FOXG1syndrome in a mammal, such as a human being, the method comprising administering to said patient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib. In certain embodiments, the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.

[0301] In certain embodiments, the application relates to a method of treating or preventing CDD and / or one or more symptoms associated with CDD in a mammal, such as a human being, the method comprising administering to said patient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib. 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.

[0302] In certain embodiments, the application relates to a method of treating or preventing CHD8-NDD and / or one or more symptoms associated with CHD8-NDD in a mammal, such as a human being, the method comprising administering to said patient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib. 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.

[0303] In certain embodiments, the application relates to a method of treating or preventing chronic heart failure in a mammal, such as a human being, the method comprising administering to said patient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable saltof the compound according to formula I, such as Ia or Ib. In certain embodiments, the application relates to a method of treating or preventing HfpEF, HfrEF, or HfmrEF in a mammal, such as a human being, the method comprising administering to said patient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib.

[0304] In certain embodiments, a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, as disclosed herein is a brain penetrant. In certain embodiments, a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, as disclosed herein is capable of crossing the blood brain barrier. In certain such embodiments, the compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, is useful in methods of treating or preventing Rett syndrome and / or one or more symptoms associated with Rett syndrome (e.g., 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). In other such embodiments, the compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, is useful in methods of treating or preventing FOXG1 syndrome and / or one or more symptoms associated with FOXG1 syndrome (e.g., feeding problems, sleep disturbances, seizures, irritability, and excessive crying). In other such embodiments, the compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia orIb, is useful in methods of treating or preventing 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 (gastroesophageal reflux); and irregular breathing). In other such embodiments, the compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, is useful in methods of treating or preventing 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).

[0305] In certain embodiments, a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, as disclosed herein is not brain penetrant. In certain embodiments, a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, as disclosed herein is not capable of crossing the blood brain barrier (i.e., is peripherally restricted). In certain such embodiments, the compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, is useful in methods of treating or preventing chronic heart failure, HfpEF, HfrEF, and HfmrEF.

[0306] In certain embodiments of the methods a disclosed herein, the compound is selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof.

[0307] In certain embodiments, the application relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound according to formula I, such as Ia or Ib, in association with at least one pharmaceutically acceptable excipient, carrier or diluent. 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.

[0308] In certain embodiments, the application relates to a pharmaceutical composition comprising (1) a compound according to formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound of formula I, such as Ia or Ib, (2) an additional therapeutic agent, or a pharmaceutically acceptable salt thereof, and (3) pharmaceutically acceptable excipients, carriers or diluents.

[0309] In the treatment of any of the disorders disclosed herein, different compounds of the application may be (e.g., conjointly) administered with one or more other compounds of the application. Moreover, compounds of formula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound of formula I, such as Ia or Ib, or certain combinations thereof, may be conjointly administered with other conventional therapeutic agents in treating one or more disease conditions referred to herein.

[0310] In certain embodiments, compounds of the application 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 therapeutic compound 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 a separate formulation, 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.

[0311] In certain embodiments, conjoint administration of compounds of the application 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 offormula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound of formula I, such as Ia or Ib) 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 application and the one or more additional therapeutic agent(s).

[0312] Such conventional therapeutics may include one or more of the following categories of agents:

[0313] 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;

[0314] 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;

[0315] Rett syndrome therapies including, for example, trofinetide;

[0316] 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));

[0317] agents that improve artery opening and blood flow, reduce sodium retention and decreases strain on the heart, such as angiotensin-receptor neprilysininhibitors (ARNIs) (e.g., a drug combination of a neprilysin inhibitor and an ARB) including, for example, sacubitril / valsartan (Entresto);

[0318] agents that reduce heart rate, such as I(f) channel blockers including, for example, ivabradine (Corlanor);

[0319] 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);

[0320] 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);

[0321] aldosterone antagonists including, for example, spironolactone (Aldactone), and eplerenone (Inspra);

[0322] vasodilators including, for example, hydralazine and nitrates (e.g., nitroglycerin or isosorbide dinitrate) and combinations thereof;

[0323] 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);

[0324] anticoagulants;

[0325] cholesterol-lowering drugs (e.g., statins);

[0326] digoxin;

[0327] calcium channel blockers (CCBs);

[0328] potassium; and

[0329] oxygen therapy.

[0330] In certain emodiments, the present application provides conjoint administration of compounds of the application with trofinetide, providing improved efficacy relative to each individual administration of the compound of the application (e.g., compound offormula I, such as Ia or Ib, or a pharmaceutically acceptable salt of the compound of formula I, such as Ia or Ib) 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.

[0331] Such combination products employ the compounds of this application 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

[0332] The compositions and methods of the present application 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 for human 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 bepresent 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.

[0333] 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.

[0334] 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.

[0335] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, 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 and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; (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.

[0336] 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.

[0337] 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 asingle 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 active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0338] 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, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0339] Formulations of the application 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.

[0340] 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)wetting 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 as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0341] 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 or hydroxypropylmethyl 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.

[0342] 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 pharmaceuticalformulating 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-retaining filter, 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 ingrcdicnt(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.

[0343] 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.

[0344] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0345] 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.

[0346] 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 waxor 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.

[0347] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present application 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 the flux of the compound across the skin. The rateof such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0354] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this application. 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 lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0355] 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.

[0356] 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.

[0357] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the application 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. Proper fluidity can be maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0358] These compositions may also contain adjuvants such as preservatives, wetting 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.

[0359] 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.

[0360] 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.

[0361] For use in the methods of this application, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0362] 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.

[0363] 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 desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0364] 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.

[0365] 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 patien’’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).

[0366] In general, a suitable daily dose of an active compound used in the compositions and methods of the application 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.

[0367] 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 application, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0368] The patient receiving this treatment is any animal in need, including primates, in particular humans.

[0369] This application includes the use of pharmaceutically acceptable salts of compounds of the application in the compositions and methods of the present application. 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 invention 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 invention contain relatively basic functionalities, such as an amine, acid addition salts can be obtained bycontacting 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 invention may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0370] 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 saltforms 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 invention.

[0371] The compounds of the application, 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.

[0372] The compounds of the application, including their pharmaceutically acceptable salts, can also exist as various polymorphs, pseudo-polymorphs, or in amorphous state. As used herein, the term “polymorph” refers to different crystalline forms of the same compound and other solid state molecular forms including pseudo- polymorphs, such as hydrates, solvates, or salts of the same compound. Different crystalline polymorphs have different crystal structures due to a different packing of molecules in the lattice, as a result of changes in temperature, pressure, or variations in the crystallization process. Polymorphs differ from each other in their physical properties, such as x-ray diffraction characteristics, stability, melting points, solubility, or rates of dissolution in certain solvents. Thus, crystalline polymorphic forms are important aspects in the development of suitable dosage forms in pharmaceutical industry.

[0373] Wetting 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.

[0374] 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 ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0375] In certain embodiments, the application comprises a method for conducting a pharmaceutical business, by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the diseases or conditions as described herein, conducting therapeutic profiling of identified formulations for efficacy and toxicity in animals, and providing a distribution network for selling an identified preparation as having an acceptable therapeutic profile. In certain embodiments, the method further includes providing a sales group for marketing the preparation to healthcare providers.

[0376] In certain embodiments, the application relates to a method for conducting a pharmaceutical business by determining an appropriate formulation and dosage of a compound of the application for treating or preventing any of the disease or conditions as described herein, and licensing, to a third party, the rights for further development and sale of the formulation.

[0377] Exemplary Embodiments Embodiment 1. A compound of formula I,, or a pharmaceutically acceptable salt thereof, wherein: each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=;A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and -N(R2)(R3); Z is selected from -H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen, orR1and 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 selected from -H, halogen, and C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; orR17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when L is -N=, each of J, M, and Q is -CH= (i.e., formula Ia), V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (B) when J is -N=, each of L, M, and Q is -CH=, (i.e., formula Ib) V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -N(H)-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is - H, then A is not optionally substituted thiazolyl; (D) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl;(F) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when J is -N=, each of L, M, and Q is -CH= (i.e., formula Ib), V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl. Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L is -N=. Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein L is -N= and each of J, M, and Q is -CH=. Embodiment 4. A compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-;Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen (e.g., F), -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen (e.g., F), C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl;R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl. Embodiment 5. A compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen (e.g., F), -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R2and R3taken together with the nitrogen atom 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;R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen (e.g., F), C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl); R8is selected from -H, C1-6alkyl (e.g., C1-3alkyl), and C1-6haloalkyl (e.g., C1-3haloalkyl), or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H or halogen (e.g., F), 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 selected from -H, halogen (e.g., F), and C1-6alkyl (e.g., C1-3alkyl); R11and R12each independently is selected from -H, -OH, halogen (e.g., F), C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen (e.g., F) or -OH; or R17and R18taken together with the nitrogen atom to which they are attached form a 7-membered spiroheterocyclyl ring, wherein the 7-memberedspiroheterocyclyl ring is optionally substituted with one or more substituents independently selected from alkyl; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (B) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when V is -NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and(G) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl. Embodiment 6. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted heteroaryl. Embodiment 7. The compound of Embodiment 6, or a pharmaceutically acceptable salt thereof, wherein A is selected from optionally substituted pyridyl, optionally substituted pyridizinyl, and optionally substituted pyrimidinyl. Embodiment 8. The compound of Embodiment 7, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted pyridyl. Embodiment 9. The compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted heterocyclyl. Embodiment 10. The compound of Embodiment 9, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted oxetanyl. Embodiment 11. The compound of Embodiment 9, or a pharmaceutically acceptable salt thereof, wherein A is 3-oxetanyl. Embodiment 12. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein V is -O-. Embodiment 13. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein n is 1. Embodiment 14. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein R12is -H.Embodiment 15. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein R11is -H. Embodiment 16. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein X is -S-. Embodiment 17. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein Y is -N(R2)(R3). Embodiment 18. The compound of Embodiment 17, or a pharmaceutically acceptable salt thereof, wherein R2and R3each independently is selected from -H and C1-6alkyl. Embodiment 19. The compound of Embodiment 17, or a pharmaceutically acceptable salt thereof, wherein R2and R3are each -H. Embodiment 20. The compound of Embodiment 17, or a pharmaceutically acceptable salt thereof, wherein R2is -H and R3is C1-6alkyl. Embodiment 21. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein Z is -OR1. Embodiment 22. The compound of Embodiment 21, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6alkyl. Embodiment 23. The compound of Embodiment 21, or a pharmaceutically acceptable salt thereof, wherein R1is -CH3. Embodiment 24. The compound of Embodiment 21, or a pharmaceutically acceptable salt thereof, wherein R1is -C(2H)3. Embodiment 25. The compound of Embodiment 21, or a pharmaceutically acceptable salt thereof, wherein R1is -H.Embodiment 26. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein m is 0. Embodiment 27. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein l is 1. Embodiment 28. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein R7is -H. Embodiment 29. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein R8is -H. Embodiment 30. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein R8is C1-6alkyl. Embodiment 31. The compound of Embodiment 30, or a pharmaceutically acceptable salt thereof, wherein R8is -CH3. Embodiment 32. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein R9is -H. Embodiment 33. The compound of any preceding Embodiment, or a pharmaceutically acceptable salt thereof, wherein R10is -H. Embodiment 34. A compound selected from any one of compounds 1-294, and or a pharmaceutically acceptable salts thereof. Embodiment 35. A pharmaceutical composition comprising (a) a compound of any preceding Embodiment; and (b) a pharmaceutically acceptable excipient. Embodiment 36. A compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35 for use as a medicament.Embodiment 37. 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, or CHD8-related neurodevelopmental disorder (CHD8-NDD) and / or one or more symptoms associated with CHD8-NDD in a subject comprising administering to a subject in need thereof an effective amount of at least one compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35.Embodiment 38. The method of Embodiment 37, the method comprising treatingRett syndrome and / or one or more symptoms associated with Rett syndrome.Embodiment 39. The method of Embodiment 38, comprising co-administering to the subject an additional therapeutic agent.Embodiment 40. The method of Embodiment 39, wherein the additional therapeutic agent comprises trofinetide.Embodiment 41. The method of any one of Embodiments 37-40, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism.Embodiment 42. The method of Embodiment 37, wherein the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.Embodiment 43. The method of Embodiment 37, 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 includingconstipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux); and irregular breathing. Embodiment 44. The method of Embodiment 37, 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. Embodiment 45. A method of treating chronic heart failure in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35. Embodiment 46. A method of treating heart failure with preserved ejection fraction (HFpEF), comprising administering to a subject in need thereof an effective amount of at least one compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35. Embodiment 47. A method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of at least one compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35. Embodiment 48. A method of treating heart failure with mid-range ejection fraction (HFmrEF), comprising administering to a subject in need thereof an effective amount of at least one compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35. Embodiment 49. The method of any one of Embodiments 37-48, wherein the compound is selected from any one of compounds 1-294, and or a pharmaceutically acceptable salt thereof.Embodiment 50. Use of a compound of any one of Embodiments 1-29 or a pharmaceutical composition of Embodiment 30, in the preparation of a medicament for 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, or CHD8-NDD and / or one or more symptoms associated with CHD8-NDD. Embodiment 51. The use of Embodiment 50, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism. Embodiment 52. The use of Embodiment 50, wherein the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying. Embodiment 53. The use of Embodiment 50, 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. Embodiment 54. The use of Embodiment 50, 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. Embodiment 55. Use of a compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35, in the preparation of a medicament for the treatment of chronic heart failure.Embodiment 56. Use of a compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35, in the preparation of a medicament for the treatment of HFpEF. Embodiment 57. Use of a compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35, in the preparation of a medicament for the treatment HFrEF. Embodiment 58. Use of a compound of any one of Embodiments 1-34 or a pharmaceutical composition of Embodiment 35, in the preparation of a medicament for the treatment of HFmrEF. Embodiment 59. The use of any one of Embodiments 50-58, wherein the compound is selected from any one of compounds 1-294, and or a pharmaceutically acceptable salts thereof.

[0378] Examples

[0379] Example 1: Synthetic Protocols

[0380] Below follows non-limiting examples of compounds of the application. 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-pressure 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 supercritical fluid chromatography (SFC). Silica gel chromatography was performed on silica gel 60 (230-400 mesh). Chromatography columns available for use in the separation / purification of theenantiomers / diastereoisomers provided herein include, but are not limited to, Waters Xbridge Prep OBD®, Waters Xbridge BEH®, Kromasil®, Phenomenex Luna®, etc.

[0381] The structure and purity of all final 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 shift (δ) is given in parts per million (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.

[0382] The following abbreviations have been used: BOC tert-butoxycarbonyl DEAD diethyl azodicarboxylate DCCI 1,3-dicyclohexylcarbodiimide DCM Dichloromethane DMA N,N-dimethylacetamide DMAP 4-dimethyl-aminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDCI 1–(3-dimethylaminopropyl)-3-ethyl-carbodiimide EEDQ 2- ethoxy-1 -ethoxycarbonyl-1,2-dihydroquinoline EtOAc Ethyl acetate HOBT hydroxybenzotriazole MeCN acetonitrile mCPBA m-chloroperoxybenzoic acid NMM N-methylmorpholine NMMO N-methylmorpholine-N-oxide PE Petroleum ether TBAF tetra-n-butylammonium fluorideTFA trifluoroacetic acid THF tetrahydrofuran TMEDA Ν,Ν,Ν’,Ν’-tetramethylethylenediamine TMSI trimethylsilyliodide TPAP tetrapropylammonium perruthenate

[0383] General synthetic methods for the preparation of the compounds of the present invention

[0384] 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 starting materials such as 5- hydroxypicolinaldehyde 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 (Scheme 1; Matrosova, S. V.; Zav’yalova, V. K.; Litvinov, V. P.; Sharanin, Yu. A. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya (1991), (7), 1643-6).

[0385] Scheme 1

[0386] 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-butylnitrite 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).

[0387] Scheme 2

[0388] Preparation of Compounds of Formula I:

[0389] Compounds of formula I where X is -S- and R2and R3are -H

[0390] are prepared by treatment of a phenol with an alkylating agent such as 1- bromo-2-methoxyethane or 1-bromo-hydroxyethane and a base such as K2CO3in a solvent such as DMF or acetonitrile to give an intermediate aldehyde.

[0391] The aromatic aldehyde can be condensed with 2-cyanothioacetamide in the presence of a base such as N-methylmorpholine or K2CO3in a solvent such as ethanol to give a 4-aryl-2-mercaptopyridine.

[0392] 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 -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), -N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, aryl, or optionally substituted heteroaryl.

[0393] 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 atom to which they are attached form a 4- or 5-membered heterocyclyl 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 atom to which they are attached form a 4- or 5-membered heterocyclyl ring.

[0394] The following protocols provide detailed examples on how the compounds of the present invention were synthesized.

[0395] Protocol 1. (S)-2'-amino-5-(2-methoxypropoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (48)

[0396] Step 1. Preparation of (S)-2-methoxypropyl methanesulfonate (48B)

[0397] To a solution of (S)-2-methoxypropan-1-ol (2.0 g, 22.2 mmol, 2.13 mL, 1 eq) in DCM (20 mL) was added TEA (6.74g, 66.6 mmol, 9.27 mL, 3 eq) andmethanesulfonyl chloride (3.05 g, 26.6 mmol, 2.06 mL, 1.2 eq) at 0 °C. TLC (Plate1, Petroleum ether: Ethyl acetate = 3:1) indicated Reactant 1 was consumed completely and one new spot was formed. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of saturated aqueous Na2CO3solution (50 mL) at 0 °C, and stirred at 0 °C for 0.5 hrs, then extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (S)-2-methoxypropyl methanesulfonate (48-B) (3.5 g, crude) as white solid.

[0398] Step 2. Preparation of (S)-5-(2-methoxypropoxy)picolinaldehyde (48-D)

[0399] To a solution of 5-hydroxypicolinaldehyde (1 g, 8.12 mmol, 1 eq) in DMF (10 mL) was added Cs2CO3(5.29 g, 16.3 mmol, 2 eq) and [(2S)-2-methoxypropyl] methanesulfonate (2.05 g, 12.2 mmol, 1.5 eq). The mixture was stirred at 100°C for 1 hr, then diluted with 50 mL of H2O and extracted with Ethyl acetate 120mL (40 mL × 3). The combined organic layers were washed with brine 60 mL (30 mL × 2), 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 =20:1 to 10:1) to give (S)-5-(2-methoxypropoxy)picolinaldehyde (48-D) (1.5 g, 4.61 mmol, 56.76% yield, 60% purity) as white solid. [M+H]=196.2

[0400] Step 3. Preparation of (S)-2'-amino-6'-mercapto-5-(2-methoxypropoxy)- [2,4'-bipyridine]-3',5'-dicarbonitrile (48-E)

[0401] To a solution of (S)-5-(2-methoxypropoxy)picolinaldehyde (500 mg, 2.56 mmol, 1 eq) in EtOH (5 mL) was added NMM (777 mg, 7.68 mmol, 845 μL, 3 eq) and 2- cyanothioacetamide (641 mg, 6.40 mmol, 2.5 eq). The mixture was stirred at 20 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give (S)-2'- amino-6'-mercapto-5-(2-methoxypropoxy)-[2,4'-bipyridine]-3',5'-dicarbonitrile (48-E) (500 mg, crude) as white solid. [M+H]=342.1

[0402] Step 4. Preparation of (S)-2'-amino-5-(2-methoxypropoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (48)

[0403] To a solution of (S)-2'-amino-6'-mercapto-5-(2-methoxypropoxy)-[2,4'- bipyridine]-3',5'-dicarbonitrile (500 mg, 1.46 mmol, 1 eq) in DMF (3 mL) was added K2CO3(607 mg, 4.39 mmol, 3 eq) and 2- (chloromethyl)pyridine;hydrochloride (360 mg, 2.20 mmol, 1.5 eq). The mixture was stirred at 20 °C for 1 hr and then filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue waspurified by preparative HPLC (Waters Xbridge BEH C18(100 × 25 mm × 10 um ); flow rate: 25 mL / min; gradient: 25% – 60% B over 8 min; mobile phase A:10 mM aqueous NH4HCO3,mobile phase B: acetonitrile) to give (S)-2'-amino-5-(2- methoxypropoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile 48 (100 mg, 218 μmol, 14.9% yield, 94.1% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.58 - 8.43 (m, 2H), 7.79 - 7.57 (m, 4H), 7.35 - 7.24 (m, 1H), 4.62 (s, 2H), 4.21 - 4.06 (m, 2H), 3.77 - 3.65 (m, 1H), 3.32 - 3.32 (m, 3H), 1.20 (d, J = 6.4 Hz, 3H). [M+H]=433.0

[0404] The compounds in Table 1 were prepared according to procedures analogous to preparation of Compound 48 in protocol 1, using analogous starting materials and / or intermediates.

[0405] Table 1:Protocol 2. (S)-2'-amino-5-(2-methoxypropoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'- bipyridine]-3',5'-dicarbonitrile (38)

[0406] Step 1. Preparation of (S)-2'-chloro-5-(2-methoxypropoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (38-A)

[0407] To a solution of (S)-2'-amino-5-(2-methoxypropoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (60 mg, 138.73 μmol, 1 eq) in ACN (2 mL) was added tert-butyl nitrite (28.61 mg, 277.46 μmol, 33.00 μL, 2 eq) and CuCl2(37.30 mg, 277.46 μmol, 2 eq). The mixture was stirred at 60°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give (S)-2'-chloro-5-(2- methoxypropoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (60 mg, crude) as a black solid. [M+H]=452.1

[0408] Step 2. Preparation of (S)-2'-(3-fluoroazetidin-1-yl)-5-(2- methoxypropoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (38)

[0409] To a solution of (S)-2'-chloro-5-(2-methoxypropoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (60 mg, 132.76 μmol, 1 eq) in THF (2mL) was added TEA (40.30 mg, 398.29 μmol, 55.44 μL, 3 eq) and 3- fluoroazetidine;hydrochloride (22.21 mg, 199.15 μmol, 1.5 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 (100 × 30 mm × 3 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 (S)-2'-(3-fluoroazetidin-1-yl)- 5-(2-methoxypropoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (4.1 mg, 7.37 μmol, 5.55% yield, 96.4% purity, FA salt) as a white solid.1H NMR (400 MHz, CD3OD) δ = 8.54 - 8.42 (m, 2H), 7.82 (dt, J = 7.6, 1.6 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.34 (dd, J = 7.2, 5.2 Hz, 1H), 5.53 - 5.31 (m, 1H), 4.78 - 4.65 (m, 4H), 4.52 - 4.39 (m, 2H), 4.17 - 4.10 (m, 2H), 3.80 (dt, J = 6.0, 4.2 Hz, 1H), 3.44 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H). [M+H]=491.2

[0410] The compounds in Table 2 were prepared according to procedures analogous to preparation of Compound 48 in protocol 2, using analogous starting materials and / or intermediates.

[0411] Table 2:

[0412] Protocol 3.5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- ((pyridazin-3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (71)

[0413]

[0414] Step 1. Preparation of 2'-amino-5-(2,2-difluoroethoxy)-6'-(methylthio)- [2,4'-bipyridine]-3',5'-dicarbonitrile (71-B)

[0415] To the mixture of 2'-amino-5-(2,2-difluoroethoxy)-6'-mercapto-[2,4'- bipyridine]-3',5'-dicarbonitrile (1 g, 3.00 mmol, 1 eq) in DMF (10 mL) was added K2CO3(829.28 mg, 6.00 mmol, 2 eq) and CH3I (2.13 g, 15.00 mmol, 933.85 μL, 5 eq), the mixture was stirred at 25°C for 1 hr. The mixture was added H2O (10 mL). The reaction mixture was filtered and the filtrate cake was concentrated under reduced pressure to give 2'-amino-5-(2,2-difluoroethoxy)-6'-(methylthio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (1.1 g, crude) as a black solid. [M+H]= 348.2

[0416] Step 2. Preparation of 2'-chloro-5-(2,2-difluoroethoxy)-6'-(methylthio)- [2,4'-bipyridine]-3',5'-dicarbonitrile (71-C)

[0417] To the mixture of 2'-amino-5-(2,2-difluoroethoxy)-6'-(methylthio)-[2,4'- bipyridine]-3',5'-dicarbonitrile (1 g, 2.88 mmol, 1 eq) in ACN (50 mL) was added CuCl (570.04 mg, 5.76 mmol, 137.69 μL, 2 eq) and tert-butyl nitrite (593.77 mg, 5.76 mmol, 684.85 μL, 2 eq), the mixture was stirred at 60°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2'-chloro-5-(2,2-difluoroethoxy)-6'-(methylthio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (1 g, crude) as a black solid. [M+H]= 367.3

[0418] Step 3. Preparation of 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- (methylthio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (71-D)

[0419] To the mixture of 2'-chloro-5-(2,2-difluoroethoxy)-6'-(methylthio)-[2,4'- bipyridine]-3',5'-dicarbonitrile (1 g, 2.73 mmol, 1 eq) and 3-fluoroazetidine (1.02 g, 13.63 mmol, 5 eq) in THF (20 mL) was added TEA (827.67 mg, 8.18 mmol, 1.14 mL, 3 eq), the mixture was stirred at 25°C for 1 hr. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 100:1 to 1:1) to give 5- (2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'-(methylthio)-[2,4'-bipyridine]-3',5'- dicarbonitrile (290 mg, 715.35 μmol, 26.24% yield) as black solid. [M+H]= 406.3

[0420] Step 4. Preparation of 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- (methylsulfinyl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (71-E)

[0421] To a solution of 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- (methylthio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (280 mg, 690.68 μmol, 1 eq) in DCM (5 mL) was added m-CPBA (140.22 mg, 690.68 μmol, 85% purity, 1 eq) in portion sat 0°C. The resulting solution was allowed to warm to 25°C gradully and stirred at this temperature for 1 hr. The reaction mixture was filtered, the filter cake was quenched by addition aq. Na2SO3(20 mL) slowly at 0°C for 0.5 hrs until potassium iodide-starch test paper was negative, then discarded. The combined organic phase was quenched by addition aq. Na2SO3(20 mL) slowly at 0°C for 0.5 hrs until potassium iodide-starch test paper was negative, washed with brine (20 mL × 3), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, Petroleum Ether : Ethyl acetate = 0 : 1) to give 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- (methylsulfinyl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (130 mg, 308.50 μmol, 44.67% yield) as yellow solid. [M+H]= 422.2

[0422] Step 5. Preparation 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- mercapto-[2,4'-bipyridine]-3',5'-dicarbonitrile (71-F)

[0423] To the mixture of 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- (methylsulfinyl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (120 mg, 284.77 μmol, 1 eq) in DMF (3 mL) was added potassium ethanethioate (325.23 mg, 2.85 mmol, 10 eq), the mixture was stirred at 25°C for 1 hr. The reaction mixture was added to the aq. NaClO (10 mL) at 0°C and stirred at 25°C for 0.1 hrs, then the reaction mixture was partitioned between EtOAc (10 mL) and H2O (5 mL), the water phase was extracted with EtOAc (10 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated togive 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'-mercapto-[2,4'-bipyridine]-3',5'- dicarbonitrile (100 mg, crude) as a yellow solid. [M+H]= 392.2

[0424] Step 6. Preparation of 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- ((pyridazin-3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (71)

[0425] To the mixture of 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'- mercapto-[2,4'-bipyridine]-3',5'-dicarbonitrile (50 mg, 127.76 μmol, 1 eq) and 3- (chloromethyl)pyridazine hydrochloride (82.12 mg, 638.78 μmol, 5 eq) in DMF (2 mL) was added K2CO3(35.31 mg, 255.51 μmol, 2 eq), the mixture was stirred at 25°C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC(Phenomenex Gemini C18 column (80 × 10 mm, 3 um); flow rate: 60 mL / min; gradient: 15% – 45% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 5-(2,2-difluoroethoxy)-2'-(3-fluoroazetidin-1-yl)-6'-((pyridazin-3-ylmethyl)thio)- [2,4'-bipyridine]-3',5'-dicarbonitrile (7.2 mg, 14.89 μmol, 11.66% yield, 100.0% purity) as a yellow solid.1H NMR (400 MHz, CD3OD) δ = 9.13 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 7.93 (dd, J = 8.4, 1.6 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.69 - 7.64 (m,1H), 6.43 - 6.11 (m, 1H), 5.53 - 5.34 (m, 1H), 4.87 (s, 2H), 4.66 (br s, 2H), 4.46 (dt, J = 13.6, 3.6 Hz, 4H) [M+H]= 484.0

[0426] The compounds in Table 3 were prepared according to procedures analogous to preparation of Compound 71 in protocol 3, using analogous starting materials and / or intermedites.

[0427] Table 3:

[0428] Protocol 4.2'-methoxy-5-(2-methoxyethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (51)

[0429] Step 1. Preparation of 2'-methoxy-5-(2-methoxyethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile

[0430] To a mixture of 2'-chloro-5-(2-methoxyethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (200 mg, 456.72 μmol, 1 eq) in MeOH (3 mL) was added NaOMe (61.68 mg, 1.14 mmol, 2.5 eq), the mixture was sirred at 25 °C for 0.5 hrs. The reaction mixture 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: 30% – 65% B over 8 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 2'-methoxy-5- (2-methoxyethoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (4.7mg, 10.76 μmol, 2.36% yield, 99.256% purity) as a white solid. 1H-NMR (400 MHz,CD3OD) δ = 8.59 - 8.47 (m, 2 H), 7.89 - 7.77 (m, 2 H), 7.67 - 7.59 (m, 2 H), 7.37 (dd, J = 7.2, 5.2 Hz, 1 H), 4.79 (s, 2 H), 4.33 (dd, = 5.2, 3.6 Hz, 2 H), 4.12 (s, 3 H), 3.83 (dd, J = 5.2, 3.6 Hz, 2 H), 3.46 (s, 3 H). [M+H]=434.0.

[0431] Protocol 5.5-(2-methoxyethoxy)-2'-((pyridin-2-ylmethyl)thio)-6'-(2,6- diazaspiro[3.3]heptan-2-yl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (62)

[0432] Step 1. Preparation of 2'-chloro-5-(2-methoxyethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (62-A)

[0433] To a solution of 2'-amino-5-(2-methoxyethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (110 mg, 262.86 μmol, 1 eq) in ACN (4 mL) was added t-BuONO (54.21 mg, 525.72 μmol, 62.53 μL, 2 eq) and CuCl2(70.68 mg, 525.72 μmol, 2 eq). The mixture was stirred at 60 °C for 1 hr under N2. The reaction mixture was concentrated under reduced pressure to give 2'-chloro-5-(2- methoxyethoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (110mg, crude) as a black solid and used directly into the next step without further purification. [M+H]=438.1.

[0434] Step 2. Preparation of tert-butyl 6-(3',5'-dicyano-5-(2-methoxyethoxy)-6'- ((pyridin-2-ylmethyl)thio)-[2,4'-bipyridin]-2'-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (62-B)

[0435] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (99.61 mg, 502.40 μmol, 2.2 eq) in THF (1 mL) was added TEA (69.32 mg, 685.09 μmol, 95.36 μL, 3 eq) and 2'-chloro-5-(2-methoxyethoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'- bipyridine]-3',5'-dicarbonitrile (100 mg, 228.36 μmol, 1 eq). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 0:1) to give tert-butyl 6-(3',5'-dicyano-5-(2- methoxyethoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridin]-2'-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (50 mg, 83.37 μmol, 36.51% yield) as a pink oil. [M+H]=600.2

[0436] Step 3. Preparation of 5-(2-methoxyethoxy)-2'-((pyridin-2-ylmethyl)thio)- 6'-(2,6-diazaspiro[3.3]heptan-2-yl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (62)

[0437] To a solution of tert-butyl 6-(3',5'-dicyano-5-(2-methoxyethoxy)-6'- ((pyridin-2-ylmethyl)thio)-[2,4'-bipyridin]-2'-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (20 mg, 33.35 μmol, 1 eq) in DCM (0.5 mL) was added TFA (0.1 mL). The mixture was stirred at 25 °C for 0.5hr, then concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 (100 × 30 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 5-(2-methoxyethoxy)-2'- ((pyridin-2-ylmethyl)thio)-6'-(2,6-diazaspiro[3.3]heptan-2-yl)-[2,4'-bipyridine]-3',5'- dicarbonitrile (4.2 mg, 7.37 μmol, 22.09% yield, 95.7% purity, FA salt) as a white solid.1H NMR (400 MHz, CD3OD) δ = 8.55 - 8.50 (m, 1H), 8.44 (d, J = 2.8 Hz, 1H), 7.83 (dt, J = 7.6, 1.6 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.61 - 7.57 (m, 2H), 7.35 (dd, J = 6.8, 4.8 Hz,1H), 4.66 (s, 2H), 4.65 - 4.52 (m, 4H), 4.31 - 4.28 (m, 2H), 4.10 (s, 4H), 3.82 - 3.79 (m, 2H), 3.44 (s, 3H). [M+H]=500.3

[0438] Protocol 6.5-(2-Methoxyethoxy)-2'-(6-methyl-2,6- diazaspiro[3.3]heptan-2-yl)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'- dicarbonitrile (61)

[0439] Step 1. Preparation of 5-(2-Methoxyethoxy)-2'-(6-methyl-2,6- diazaspiro[3.3]heptan-2-yl)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'- dicarbonitrile (61)

[0440] To a solution of 5-(2-methoxyethoxy)-2'-((pyridin-2-ylmethyl)thio)-6'- (2,6-diazaspiro[3.3]heptan-2-yl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (27 mg, 54.04 μmol, 1 eq) in MeOH (1 mL) was was adjusted to pH >10 with DIEA (20.95 mg, 162.13 μmol, 28.24 μL, 3 eq) and then the mixture was adjusted to pH = 4~5 with AcOH (9.74 mg, 162.13 μmol, 9.28 μL, 3 eq), then HCHO (17.54 mg, 216.18 μmol, 16.09 μL, 4 eq) was added to the mixture and stirred at 25 °C for 0.5 hr. Then NaBH3CN (6.79 mg, 108.09 μmol, 2 eq) was added to the mixture and stirred at 25 °C for 0.5 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 (100 × 30 mm, 3 um); flow rate: 25 mL / min; gradient: 1% – 35% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 5-(2-methoxyethoxy)-2'-(6-methyl-2,6- diazaspiro[3.3]heptan-2-yl)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'- dicarbonitrile (11.7 mg, 20.34 μmol, 37.64% yield, 97.3% purity, FA salt) as a white solid.1H NMR (400 MHz, CD3OD) δ = 8.55 - 8.50 (m, 1H), 8.44 (d, J = 2.8 Hz, 1H),7.82 (dt, J = 7.6, 1.6 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.60 - 7.55 (m, 2H), 7.34 (dd, J = 6.8, 5.6 Hz, 1H), 4.65 (s, 2H), 4.53 (br s, 4H), 4.31 - 4.28 (m, 2H), 3.81 - 3.78 (m, 2H), 3.66 (s, 4H), 3.43 (s, 3H), 2.46 (s, 3H). [M+H]=514.2

[0441] Protocol 7.5-(1,1-difluoro-2-hydroxyethoxy)-2'-(methylamino)-6'- ((pyridin-3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (104)

[0442] Step 1. Ethyl 2-((6-bromopyridin-3-yl)oxy)-2,2-difluoroacetate (104-B)

[0443] To a solution of 6-bromopyridin-3-ol (30 g, 172.42 mmol, 1 eq) and ethyl 2-bromo-2,2-difluoroacetate (45.50 g, 224.14 mmol, 1.3 eq) in DMF (250 mL) was added DBU (52.50 g, 344.84 mmol, 2 eq) at 25 °C. The mixture was stirred at 70 °C for 2 hrs under N2. The reaction mixture was partitioned between EtOAc (500 mL) and H2O (500 mL), the water phase was extracted with EtOAc (500 mL × 3), the combinedorganic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate= 1:0 to 5:1) to give ethyl 2-((6-bromopyridin-3-yl)oxy)-2,2-difluoroacetate (29 g, 97.95 mmol, 56.81% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.36 (d, J = 2.4 Hz, 1H), 7.58 - 7.46 (m, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). [M+H] = 282.1

[0444] Step 2.2-((6-Bromopyridin-3-yl)oxy)-2,2-difluoroethan-1-ol (104-C)

[0445] To a solution of ethyl 2-((6-bromopyridin-3-yl)oxy)-2,2-difluoroacetate (29 g, 97.95 mmol, 1 eq) in THF (300 mL) was added LiAlH4(3.72 g, 97.95 mmol, 1 eq) at - 10 °C. The mixture was stirred at -10 °C for 2 hrs under N2. The reaction mixture was quenched by addition Na2SO4.10H2O 5 g at 0 °C, and then diluted with THF 500 mL, The mixture were dried over Na2SO4filtered 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 3:1) to give 2-((6-bromopyridin-3-yl)oxy)-2,2-difluoroethan- 1-ol (12 g, 47.24 mmol, 48.23% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.32 (d, J = 2.4 Hz, 1H), 7.56 - 7.42 (m, 2H), 4.07 (dt, J = 8.8, 7.6 Hz, 2H) [M+H] = 254.1

[0446] Step 3.2,2-Difluoro-2-((6-vinylpyridin-3-yl)oxy)ethan-1-ol (104-D)

[0447] To a solution of 2-((6-bromopyridin-3-yl)oxy)-2,2-difluoroethan-1-ol (11 g, 43.30 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (8.00 g, 51.96 mmol, 1.2 eq) in EtOH (150 mL) and H2O (15 mL) was added Pd(Amphos)2Cl2(3.07 g, 4.33 mmol, 0.1 eq) and KOAc (8.50 g, 86.60 mmol, 2 eq). The mixture was stirred at 80°C for 6 hrs under N2. The reaction mixture was filtered and the filtrate 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 2,2- difluoro-2-((6-vinylpyridin-3-yl)oxy)ethan-1-ol (5.7 g, 28.33 mmol, 65.43% yield) as a yellow oil. [M+H] = 202.2

[0448] Step 4.5-(1,1-Difluoro-2-hydroxyethoxy)picolinaldehyde (104-E)

[0449] O3(1.36 g, 28.33 mmol, 1 eq) was bubbled into a solution of 2,2-difluoro- 2-((6-vinylpyridin-3-yl)oxy)ethan-1-ol (5.7 g, 28.33 mmol, 1 eq) in DCM (100 mL) and MeOH (100 mL) at -78 °C for 1 hr. After excess O3was purged by O2. The reaction mixture was concentrated under reduced pressure to give a residue. The residuewas purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 1:1) to give 5-(1,1-difluoro-2-hydroxyethoxy)picolinaldehyde (5.3 g, 26.09 mmol, 92.08% yield) as a yellow oil. [M+H] = 204.2

[0450] Step 5.2-Amino-4-[5-(1,1-difluoro-2-hydroxy-ethoxy)-2-pyridyl]-6-sulfan yl-pyridine-3,5-dicarbonitrile (104-F)

[0451] To a solution of 5-(1,1-difluoro-2-hydroxyethoxy)picolinaldehyde (5.1 g, 25.11 mmol, 1 eq) in EtOH (50 mL) was added NMM (6.35 g, 62.76 mmol, 2.5 eq) and 2-cyanoethanethioamide (6.29 g, 62.76 mmol, 2.5 eq). The mixture was stirred at 25 °C for 3.5 hrs. The reaction mixture was concentrated under reduced pressure to give 2-amino-4-[5-(1,1-difluoro-2-hydroxy-ethoxy)-2-pyridyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (4.8 g, crude) as a yellow oil and used directly into the next step without further purification. [M+H] = 349.9

[0452] Step 6.2'-Amino-5-(1,1-difluoro-2-hydroxyethoxy)-6'-((pyridin-3-ylmethy l)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (104-G)

[0453] To a solution of 2-amino-4-[5-(1,1-difluoro-2-hydroxy-ethoxy)-2- pyridyl]-6-sulfanyl-pyridine-3,5-dicarbonitrile (4.38 g, 12.54 mmol, 1 eq) in DMF (10 mL) was added K2CO3(3.47 g, 25.08 mmol, 2 eq) and 3-(chloromethyl)pyridine hydrochloride (2.47 g, 15.05 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:3 to 0:1) to give 2'-amino-5-(1,1-difluoro-2-hydroxyethoxy)-6'-((pyridin-3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (3.8 g, 8.63 mmol, 68.81% yield) as a brown solid. [M+H] = 441.0

[0454] Step 7.2'-Chloro-5-(1,1-difluoro-2-hydroxyethoxy)-6'-((pyridin-3-ylmethy l)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (104-I)

[0455] To a solution of 2'-amino-5-(1,1-difluoro-2-hydroxyethoxy)-6'-((pyridin- 3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (300 mg, 681.16 μmol, 1 eq) in ACN (5 mL) was added t-BuONO (140.48 mg, 1.36 mmol, 2 eq) and CuCl (134.87 mg, 1.36 mmol, 2 eq). The mixture was stirred at 60 °C for 1 hr under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2'-chloro-5-(1,1-difluoro-2-hydroxyethoxy)-6'-((pyridin-3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (300 mg, crude) as a green solid and used directly into the next step without further purification. [M+H] = 460.0

[0456] Step 8.5-(1,1-Difluoro-2-hydroxyethoxy)-2'-(methylamino)-6'-((pyridin-3 -ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (104)

[0457] To a solution of 2'-chloro-5-(1,1-difluoro-2-hydroxyethoxy)-6'-((pyridin- 3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (300 mg, 652.38 μmol, 1 eq) in THF (5 mL) was added TEA (198.04 mg, 1.96 mmol, 3 eq) and methanamine hydrochloride (220.24 mg, 3.26 mmol, 5 eq). The mixture was stirred at 25 °C for 0.5 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (C18-6 (100 × 30 mm, 5 mm); flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A: 0.2% aqueous FA , mobile phase B: acetonitrile) to give 5-(1,1-difluoro-2- hydroxyethoxy)-2'-(methylamino)-6'-((pyridin-3-ylmethyl)thio)-[2,4'-bipyridine]-3',5'- dicarbonitrile (17.6 mg, 34.67 μmol, 5.32% yield, 98.6% purity, FA salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.68 (d, J = 2.0 Hz, 2H), 8.49 (d, J = 4.0 Hz, 1H), 8.31 (q, J = 4.0 Hz, 1H), 8.00 - 7.94 (m, 1H), 7.92 - 7.85 (m, 2H), 7.38 (dd, J = 8.0, 4.8Hz, 1H), 6.04 (t, J = 6.8 Hz, 1H), 4.64 (s, 2H), 3.95 (dt, J = 10.4, 6.8 Hz, 2H), 3.01 (d, J = 4.4 Hz, 3H). [M+H] = 455.1

[0458] The compounds in Table 4 were prepared according to procedures analogous to preparation of Compound 104 in protocol 7, using analogous starting materials and / or intermediates.

[0459] Table 4:

[0460] Protocol 8. R-2'-Amino-6'-mercapto-5-(tetrahydrofuran-3-yl)-[2,4'- bipyridine]-3',5'-dicarbonitrile (287) and enantiomers (287-1 and 287-2)

[0461] Step 1.5-(2,5-Dihydrofuran-3-yl)picolinaldehyde (287-B)

[0462] To a solution of 5-bromopicolinaldehyde (4.31 g, 23.19 mmol, 1 eq) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5 g, 25.50 mmol, 1.1 eq) in dioxane (50 mL) and H2O (25 mL) was added Pd(dtbpf)Cl2(1.51 g, 2.32 mmol, 0.1 eq) and K2CO3(9.61 g, 69.56 mmol, 3 eq). The mixture was stirred at 60 °C for 2 hrs under N2. The reaction mixture was partitioned between EtOAc (200 mL) and H2O (200 mL), the water phase was extracted with EtOAc (200 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate = 1:0 to 1:1) to give 5-(2,5-dihydrofuran-3-yl)picolinaldehyde (4 g, 22.83 mmol, 98.48% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 10.06 (s, 1H), 8.77 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.0, 2.0 Hz, 1H), 6.56 (t, J = 2.0 Hz, 1H), 5.06 (dt, J = 4.8, 2.0 Hz, 2H), 4.91 (dt, J = 4.8, 2.0 Hz, 2H). [M+H] = 176.1

[0463] Step 2. (5-(Tetrahydrofuran-3-yl)pyridin-2-yl)methanol (287-C)

[0464]

[0465] To a solution of 5-(2,5-dihydrofuran-3-yl)picolinaldehyde (3.9 g, 22.26 mmol, 1 eq) in MeOH (40 mL) and THF (20 mL) was added Pd / C (10% purity). The mixture was stirred at 20 °C for 12 hrs under H2(15psi). The suspension was filtered through a pad of Celite and the filter cake was washed with MeOH (100 mL × 3). And the filter cake was collected and handled safely. Then the filtrate was concentrated under reduced pressure to give (5-(tetrahydrofuran-3-yl)pyridin-2-yl)methanol (3.95 g, 22.04 mmol, 99.00% yield) as a yellow oil and used directly into the next step without further purification. [M+H] = 180.1

[0466] Step 3.5-(Tetrahydrofuran-3-yl)picolinaldehyde (287-D)

[0467]

[0468] To a solution of (5-(tetrahydrofuran-3-yl)pyridin-2-yl)methanol (3.9 g, 21.76 mmol, 1 eq) in DCM (150 mL) was added MnO2(22.70 g, 261.14 mmol, 12 eq). The mixture was stirred at 20 °C for 4 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Agela DuraShell C18column (250 × 70 mm, 10 mm); flow rate: 130 mL / min; gradient: 0% – 30% B over 20 min; mobile phase A: 10 mM aqueous NH4HCO3, mobile phase B: acetonitrile) to give 5-(tetrahydrofuran-3- yl)picolinaldehyde (1.6 g, 9.03 mmol, 41.49% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 10.07 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.01 - 3.92 (m, 1H), 3.82 (dd, J = 8.8, 6.4Hz, 1H), 3.53 (quin, J = 7.2 Hz, 1H), 2.49 (dtd, J = 12.4, 8.0, 4.8 Hz, 1H), 2.02 (qd, J = 12.8, 7.6 Hz, 1H). [M+H] = 178.1

[0469] Step 4.2'-Amino-6'-mercapto-5-(tetrahydrofuran-3-yl)-[2,4'-bipyridine]- 3',5'-dicarbonitrile (287-E)

[0470] To a solution of 5-(tetrahydrofuran-3-yl)picolinaldehyde (1.5 g, 8.47 mmol, 1 eq) in EtOH (300 mL) was added piperidine (1.08 g, 12.70 mmol, 1.25 mL, 1.5 eq) and 2-cyanothioacetamide (2.12 g, 21.16 mmol, 2.5 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give 2'-amino-6'-mercapto-5-(tetrahydrofuran-3-yl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (2.7 g, crude) as a brown solid and used directly into the next step without further purification.[M+H] = 324.1Step 5.2'-Amino-6'-mercapto-5-(tetrahydrofuran-3-yl)-[2,4'-bipyridine]- 3',5'-dicarbonitrile (287) and enantiomers (287-1 and 287-2)

[0471] To a solution of 2'-amino-6'-mercapto-5-(tetrahydrofuran-3-yl)-[2,4'- bipyridine]-3',5'-dicarbonitrile (900 mg, 2.78 mmol, 1 eq) in DMF (10 mL) was added K2CO3(769.30 mg, 5.57 mmol, 2 eq) and 3-(chloromethyl)pyridine hydrochloride (684.80 mg, 4.17 mmol, 1.5 eq). The mixture was stirred at 20 °C for 1 hr. 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. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate= 1:0 to 0:1) to give crude product. The crude product was triturated with Petroleum ether (20 mL) and EtOH (3 mL) at 25 °C and stirred 5 min. Then the mixture was filtered and collected filter cake. The residue (100 mg) was separated by SFC (Instrument: Waters SFC150AP Preparative SFC System; Column:ChiralPak IH, 250*30mm, 10um; Mobile phase A: CO2and B: 0.1%NH3H2O in MeOH; Gradient: B%=50% isocratic elution mode; Flow rate:CO2(70 g / min) and B (70 g / min); Wavelength: 220&254nm; Column temperature: 40 °C; Systemback pressure: 100 bar) to generate two enantiomers. Then the Peak 1 (Rt = 2.529) was purified by preparative HPLC (Phenomenex Luna C18 (75 × 30 mm, 3mm); flow rate: 40 mL / min; gradient: 20% – 50% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2'-amino-6'-((pyridin-3-ylmethyl)thio)-5-(tetrahydrofuran- 3-yl)-[2,4'-bipyridine]-3',5'-dicarbonitrile (287-1) (53.0 mg, 115.09 μmol, 4.14% yield, 100% purity, FA salt) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 (dd, J = 8.0, 2.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 7.6, 5.2 Hz, 1H), 4.52 (s, 2H), 4.09 (t, J = 7.6 Hz, 1H), 4.00 (dt, J = 8.4, 4.4 Hz, 1H), 3.84 (q, J = 7.6 Hz, 1H), 3.63 (t, J = 7.6 Hz, 1H), 3.53 (quin, J = 7.6 Hz– 1H), 2.44 - 2.35 (m, 1H), 2.01 (qd, J = 12.4, 8.0 Hz, 1H). [M+H] = 415.1. The Peak 2 (Rt = 2.754) was purified by preparative HPLC (Phenomenex luna C18 (100 × 30 mm, 3mm); 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-6'-((pyridin-3-ylmethyl)thio)-5-(tetrahydrofuran-3-yl)-[2,4'-bipyridine]- 3',5'-dicarbonitrile (287-2) (49.6 mg, 107.71 μmol, 3.87% yield, 100% purity, FA salt) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 7.96 (dd, J = 8.0, 2.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 4.52 (s, 2H), 4.09 (t, J = 7.6 Hz, 1H), 4.00 (dt, J = 8.4, 4.4 Hz, 1H), 3.84 (q, J = 7.6 Hz– 1H), 3.66 - 3.61 (m, 1H), 3.53 (quin, J = 7.6 Hz, 1H), 2.40 (dq, J = 8.0, 4.0 Hz, 1H), 2.01 (qd, J = 12.4, 8.0 Hz, 1H). [M+H] = 415.1

[0472] The compounds in Table 5 were prepared according to procedures analogous to preparation of Compound 287, 287-1, and 287-2 in protocol 8, using analogous starting materials and / or intermediates.

[0473] Table 5:

[0474]

[0475] Protocol 9. -2'-Amino-6'-mercapto-5-(tetrahydrofuran-3-yl)-[2,4'- bipyridine]-3',5'-dicarbonitrile (58)

[0476] Step 1. tert-Butyl (2-((2'-amino-3',5'-dicyano-6'-mercapto-[2,4'-bipyridin]- 5-yl)oxy)ethyl)(methyl)carbamate (58-B)

[0477] To the mixture of tert-butyl (2-((6-formylpyridin-3- yl)oxy)ethyl)(methyl)carbamate (1.8 g, 6.42 mmol, 1 eq) and 2-cyanoethanethioamide (1.41 g, 14.13 mmol, 2.2 eq) in EtOH (100 mL) was added NMM (649.49 mg, 6.42 mmol, 705.97 μL, 1 eq), the mixture was stirred at 25°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give tert-butyl (2-((2'-amino-3',5'-dicyano-6'- mercapto-[2,4'-bipyridin]-5-yl)oxy)ethyl)(methyl)carbamate (1.8 g, crude) as a black solid. [M+H]= 427.2

[0478] Step 2. tert-butyl (2-((2'-amino-3',5'-dicyano-6'-((pyridin-2-ylmethyl)thio)- [2,4'-bipyridin]-5-yl)oxy)ethyl)(methyl)carbamate (58-C)

[0479] To the mixture of tert-butyl (2-((2'-amino-3',5'-dicyano-6'-mercapto-[2,4'- bipyridin]-5-yl)oxy)ethyl)(methyl)carbamate (1.8 g, 4.22 mmol, 1 eq) and 2- (chloromethyl)pyridine hydrochloride (1.62 g, 9.85 mmol, 2.33 eq) in DMF (20 mL) was added K2CO3(1.75 g, 12.66 mmol, 3 eq), the mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl (2-((2'-amino-3',5'-dicyano-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridin]-5- yl)oxy)ethyl)(methyl)carbamate (1 g, crude) as a black solid. [M+H]= 518.3

[0480] Step 3. 2'-Amino-5-(2-(methylamino)ethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (58)

[0481] A mixture of tert-butyl (2-((2'-amino-3',5'-dicyano-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridin]-5-yl)oxy)ethyl)(methyl)carbamate (30 mg, 57.96 μmol, 1 eq) in DCM (1 mL) and TFA (1 mL) 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 preparative HPLC (Phenomenex Gemini C18 column (100 ×30 mm, 3um); flow rate: 25 mL / min; gradient: 1% – 25% B over 8 min; mobile phase A: 0.2% aqueous FA, mobile phase B: acetonitrile) to give 2'-amino-5-(2-(methylamino)ethoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (3.0 mg, 6.11 μmol, 10.54% yield, 94.4% purity, FA salt) as a brown solid.

[0482] 1H NMR (400 MHz, CD3OD) δ = 8.60 - 8.46 (m, 3H), 7.87 - 7.74 (m, 2H), 7.71 - 7.64 (m, 2H), 7.38 - 7.31 (m, 1H), 4.66 (s, 2H), 4.49 - 4.42 (m, 2H), 3.50 - 3.45 (m, 2H), 2.79 (s, 3H). [M+H]= 418.2.

[0483] The compounds in Table 6 were prepared according to procedures analogous to preparation of Compound 58 in protocol 9, using analogous starting materials and / or intermediates.

[0484] Table 6:

[0485] Protocol 10.2'-amino-5-(2-fluorobutoxy)-6'-((pyridin-2-ylmethyl)thio)- [2,4'-bipyridine]-3',5'-dicarbonitrile (292-1), 2'-amino-5-(2-fluorobutoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (292-2), 2'-amino-5-(2-fluorobutoxy)- 6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (291-2) and 2'-amino-5-(2-fluorobutoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (291- 1)

[0486] Step 1. Preparation of 5-(2-hydroxybutoxy)picolinaldehyde and 5-((1- hydroxybutan-2-yl)oxy)picolinaldehyde

[0487] To a solution of 5-hydroxypicolinaldehyde (2 g, 16.25 mmol, 1 eq) in DMF (20 mL) was added K2CO3(4.49 g, 32.49 mmol, 2 eq) and 2-ethyloxirane (9.37 g, 129.97 mmol, 11.30 mL, 8 eq). The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), the waterphase was extracted with EtOAc (100 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate= 1:0 to 0:1) to give 5-(2- hydroxybutoxy)picolinaldehyde (1 g, 5.12 mmol, 31.53% yield) and 5-((1-hydroxybutan- 2-yl)oxy)picolinaldehyde (1 g, 5.12 mmol, 31.53% yield) as yellow oil. [M+H] = 196.1

[0488] Step 2. Preparation of 1-((6-formylpyridin-3-yl)oxy)butan-2-yl methanesu lfonate and 2-((6-formylpyridin-3-yl)oxy)butyl methanesulfonate

[0489] To a solution of 5-(2-hydroxybutoxy)picolinaldehyde (975.00 mg, 4.99 mmol, 0.5 eq) and 5-((1-hydroxybutan-2-yl)oxy)picolinaldehyde (975.00 mg, 4.99 mmol, 0.5 eq) in DCM (40 mL) was added TEA (2.02 g, 19.98 mmol, 2.78 mL, 2 eq) and Ms2O (2.09 g, 11.99 mmol, 1.2 eq) at 0°C. The mixture was stirred at 20°C for 1 hr. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), the water phase was extracted with EtOAc (100 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated to give 1-((6-formylpyridin-3-yl)oxy)butan-2-yl methanesulfonate (1.34 g, crude) and 2-((6-formylpyridin-3-yl)oxy)butyl methanesulfonate (1.34 g, crude) as brown oil and used directly into the next step without further purification. [M+H] = 274.1

[0490] Step 3. Preparation of 5-(2-fluorobutoxy)picolinaldehyde and 5-((1-fluoro butan-2-yl)oxy)picolinaldehyde

[0491] To a solution of 1-((6-formylpyridin-3-yl)oxy)butan-2-yl methanesulfonate (1.34 g, 4.90 mmol, 0.5 eq) and 2-((6-formylpyridin-3-yl)oxy)butyl methanesulfonate (1.34 g, 4.90 mmol, 0.5 eq) in t-BuOH (30 mL) was added CsF (7.45 g, 49.03 mmol, 1.81 mL, 5 eq). The mixture was stirred at 90°C for 6 hrs. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), the water phase was extracted with EtOAc (100 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate= 1:0 to 3:1) to give 5-(2- fluorobutoxy)picolinaldehyde (250 mg, 1.27 mmol, 12.93% yield) and 5-((1-fluorobutan- 2-yl)oxy)picolinaldehyde (250 mg, 1.27 mmol, 12.93% yield) as yellow oil.NMR(400 MHz, CDCl3) δ = 10.00 - 9.87 (m, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.95 - 7.81 (m, 1H), 7.34 - 7.23 (m, 1H), 4.85 - 4.63 (m, 1H), 4.62 - 4.44 (m, 1H), 4.19 - 4.12 (m, 1H), 1.86 - 1.66 (m, 2H), 1.05 - 0.94 (m, 3H) [M+H] = 198.1

[0492] Step 4. Preparation of 2'-amino-5-(2-fluorobutoxy)-6'-mercapto-[2,4'-bipy ridine]-3',5'-dicarbonitrile and 2'-amino-5-((1-fluorobutan-2-yl)oxy)-6'-mercapto-[2,4'-bip yridine]-3',5'-dicarbonitrile

[0493] To a solution of 5-(2-fluorobutoxy)picolinaldehyde (245 mg, 1.24 mmol, 0.50 eq) and 5-((1-fluorobutan-2-yl)oxy)picolinaldehyde (245 mg, 1.24 mmol, 0.50 eq) in EtOH (100 mL) was added piperidine (317.36 mg, 3.73 mmol, 368.08 μL, 1.5 eq) and 2-cyanoethanethioamide (622.06 mg, 6.21 mmol, 2.5 eq). The mixture was stirred at 20°C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give 2'-amino-5-(2-fluorobutoxy)-6'-mercapto-[2,4'-bipyridine]-3',5'-dicarbonitrile (400 mg, crude) and 2'-amino-5-((1-fluorobutan-2-yl)oxy)-6'-mercapto-[2,4'-bipyridine]- 3',5'-dicarbonitrile (400 mg, crude) as brown solid and used directly into the next step without further purification. [M+H] = 344.1

[0494] Step 5. Preparation of 2'-amino-5-(2-fluorobutoxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (292-1), 2'-amino-5-(2-fluorobutoxy)- 6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (292-2), 2'-amino-5-(2- fluorobutoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (291-2) and 2'-amino-5-(2-fluorobutoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'- dicarbonitrile (291-1)

[0495] To a solution of 2'-amino-5-(2-fluorobutoxy)-6'-mercapto-[2,4'- bipyridine]-3',5'-dicarbonitrile (400 mg, 1.16 mmol, 0.50 eq) and 2'-amino-5-((1- fluorobutan-2-yl)oxy)-6'-mercapto-[2,4'-bipyridine]-3',5'-dicarbonitrile (400 mg, 1.16 mmol, 0.50 eq) in DMF (10 mL) was added K2CO3(643.98 mg, 4.66 mmol, 2 eq) and 3- (chloromethyl)pyridine hydrochloride (573.24 mg, 3.49 mmol, 1.5 eq). The mixture was stirred at 20°C for 1 hr. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL), the water phase was extracted with EtOAc (100 mL × 3), the combined organic phase was dried over Na2SO4, filtered and concentrated. The residuewas purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate= 1:0 to 0:1) to give crude product. The residue was separated by SFC (Instrument: Waters SFC80Q Preparative SFC System; Column: DAICEL CHIRALPAK IG(250mm * 50mm, 10um); Mobile phase A: CO2and B:0.1%NH3H2O in EtOH; Gradient: B% = 50% isocratic elution mode; Flow rate: CO2(80 g / min) and B (80 g / min); Wavelength: 220&254nm; Column temperature: 40 °C; System back pressure: 100 bar) Peak 1 (Rt = 0.461) was purified by preparative HPLC (Phenomenex Luna C18(100 × 30 mm, 3mm); flow rate: 25 mL / min; gradient: 30% – 60% B over 8 min; mobile phase A:0.2% aqueous FA, mobile phase B: acetonitrile) to give 2'-amino-5-((1-fluorobutan-2-yl)oxy)-6'- ((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (52.6 mg, 108.70 μmol, 4.67% yield, 99.3% purity, FA salt) as pale yellow solid and the Peak 2 (Rt = 0.540) was purified by preparative HPLC (Phenomenex luna C18(75 × 30 mm, 3mm); flow rate: 40 mL / min; gradient: 20% – 50% B over 8 min; mobile phase A:0.2% aqueous FA, mobile phase B: acetonitrile) to give 2'-amino-5-((1-fluorobutan-2-yl)oxy)-6'-((pyridin-2- ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (71.9 mg, 149.63 μmol, 6.42% yield, 100% purity, FA salt) as yellow solid and the Peak 3 (Rt = 0.689) was purified by preparative HPLC (Phenomenex Luna C18(75 × 30 mm, 3mm); 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-5-(2-fluorobutoxy)-6'-((pyridin-2-ylmethyl)thio)- [2,4'-bipyridine]-3',5'-dicarbonitrile (40.9 mg, 85.12 μmol, 3.65% yield, 100% purity, FA salt) as pale yellow solid and the Peak 4 (Rt = 1.111) was purified by preparative HPLC (Phenomenex luna C18(100 × 30 mm, 3mm); flow rate: 25 mL / min; gradient: 15% – 50% B over 8 min; mobile phase A:0.2% aqueous FA, mobile phase B: acetonitrile) to give 2'-amino-5-(2-fluorobutoxy)-6'-((pyridin-2-ylmethyl)thio)-[2,4'-bipyridine]-3',5'-dicarbonitrile (39.5 mg, 80.48 μmol, 3.45% yield, 97.9% purity, FA salt) as pale yellow solid.

[0496] 1H NMR (400 MHz, DMSO-d6) δ = 8.57 - 8.52 (m, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.46 - 7.84 (m, 2H), 7.82 - 7.72 (m, 2H), 7.71 - 7.63 (m, 2H), 7.30 (dd, J = 6.4, 5.2 Hz, 1H), 4.89 - 4.52 (m, 5H), 1.72 (quin, J = 7.2 Hz, 2H), 0.98 (t, J = 7.6 Hz, 3H). [M+H] = 435.2

[0497] 1H NMR (400 MHz, DMSO-d6) δ = 8.58 - 8.52 (m, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.43 - 7.84 (m, 2H), 7.82 - 7.73 (m, 2H), 7.72 - 7.62 (m, 2H), 7.30 (ddd, J = 7.2,4.8, 0.8 Hz, 1H), 4.90 - 4.52 (m, 5H), 1.72 (quin, J = 7.2 Hz, 2H), 0.98 (t, J = 7.6 Hz, 3H). [M+H] = 435.1

[0498] 1H NMR (400 MHz, DMSO-d6) δ = 8.54 (dd, J = 4.8, 0.8 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.43 - 7.82 (m, 2H), 7.80 - 7.72 (m, 2H), 7.66 (dt, J = 5.6, 2.4 Hz, 2H), 7.36 - 7.22 (m, 1H), 4.96 - 4.73 (m, 1H), 4.62 (s, 2H), 4.47 - 4.24 (m, 2H), 1.86 - 1.66 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). [M+H] = 435.2

[0499] 1H NMR (400 MHz, DMSO-d6) δ = 8.54 (d, J = 4.4 Hz, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.44 - 7.82 (m, 2H), 7.80 - 7.71 (m, 2H), 7.70 - 7.59 (m, 2H), 7.30 (dd, J =6.8, 5.2 Hz, 1H), 4.96 - 4.74 (m, 1H), 4.63 (s, 2H), 4.47 - 4.22 (m, 2H), 1.87 - 1.64 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). [M+H] = 435.1

[0500] The compounds in Table 7 were prepared according to procedures analogous to preparation of Compounds 292-2, 292-1, 291-1, and 291-2 in protocol 10, using analogous starting materials and / or inetrmediates.

[0501] Table 7:

[0502]

[0503] Protocol 11.4-[5-(2-methoxyethoxy)-2-pyridyl]-2-methyl-6-(3,3,3- trifluoro-propylsulfanyl)pyridine-3,5-dicarbonitrile (112)

[0504] Step 1. Preparation 4-[5-(2-methoxyethoxy)-2-pyridyl]-2-methyl-6- sulfanyl-pyridine-3,5-dicarbonitrile (112-B)

[0505] To a solution of 5-(2-methoxyethoxy)pyridine-2-carbaldehyde (400 mg, 2.21 mmol, 1 eq) ,3-oxobutanenitrile (220.12 mg, 2.65 mmol, 1.2 eq) and 2- cyanothioacetamide (265.29 mg, 2.65 mmol, 1.2 eq) in EtOH (1 mL) was added NMM (669.89 mg, 6.62 mmol, 728.14 uL, 3 eq). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give 4-[5-(2- methoxyethoxy)-2-pyridyl]-2-methyl-6-sulfanyl-pyridine-3,5-dicarbonitrile (720 mg, crude) as black solid. [M+H] = 327.2

[0506] Step 2. Preparation 4-[5-(2-methoxyethoxy)-2-pyridyl]-2-methyl-6- sulfanyl-pyridine-3,5-dicarbonitrile (112)

[0507] To a solution of 4-[5-(2-methoxyethoxy)-2-pyridyl]-2-methyl-6-sulfanyl- pyridine-3,5-dicarbonitrile (300 mg, 919.20 umol, 1 eq) and 1,1,1-trifluoro-3-iodo- propane (205.87 mg, 919.20 umol, 107.78 uL, 1 eq) in DMF (2 mL) was added K2CO3(508.15 mg, 3.68 mmol, 4 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [water(FA)-ACN];B%: 65%-98%,8min) to give 4-[5-(2-methoxyethoxy)-2-pyridyl]-2-methyl-6-(3,3,3-trifluoropropylsulfanyl) pyridine-3,5- dicarbonitrile (86.4 mg, 184.44 umol, 20.07% yield, 100.000% purity, FA) as a yellow solid.1HNMR (400MHz, CD3OD) δ = 8.53 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.8, 2.8 Hz, 1H), 4.38 - 4.32 (m, 2H), 3.88 - 3.81 (m, 2H), 3.61 - 3.53 (m, 2H), 3.48 (s, 3H), 2.91 - 2.84 (m, 3H), 2.80 - 2.64 (m, 2H). [M+H] = 423.0

[0508] The compounds in Table 8 were prepared according to procedures analogous to preparation of Compound 112 in protocol 11, using analogous starting materials and / or intermediates.

[0509] Table 8:

[0510] Protocol 12: Synthesis of 2-(cyclopropylamino)-6-(oxetan-3- ylmethylsulfanyl)-4-[6-[rac-(2R)-2-(trideuteriomethoxy)propoxy]-3-pyridyl]pyridine-3,5- dicarbonitrile (254)

[0511] Step 1: (R)-((2-(methoxy-d3)propoxy)methyl)benzene (254-B). To a solution of (R)-1-(benzyloxy)propan-2-ol (30 g, 180.49 mmol, 1 eq) in THF (500 mL) was added NaH (10.83 g, 270.73 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hr followed by addition of iodomethane-d3(31.40 g, 216.59 mmol, 13.48 mL, 1.2 eq) at 0 °C, the mixture was stirred at 25 °C for 3 hrs under N2. TLC (PE: EtOAc = 5:1)indicated Reactant 1 was consumed completely and one major new spot was detected. The reaction mixture was quenched by addition sat.aq. NH4Cl 300 mL at 0 °C, and then extracted with EtOAc 900 mL (300 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1:0 to 5:1) to give (R)-((2-(methoxy- d3)propoxy)methyl)benzene (45 g, 171.89 mmol, 95.23% yield, 70% purity) as a yellow oil.

[0512] Step 2: (R)-2-(methoxy-d3)propan-1-ol (254-C). To a solution of (R)-((2- (methoxy-d3)propoxy)methyl)benzene (30 g, 163.70 mmol, 1 eq) in THF (300 mL) was added Pd / C (17 g, 15.97 mmol, 10% purity, 9.76e-2 eq). The mixture was stirred at 25 °C for 12 hrs under H2(40 Psi). TLC (PE: EtOAc =1:1) indicated Reactant 1 was consumed completely and one major new spot was detected. The suspension was filtered through a pad of silica gel and washed through with THF (150 mL×3), the filtrate was concentrated under reduced pressure to give (R)-2-(methoxy-d3)propan-1-ol (18 g, crude) as a white solid.

[0513] Step 3: (R)-6-(2-(methoxy-d3)propoxy)nicotinaldehyde (254-D). To a solution of (R)-2-(methoxy-d3)propan-1-ol (7.55 g, 81.05 mmol, 1.3 eq) in THF (150 mL) was added NaH (3.74 g, 93.52 mmol, 60% purity, 1.5 eq) at 0°C. The mixture was stirred at 25 °C for 0.5 hr under N2. Then 6-fluoropyridine-3-carbaldehyde (7.8 g, 62.35 mmol, 1 eq) was added to the solution at 0 °C. The mixture was stirred at 0 °C for 0.5 hr under N2. The reaction mixture was quenched by addition NH4Cl sat.aq.150 mL at 0 °C under N2, and then extracted with EtOAc 600 mL (200 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (PE: EtOAc = 1:0 to 3:1) to give (R)-6-(2- (methoxy-d3)propoxy)nicotinaldehyde (254-D) (2.1 g, 10.59 mmol, 16.99% yield) as a yellow oil. ESI [M+H] = 199.0

[0514] Step 4: (R)-2'-amino-6'-mercapto-6-(2-(methoxy-d3)propoxy)-[3,4'- bipyridine]-3',5'-dicarbonitrile (254-E). To a solution of (R)-6-(2-(methoxy- d3)propoxy)nicotinaldehyde (2.1 g, 10.59 mmol, 1 eq) and 2- cyanothioacetamide (2.65g, 26.48 mmol, 2.5 eq) in EtOH (60 mL) was added piperidine (1.35 g, 15.89 mmol, 1.57 mL, 1.5 eq). The mixture was stirred at 25 °C for 6 hrs. The reaction mixture was concentrated under reduced pressure to give (R)-2'-amino-6'-mercapto-6-(2-(methoxy- d3)propoxy)-[3,4'-bipyridine]-3',5'-dicarbonitrile (254-E) (2 g, crude) as a white solid. ESI [M+H] = 345.0.

[0515] Step 5: (R)-2'-amino-6-(2-(methoxy-d3)propoxy)-6'-((oxetan-3- ylmethyl)thio)-[3,4'-bipyridine]-3',5'-dicarbonitrile (254-F). To a solution of (R)-2'- amino-6'-mercapto-6-(2-(methoxy-d3)propoxy)-[3,4'-bipyridine]-3',5'-dicarbonitrile (2 g, 5.81 mmol, 1 eq) in DMF (15 mL) was added K2CO3(2.01 g, 14.52 mmol, 2.5 eq) and 3- (bromomethyl)oxetane (1.32 g, 8.71 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched by addition saturated aqueous H2O (10 mL) at 0 °C, filtered and concentrated under reduced pressure to give (R)-2'-amino-6-(2-(methoxy- d3)propoxy)-6'-((oxetan-3-ylmethyl)thio)-[3,4'-bipyridine]-3',5'-dicarbonitrile (2 g, crude) as a white solid. ESI [M+H] = 415.2.

[0516] Step 6: (R)-2'-chloro-6-(2-(methoxy-d3)propoxy)-6'-((oxetan-3- ylmethyl)thio)-[3,4'-bipyridine]-3',5'-dicarbonitrile (254-G). To a solution of (R)-2'- amino-6-(2-(methoxy-d3)propoxy)-6'-((oxetan-3-ylmethyl)thio)-[3,4'-bipyridine]-3',5'- dicarbonitrile (200 mg, 482.51 μmol, 1 eq) in ACN (10 mL) was added tert-butyl nitrite (199.03 mg, 1.93 mmol, 229.56 μL, 4 eq) and CuCl2(194.63 mg, 1.45 mmol, 3 eq). The mixture was stirred at 60°C for 1 hr under N2. The reaction mixture was quenched by addition saturated aqueous H2O (3 mL) at 0 °C, and then extracted with EtOAc (3 mL×3). The combined organic layers were filtered and concentrated under reduced pressure to give (R)-2'-chloro-6-(2-(methoxy-d3)propoxy)-6'-((oxetan-3-ylmethyl)thio)- [3,4'-bipyridine]-3',5'-dicarbonitrile (254-G) (200 mg, crude) as a white solid. ESI [M+H] = 434.1

[0517] Step 7: (R)-2'-(cyclopropylamino)-6-(2-(methoxy-d3)propoxy)-6'-((oxetan- 3-ylmethyl)thio)-[3,4'-bipyridine]-3',5'-dicarbonitrile (254). To a solution of (R)-2'- chloro-6-(2-(methoxy-d3)propoxy)-6'-((oxetan-3-ylmethyl)thio)-[3,4'-bipyridine]-3',5'- dicarbonitrile (100 mg, 230.45 μmol, 1 eq) in THF (3 mL) was added TEA (69.96 mg,691.36 μmol, 96.23 μL, 3 eq) and cyclopropanamine (19.74 mg, 345.68 μmol, 23.95 μL, 1.5 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini C18 column column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:35%-65% B over 8.0 min; mobile phase A:10 mM aqueous 0.2% aqueous FA, mobile phase B: acetonitrile) to give (R)-2'-(cyclopropylamino)-6-(2-(methoxy- d3)propoxy)-6'-((oxetan-3-ylmethyl)thio)-[3,4'-bipyridine]-3',5'-dicarbonitrile (254) (24.3 mg, 52.44μmol, 22.76% yield, 98.1% purity) as a white solid. ESI [M+H] = 455.2.1H NMR (400 MHz, DMSO-d6) δ = 8.4 (br s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.4, 2.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.66 (dd, J = 7.2, 6.4 Hz, 2H), 4.38 - 4.34 (m, 2H), 4.32 - 4.26 (m, 2H), 3.75 - 3.68 (m, 1H), 3.66 (d, J = 7.2 Hz, 2H), 3.45 - 3.37 (m, 1H), 2.89 (dt, J = 6.4, 4.4 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H), 0.79 - 0.73 (m, 2H), 0.73 - 0.68 (m, 2H).

[0518] The compounds in Table 9 were prepared according to procedures analogous to preparation of Compounds 254-G and 254 in protocol 12, using analogous starting materials and / or intermediates.

[0519] Table 9:O

[0520] Example 2: Biological Assays

[0521] Example 2.1. Adenosine A1, A2A and A2B Agonist Assays

[0522] Material and Methods: Biological materials

[0523] 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 10. Table 10. Cell lines used for in vitro assaysConditions for the GTPγS scintillation proximity assay are shown in Table 11. Table 11. GTPγS scintillation proximity assay (96 w)Assay 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 a final 0.1 nM assay concentration.

[0524] 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. Conditions for the GTPγS scintillation proximity assay are shown in Table 12. Table 12. cAMP HTRF assaysRT = room temperature

[0525] cAMP HTRF assay for Gs coupled receptor: HEK293 cells expressing recombinant receptor were grown prior to the test in media without antibiotic were detached by gentle flushing 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).

[0526] Dose response curves were performed in parallel with the reference compounds.

[0527] 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. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated for 1 hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. Results are provided in Table 13 below. Table 13: Adenosine Agonist Activity against A1 (GTPγS) method, A1 (cAMP HTRF) method, A2A (cAMP HTRF) method and A2B (cAMP HTRF) method.

[0528] Example 2.2: BCRP Permeability Assay

[0529] Material and Methods: Biological materials

[0530] MDCK cell lines transfected with the BCRP gene were grown in 75 cm2tissue culture flasks 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 toB and B to A) for 90 minutes at 37 °C. Dosing solutions were prepared as shown in Table 14. Teriflunomide, Metoprolol and atenolol were included as reference standards. Table 14. Summary of donor solution and compound preparation

[0531] Dosing solutions were added to the plate as outlined in Table 15 below.Table 15. Outline of how dosing solutions were added to the plate

[0532] 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 comparments 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 AreaDrug 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-min and [RFU]donor, 0-min are 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; The Dilution Factor is the fold of dilution of the donor sample before loaded to LC-MS / MS.

[0533] 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. 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.

[0534] Results are provided in Table 16 below. Table 16: BCRP Permeability and efflux ratio data

[0535] The embodiments of the disclosure described above are intended to be merely exemplary, numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present disclosure as defined in any appended claims. Incorporation by Reference

[0536] 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

[0537] 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 bedetermined 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: each of J, L, M, and Q is independently selected from -N= and -CH=, such that at least one of J, L, M, and Q is -N=, and at least one of J, L, M, and Q is -CH=; A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; orR2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when L is -N=, each of J, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (B) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4- pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when J is -N=, each of L, M, and Q is -CH=, V is -NH-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, Z is - OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, and each €R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl;(E) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when J is -N=, each of L, M, and Q is -CH=, V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

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

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is N and each of J, M, and Q is CH.

4. A compound of formula Ia, or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl; R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and C1-6alkyl; R11and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl;R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; or R17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l Is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (A) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl.

5. A compound of formula Ib, or a pharmaceutically acceptable salt thereof, wherein: A is selected from -CN, -OH, optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, -C(O)OH, -C(O)C1-6alkoxy, -C(O)N(R5)(R6), -N(R5)(R6), - N(R5)C(O)(C1-6alkyl), optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; V is selected from -C(R14)(R15)-, -O-, and -N(R16)-; X is selected from a bond, -S-, -O-, and -N(R4)-; Y is selected from -H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -OR13, and - N(R2)(R3); Z is selected from H, halogen, -CN, -OR1, and -N(R17)(R18); R1is selected from -H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; R2and R3each independently is selected from -H, C1-6alkyl, and C3-6cycloalkyl; or R2and R3taken together with the nitrogen atom 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 halogen or -OH; or R2and R3taken together with the nitrogen atom 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; R4is -H or C1-6alkyl;R5and R6each independently is selected from -H and C1-6alkyl; R7is selected from -H, halogen, C1-6alkyl, and C1-6haloalkyl; R8is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R8taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R9is -H 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, 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 selected from -H, halogen, and C1-6alkyl; R12and R12each independently is selected from -H, -OH, halogen, C1-6alkyl, and C1-6haloalkyl; R13is selected from -H, C1-6alkyl, and C1-6haloalkyl; R14is selected from -H, C1-6alkyl, and C1-6haloalkyl; R15is selected from -H, C1-6alkyl, and C1-6haloalkyl, or R1and R15taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R16is selected from -H and C1-6alkyl, or R8and R16taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; R17and R18each independently is selected from -H and C1-6alkyl; or R17and R18taken together with the nitrogen atom 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 halogen or -OH; or R17and R18taken together with the nitrogen atom 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; orR17is selected from -H and C1-6alkyl and R18and R9taken together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclyl ring; l is 0 or 1; m is 0 or 1; and n is 0, 1, 2, or 3, provided that (B) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, A is not substituted 2-pyridyl, optionally substituted 3-pyridyl, substituted 4-pyridyl, pyridin-2(1H)-one-4-yl, optionally substituted thiazolyl, substituted pyridazinyl, substituted pyrimidinyl, substituted oxazolyl, oxadiazolyl, substituted thiophenyl, substituted pyrazolyl, or substituted triazolyl; (C) when V is -NH-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not optionally substituted thiazolyl; (D) when V is -O-, X is -S-, Y is -NH2, Z is -OR1, l is 1, m is 0, n is 1, R8and R1taken together with the atoms to which they are attached form a 5-membered heterocyclic ring, andeach of R7, R9, R10, R11, and R12is -H, then A is not substituted oxazolyl; (E) when V is -O-, X is -S-, Y is -N(R2)(R3), and R2and R3taken together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, Z is -OR1, l is 1, m is 0, n is 1, and each of R1, R7, R8, R9, R10, R11, and R12is -H, then A is not substituted thiazolyl; (F) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 0, and Z is -H, then A is not phenyl or imidazolyl; and (G) when V is -O-, X is -S-, Y is -NH2, l is 0, m is 0, n is 1, each of R11and R12is -H, and Z is -H, then A is not imidazolyl.

6. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted heteroaryl.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein A is selected from optionally substituted pyridyl, optionally substituted pyridizine, and optionally substituted pyrimidinyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted pyridyl.

9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted heterocyclyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted oxetanyl.

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein A is 3-oxetanyl.

12. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein V is -O-.

13. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R12is -H.

15. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R11is -H.

16. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein X is -S-.

17. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Y is -N(R2)(R3).

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2and R3each independently is selected from -H and C1-6alkyl.

19. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2and R3are each -H.

20. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R2is -H and R3is C1-6alkyl.

21. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein Z is -OR1.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6alkyl.

23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R1is -CH3.

24. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R1is -C(2H)3.

25. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R1is -H.

26. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein m is 0.

27. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein l is 1.

28. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R7is -H.

29. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R8is -H.

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R8is C1-6alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R8is -CH3.

32. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R9is -H.

33. The compound of any preceding claim, or a pharmaceutically acceptable salt thereof, wherein R10is -H.

34. A compound selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising (a) a compound of any preceding claim; and (b) a pharmaceutically acceptable excipient.

36. A compound of any one of claims 1-34 or a pharmaceutical composition of claim 35 for use as a medicament.

37. 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, or CHD8-related neurodevelopmental disorder (CHD8-NDD) and / or one or more symptoms associated with CHD8-NDD in a subject comprising administering to asubject in need thereof an effective amount of at least one compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

38. The method of claim 37, the method comprising treating Rett syndrome and / or one or more symptoms associated with Rett syndrome.

39. The method of claim 38, comprising co-administering to the subject an additional therapeutic agent.

40. The method of claim 39, wherein the additional therapeutic agent comprises trofinetide.

41. The method of any one of claims 37-40, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism.

42. The method of claim 37, wherein the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.

43. The method of claim 37, 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.

44. The method of claim 37, 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.

45. A method of treating chronic heart failure in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

46. A method of treating heart failure with preserved ejection fraction (HFpEF), comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

47. A method of treating heart failure with reduced ejection fraction (HFrEF), comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

48. A method of treating heart failure with mid-range ejection fraction (HFmrEF), comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1-34 or a pharmaceutical composition of claim 35.

49. The method of any one of claims 37-48, wherein the compound is selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof.

50. Use of a compound of any one of claims 1-29 or a pharmaceutical composition of claim 30, in the preparation of a medicament for 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, or CHD8-NDD and / or one or more symptoms associated with CHD8-NDD.

51. The use of claim 50, wherein the one or more symptoms associated with Rett syndrome is selected from sleep disturbances; sleep apnea; seizures; breathing disorders; irregular heartbeat; intellectual disabilities; and autism.

52. The use of claim 50, wherein the one or more symptoms associated with FOXG1 syndrome is selected from feeding problems, sleep disturbances, seizures, irritability, and excessive crying.

53. The use of claim 50, 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.

54. The use of claim 50, 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.

55. Use of a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35, in the preparation of a medicament for the treatment of chronic heart failure.

56. Use of a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35, in the preparation of a medicament for the treatment of HFpEF.

57. Use of a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35, in the preparation of a medicament for the treatment HFrEF.

58. Use of a compound of any one of claims 1-34 or a pharmaceutical composition of claim 35, in the preparation of a medicament for the treatment of HFmrEF.

59. The use of any one of claims 50-58, wherein the compound is selected from any one of compounds 1-294, or a pharmaceutically acceptable salt thereof.

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