GABA-a receptor positive allosteric modulators and methods of use thereof

Abstract

This disclosure relates to GABA-A receptor positive allosteric modulators such as compounds of Formula (I), and pharmaceutically acceptable salts thereof, which are useful in treating neurological disorders, such as essential tremor, epilepsy, and seizure.

Description

[0001] GABA-A RECEPTOR POSITIVE ALLOSTERIC MODULATORS AND METHODS OF USE THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 610,292, which was filed December 14, 2023, the entire disclosure of which is incorporated herein by reference.

[0004] FIELD

[0005] This disclosure relates to GABA-A receptor positive allosteric modulators, useful in treating neurological disorders, such as essential tremor.

[0006] BACKGROUND

[0007] Essential Tremor (ET) is the most common adult-onset movement disorder, affecting millions of individuals worldwide. It manifests as rhythmic, involuntary tremors, primarily involving the hands, although other body parts may also be affected. ET can significantly impact the quality of life of affected individuals, interfering with activities of daily living and social functioning. The precise pathophysiology of ET remains elusive, but it is believed to involve abnormal neural circuitry in the central nervous system. The primary therapeutic options for ET include beta-blockers, such as propranolol, and anticonvulsants like primidone. However, not all patients respond adequately to these treatments, and they may be associated with adverse effects.

[0008] While the exact cause of ET is unknown, current thinking points to two main hypotheses converging on how the olivo-cerebellar circuit is involved in ET. One hypothesis is that ET is caused by a dysfunction of the cerebellar forward model, which is a mechanism that predicts and compensates for the feedback delay of motor actions. A lesion in the cerebro-cerebellar loop, which includes the primary excitatory path from the deep cerebellar nuclei (DCN, the main output centers of the cerebellum) to the thalamus and other brain regions, may affect the accuracy and stability of the forward model, resulting in irregular tremor-like movements during voluntary actions. This hypothesis is supported by evidence that patients with ET have structural and functional changes in the cerebellum, such as reduced volume, increased iron deposition, altered connectivity and blood flow. The other hypothesis is that ET is caused by a synchronized oscillation of inferior olive (IO) neurons, which induces rhythmic activity in the cerebellar cortex and the DCN. The IO oscillation may be triggered by a reduced inhibitory input from the Purkinje cells to the DCN, which in turn decreases the feedback inhibition from the DCN to the IO via the dentato-rubro-olivary pathway. This hypothesis is supported by evidence that pharmacological or electrical stimulation of the IO can induce tremor in animals and humans. Moreover, deep brain stimulation of the thalamus or the cerebellum can modulate IO activity and suppress tremor in patients with ET. y- Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, playing a crucial role in regulating neuronal excitability. GABA-A receptor positive allosteric modulators (PAMs) selectively enhance the inhibitory effects of GABA at the GABA-A receptor, offering a potential therapeutic avenue for ET. Current understanding of neurotransmitter system pathology in ET is largely inferred from the clinical response to drugs that were serendipitously found to improve symptoms, while others worsen it. No current drug was specifically designed to treat ET. Drugs that improve ET include P-adrenergic antagonists, primidone, topiramate, ethanol, and benzodiazepines. Ethanol and benzodiazepines are GABA-A receptor PAMs.

[0009] GABA-A receptors are ligand-gated ion channels resulting in chloride (Cl") influx that hyperpolarizes cells, and therefore inhibits their signaling. The GABA-A receptor is a pentamer, variably employing five of 19 different proteins (al-6, pi-3, yl- 3, 5, and other less common). The most common arrangement is two a, two P, and one y. al is by far the most common subunit and is especially present in synaptic receptors. Thus, we chose to initially screen our compounds using the aip2y2 subtype as a proxy for all synaptic receptors.

[0010] GABA is essential for maintaining the balance of excitatory and inhibitory neurotransmission in the brain. Dysfunction in the GABAergic system has been implicated in various neurological disorders, including ET. Several lines of evidence suggest that a GABAergic deficit contributes to the pathophysiology of ET. First, postmortem brain tissue analyses have revealed changes in GABA receptor distribution and expression in the cerebellum, thalamus, and other brain regions in individuals with ET. These findings suggest alterations in GABAergic signaling pathways. Second, neuroimaging studies, including positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), have shown abnormalities in GABA levels and receptor density in ET patients. These findings support the notion of GABA dysregulation in ET. Third, animal studies have provided valuable insights into the role of GABA in ET. For example, pharmacological manipulation of GABA receptors in animal models can induce or alleviate tremor-like behaviors, further highlighting the involvement of the GABAergic system.

[0011] GABA-A receptor PAMs are compounds that bind to GABA-A receptors at allosteric sites, enhancing the inhibitory effects of GABA without activating the receptor in the absence of GABA. By potentiating GABAergic signaling, these drugs reduce neuronal excitability and tremor amplitude in ET patients. GABA-A receptor hypofunction has been implicated in several neurological and neuropsychiatric disorders beyond essential tremor. The GABAergic system plays a crucial role in regulating inhibitory neurotransmission in the brain, and its dysfunction can contribute to various pathological conditions. Some of the diseases and conditions associated with GABA hypofunction include epilepsy, anxiety disorders, schizophrenia, bipolar disorder, sleep disorders, tinnitus, and autism spectrum disorder, as well as rare diseases such as CDKL5 deficiency disorder (CDD).

[0012] In summary, the GABAergic system’s involvement in the pathophysiology of ET and other diseases linked to GABA functional deficits has opened up new avenues for therapeutic exploration, particularly through GABA-A receptor PAMs. While the clinical evidence is still emerging, these drugs hold promise as potential treatments that may provide relief for ET patients, either alone or in combination with existing therapies, ultimately improving the quality of life for affected individuals.

[0013] SUMMARY

[0014] This disclosure reports a series of GABA-A receptor PAMs for treating neurological disorders, such as essential tremor, epilepsy, anxiety disorders, schizophrenia, bipolar disorder, sleep disorders, tinnitus, and autism spectrum disorder, as well as rare diseases such as CDKL5 deficiency disorder (CDD).

[0015] In some embodiments, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein each Rla, Rlb, Rxl, Rx2, and R2are as described herein.

[0016] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] In some embodiments, the present disclosure provides a method of treating a neurological disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the neurological disorder is essential tremor, epilepsy, anxiety disorders, schizophrenia, bipolar disorder, sleep disorders, tinnitus, or autism spectrum disorder, as well as rare diseases such as CDKL5 deficiency disorder (CDD). In some embodiments, the neurological disorder is essential tremor.

[0018] In some embodiments, the present disclosure provides a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject propranolol and a GAB A- A receptor PAM or a pharmaceutically acceptable salt thereof.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0020] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF DRAWINGS

[0021] FIG. 1 shows example time-course of the PAM assay showing the GABA-A aip2y2 current amplitude activated by a minimum of three applications of GABA EC20 (light grey columns), pre-incubation with 300 nM Allopregnanolone, re-application of GABA EC20 in the presence of 300 nM Allopregnanolone (blue column) and finally a saturating concentration of GABA is applied as a Max Agonist (white column).

[0022] FIG. 2 shows the general study design to explore the effects of P-carboline GABA-A receptor PAMs in the inhibition of harmaline-induced tremor in male CD-I mice.

[0023] FIG. 3 shows the percentage change in tremor power during 20-min post- harmaline relative to 10-min baseline (pre-dose) in the 1-40 Hz range for 0.5 Hz bins compared to propranolol. Abecarnil was administered i.p. at 0.3 or 3 mg / kg. Below, the AUC of the corresponding curves between 7 and 20 Hz indicates that the abecarnil monotherapy shows dose proportional reduction of tremor power (efficacy) comparable to that of propranolol vs. vehicle control group.

[0024] FIG. 4 shows the percentage change in tremor power in the 1-40 Hz range for 0.5 Hz bins during 20-min post-harmaline dosing for abecarnil and propranolol (alone at 5 mg / kg i.p. or in combination with abecarnil at 0.3, 1, or 3 mg / kg. Below, the AUC of the corresponding curves between 7 and 20 Hz indicates that abecarnil shows nearly complete and dose dependent tremor suppression when combined with propranolol.

[0025] FIG. 5 shows a comparisons of the effects of efficacious doses of abecarnil and diazepam in the rotarod model. Abecarnil exhibits superior side effect profile indicated by therapeutic index values (TI) vs. diazepam (used off-label in ET). Diazepam shows efficacy in ET but motor impairment side effects hinder its use.

[0026] FIG. 6 shows the absolute power in the 1-40 Hz range for 0.5 Hz bins during 20-min post-harmaline (after propranolol and test compounds treatments). 6- (benzyloxy)-7V-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide was administered i.p. at 3 or 10 mg / kg.

[0027] FIG. 7 shows the area under the curve (AUC) for the absolute tremor power of the 7-20 Hz frequency band. 6-(benzyloxy)-7V-ethyl-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide was administered i.p. at 3 or 10 mg / kg

[0028] FIG. 8 shows mouse pharmacokinetic study on 6-(benzyloxy)-N-ethyl-4- (methoxymethyl)-9H-pyrido[3,4-b]indole-3 -carboxamide. FIG. 9 shows on the left: Concentrations of 6-(benzyloxy)-N-ethyl-4-

[0029] (methoxymethyl)-9J / -pyndo[3,4-Z>]indole-3 -carboxamide in plasma and brain after 0.25, 0.5 and 1 h following i.p. administration to C57BL6 mice (N=3) and on the Right: Values of total brain / plasma ratios at the same timepoints.

[0030] FIG. 10 shows latency to clonic / tonic seizures. Diazepam-3 mg / kg significantly increased the latency to clonic / tonic seizures induced by pentyl enetetrazole (PTZ) and reduced the number of clonic / tonic seizures compared to vehicle group. Comp. 28 at 30 and 100 mg / kg (P.O.) significantly increased the latency to clonic / tonic compared to vehicle group. Bar graphs from left to right refer PO PTZ for to Vehicle, Diazapam 3 mpk, Compound 28 at 10 mpk, Compound 28 at 30 mpk, and Compound 28 at 100 mpk, respectively. Note: mpk refers PO dose in milligrams per Kg animal mass.

[0031] FIG. 11 shows latency to death. Diazepam at 3 mpk significantly increased latency to death compound to vehicle group. Comp 28 at 100 mpk (P.O.) significantly increased the latency to death compared to vehicle group.

[0032] DETAILED DESCRIPTION

[0033] Compounds

[0034] In some embodiments, the present disclosure provides a compound of Formula

[0035] (I): or a pharmaceutically acceptable salt thereof, wherein:

[0036] Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-salkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, ORa, and O(CH2)mRa; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-salkenyl, C2-salkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rlaand Rlbare each optionally substituted with 1-3 independently selected R4groups; each Rais independently selected from Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2- salkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups; m is 1, 2, 3, 4, or 5;

[0037] R2is hydrogen or C(O)OR2y; n is 1, 2, 3, or 4;

[0038] Rxland Rx2are each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-10 membered cycloalkyl, and 3- 10 membered heterocyclyl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups; o is 1, 2, 3, 4, or 5; each Ryand R2yis independently selected from Ci-Cs alkyl, Ci-shaloalkyl, C2- salkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, and 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-10 membered cycloalkyl, and 3-10 membered heterocyclyl of Rxare each optionally substituted with 1-3 independently selected R8groups; and

[0039] R4, R5, R6, and R7are independently selected from halogen, CN, N(R8)2, OH, Ci-ealkoxyl, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and each R8is independently selected from halogen, Ci-ealkyl and Ci-ehaloalkyl; wherein when R2is hydrogen, Rxlis methoxy methyl, Rx2is C(O)ORy, and Ryis Ci-Cs alkyl; then Rlais not unsubstituted benzyloxy or unsubstituted phenoxy, or Rlbis not hydrogen. In some embodiments, when R8is connected to a nitrogen atom, for example when any of R4, R5, R6, and R7are N(R8)2, then each R8is independently selected from Ci-ealkyl and C i -ehaloalky 1.

[0040] In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-salkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, ORa, and O(CH2)mRa; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2- salkenyl, C2-salkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rlaand Rlbare each optionally substituted with 1-3 independently selected R4groups.

[0041] In some embodiments, Rais selected from Ci-Cs alkyl, Ci-shaloalkyl, C2- salkenyl, C2-salkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups.

[0042] In some embodiments, m is 1, 2, 3, 4, or 5.

[0043] In some embodiments, n is 1, 2, 3, or 4.

[0044] In some embodiments, Rxland Rx2are each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2- salkynyl, 3-10 membered cycloalkyl, and 3-10 membered heterocyclyl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups.

[0045] In some embodiments, o is 1, 2, 3, 4, or 5.

[0046] In some embodiments, Ryis Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, and 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-10 membered cycloalkyl, and 3-10 membered heterocyclyl of Rxare each optionally substituted with 1-3 independently selected R8groups. In some embodiments, R4, R5, R6, and R7are independently selected from halogen, CN, N(R8)2, OH, Ci-ealkoxyl, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2- ealkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein R8is selected from Ci-ealkyl and Ci- ehaloalkyl.

[0047] In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, ORa, and O(CH2)mRa; m is 1, 2, 3, 4, or 5; Rais selected from Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups; and the Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R1are each optionally substituted with 1-3 independently selected R4groups.

[0048] In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, 6-10 membered aryl, ORa, and O(CH2)mRa; m is 1, 2, 3, 4, or 5; Rais selected from Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups; and the Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R1are each optionally substituted with 1-3 independently selected R4groups.

[0049] In some embodiments, Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, 6-10 membered aryl, ORa, and O(CH2)mRa; m is 1; Rais selected from Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1 or 2 independently selected R5groups; and the Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R1are each optionally substituted with 1 or 2 independently selected R4groups.

[0050] In some embodiments, Rlaand Rlbare each independently selected from hydrogen and CN. In some embodiments, Rlaand Rlbare each independently selected from hydrogen and OH. In some embodiments, Rlaand Rlbare each independently selected from hydrogen and Ci-Cs alkyl. In some embodiments, Rlaand Rlbare each independently selected from hydrogen, and 6-10 membered aryl. In some embodiments, Rlaand Rlbare each independently selected from hydrogen and 0(CH2)mRa; m is 1; Rais selected from 6-10 membered aryl and 5-10 membered heteroaryl; and the 6-10 membered aryl, 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups. In some embodiments, Rlaand Rlbare each independently selected from hydrogen and O(CH2)mRa; m is 1; Rais selected from phenyl and 5-6 membered heteroaryl; and the phenyl and 5-6 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups. In some embodiments, wherein Rlaand Rlbare each independently selected from hydrogen and ORa; Rais Ci-Cs alkyl; and the Ci-Cs alkyl of Rais optionally substituted with 1 or 2 independently selected R5groups.

[0051] In some embodiments, R5is halogen.

[0052] In some embodiments, Rxland Rx2are each independently selected from hydrogen, CN, Ci-Cs alkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups; o is 1, 2, 3, 4, or 5; and Ryis Ci-Cs alkyl, Ci- shaloalkyl, or 3-8 membered cycloalkyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, and 3- 10 membered cycloalkyl of Ryare each optionally substituted with 1-3 independently selected R8groups.

[0053] In some embodiments, Rxland Rx2are each independently selected from CN, Ci-Cs alkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups; o is 1, 2, 3, 4, or 5; and Ryor R2yis independently Ci-Cs alkyl, Ci- shaloalkyl, or 3-8 membered cycloalkyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, and 3- 10 membered cycloalkyl of Ryor R2yare each optionally substituted with 1-3 independently selected R8groups.

[0054] In some embodiments, Rxland Rx2are each independently selected from CN, Ci-Cs alkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rxland Rx2are each optionally substituted with 1 or 2 independently selected R7groups; o is 1; Ryis Ci-Cs alkyl, Ci-shaloalkyl, or 3-8 membered cycloalkyl; wherein the Ci-Csalkyl, Ci-shaloalkyl, and 3-10 membered cycloalkyl of Ryare each optionally substituted with 1 or 2 independently selected R8groups; and R7and R8are independently selected from halogen, Ci-ealkyl, and Ci-ehaloalkyl.

[0055] In some embodiments, Rxland Rx2are each independently selected from CN, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, 3-8 membered heterocyclyl, 5-10 membered heteroaryl optionally substituted with 1 or 2 independently selected R7groups. In some embodiments, Rxland Rx2are each independently selected from CN and (CH2)oORy; wherein o is 1 and Ryis Ci-ealkyl. In some embodiments, Rxland Rx2are each independently selected from C(O)ORyand (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl. In some embodiments, RxlandRx2are each independently selected from 5-10 membered heteroaryl optionally substituted with a R7group and (CH2)oORy; wherein o is 1, each Ryis independently selected from Ci-ealkyl, and the R7group is Ci-ehaloalkyl. In some embodiments, Rxland Rx2are each independently selected from a 5-membered heteroaryl optionally substituted with a R7group and (CH2)oORy; wherein o is 1, Ryis Ci-ealkyl, and the R7group is Ci-ehaloalkyl. In some embodiments, Rxland Rx2are each independently selected from a 6-membered heteroaryl and (CH2)oORy; wherein o is 1, and Ryis Ci-ealkyl. In some embodiments, Rxland Rx2are each independently selected from C(O)N(Ry)2and (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl. In some embodiments, Rxland Rx2are each independently selected from C(O)NHRyand (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl. In some embodiments, Rxland Rx2are each independently selected from C(O)NHRyand (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl and Ci-ehaloalkyl. In some embodiments, Rxland Rx2are each independently selected from C(O)NHRyand (CH2)oORy; wherein o is 1, each Ryis independently selected from Ci-ealkyl and 3-8 membered cycloalkyl optionally substituted with 1 or 2 independently selected R8groups, and the 1 or 2 independently selected R8groups are halogen. In some embodiments, Rxlis (CH2)oORy; wherein o is 1 and Ryis Ci-ealkyl. In some embodiments, Rxlis (CH2)oORy; wherein o is 1 and Ryis methyl. In some embodiments, Rxland Rx2are each independently selected from H and 3-8 membered heterocyclyl. In some embodiments, Rxland Rx2are each independently selected from H and piperidine. In some embodiments, Rxland Rx2together form a 5-membered heterocyclyl. In some embodiments, Rxland Rx2are hydrogen. In some embodiments, Rxland Rx2are hydrogen or C(O)ORy. In some embodiments, Ryis Ci-ealkyl.

[0056] In some embodiments, R2is hydrogen.

[0057] In some embodiments, R2is C(O)OR2y.

[0058] In some embodiments, R2yis Cl-6alkyl.

[0059] In some embodiments, the compound of Formula I is Formula (I-a): or a pharmaceutically acceptable salt thereof.

[0060] I he compound of Formula I is Formula (I-b): , or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the compound of Formula I is Formula (I-c):

[0062] , or a pharmaceutically acceptable salt thereof.

[0063] I he compound of Formula I is Formula (I-d): , or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the compound of Formula I is Formula (I-e): or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, 5-6 membered heteroaryl or 5-6-membered heterocyclyl.

[0065] In some embodiments, the compound of Formula I is Formula (I-f): , or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound of Formula I is Formula (I-g): , or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound of Formula I is Formula (I-h):

[0068] , or a pharmaceutically acceptable salt thereof.

[0069] I he compound of Formula I is Formula (I-i): , or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the present disclosure provides a compound selected from Table A, or a pharmaceutically acceptable salt thereof.

[0071] Table A. Exemplary compounds of Formula (I)

[0072]

[0073]

[0074] Pharmaceutically acceptable salts

[0075] In some embodiments, a salt of a compound of this disclosure is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0076] In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthal ene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0077] In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds of Formula (I) include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0078] Compositions and Methods of use

[0079] The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure (e.g., Formula (I)) as described herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[0080] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0081] In some embodiments, the neurological disorder is essential tremor.

[0082] In some embodiments, the neurological disorder is epilepsy.

[0083] In some embodiments, the neurological disorder is a seizure.

[0084] In some embodiments, the neurological disorder is an anxiety disorder. In some embodiments, the neurological disorder is schizophrenia. In some embodiments, the neurological disorder is bipolar disorder. In some embodiments, the neurological disorder is a sleep disorder. In some embodiments, the neurological disorder is tinnitus. In some embodiments, the neurological disorder is autism spectrum disorder. In some embodiments, the neurological disorder is CDKL5 deficiency disorder. Combinations

[0085] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a beta blocker, or a pharmaceutically acceptable salt thereof, and a GABA-A receptor PAM, or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the GABA-A receptor PAM is abecamil (ethyl 6- (benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate).

[0087] In some embodiments, the GABA-A receptor PAM is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0088] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a beta blocker, or a pharmaceutically acceptable salt thereof, and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the beta blocker is propranolol, acebutolol, atenolol, bisoprolol, metoprolol, nadolol, or nebivolol.

[0090] In some embodiments, the beta blocker is propranolol.

[0091] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject propranolol and a GABA-A receptor PAM, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the GABA-A receptor PAM is abecamil (ethyl 6- (benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate).

[0093] In some embodiments, the GABA-A receptor PAM is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0094] Some embodiments provide a method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject propranolol and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the amount of the beta blocker is a therapeutically effective amount. In some embodiments, the amount of the propranolol is a therapeutically effective amount. In some embodiments, the amount of the GABA-A receptor PAM is a therapeutically effective amount. In some embodiments, the amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a therapeutically effective amount. In some embodiments, the amount of abecamil, or a pharmaceutically acceptable salt thereof, is a therapeutically effective amount. In some embodiments, the beta blocker and the GABA-A receptor PAM are administered together in a synergistically effective amount. In some embodiments, the propranolol and the GABA-A receptor PAM are administered together in a synergistically effective amount. In some embodiments, the propranolol and the compound of Formula (I), or a pharmaceutically acceptable salt thereof, are administered together in a synergistically effective amount. In some embodiments, the propranolol and the abecamil, or a pharmaceutically acceptable salt thereof, are administered together in a synergistically effective amount.

[0096] In some embodiments, the combination of the beta blocker (e.g., propranolol) and the GABA-A receptor PAM, or a pharmaceutically acceptable salt thereof shows a synergistic effect (e.g., abecamil). See, e.g., FIG. 4.

[0097] The term “synergy” or “synergistic” is used herein to mean that the effect of the combination of the two or more therapeutic agents of the combination therapy is greater than the sum of the effect of each agent when administered alone. A “synergistic amount” or “synergistically effective amount” is an amount of the combination of the two combination partners that results in a synergistic effect, as “synergistic” is defined herein. Exemplary synergistic effects includes, but are not limited to, enhanced therapeutic efficacy, decreased dosage at equal or increased level of efficacy, reduced or delayed development of drug resistance, reduction of unwanted drug effects (e.g. side effects and adverse events) of at least one of the therapeutic agents, and both simultaneous enhancement or equal therapeutic actions (e.g., the same therapeutic effect as at least one of the therapeutic agents) and reduction of unwanted drug effects of at least one of the therapeutic agents.

[0098] In some embodiments, the neurological disorder is essential tremor.

[0099] In some embodiments, the neurological disorder is epilepsy. In some embodiments, the neurological disorder is an anxiety disorder. In some embodiments, the neurological disorder is essential tremor. In some embodiments, the neurological disorder is schizophrenia. In some embodiments, the neurological disorder is bipolar disorder. In some embodiments, the neurological disorder is a sleep disorder. In some embodiments, the neurological disorder is tinnitus. In some embodiments, the neurological disorder is autism spectrum disorder. In some embodiments, the neurological disorder is CDKL5 deficiency disorder. Definitions

[0100] As used herein, the term “about” means plus or minus approximately 10% of the indicated value or range.

[0101] The term “halo” or “halogen” refers to any radical of fluorine, chlorine, bromine or iodine.

[0102] The term “alkyl” refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-Ce alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Any atom can be optionally substituted, e.g., by one or more substituents. Examples of alkyl groups include, without limitation, methyl, ethyl, w-propyl, isopropyl, and tert-butyl.

[0103] The term “alkenyl” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms and having one or more carboncarbon double bonds. Any atom can be optionally substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. One of the double bond carbons can optionally be the point of attachment of the alkenyl substituent.

[0104] The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon group. Any atom can be optionally substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl moieties can include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl (bicyclo[2.2.1 ]heptyl).

[0105] The term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, tricyclic or other polycyclic ring system having one or more constituent heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and / or form a salt), or S. The heteroatom or ring carbon can be the point of attachment of the heterocyclyl substituent to another moiety. Any atom can be optionally substituted, e.g., by one or more substituents. Heterocyclyl groups can include groups such as tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl. By way of example, a phrase such as “heterocyclic ring containing from 5-6 ring atoms”, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(Ci-Ce alkyl), NC(O)(Ci-Ce alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected Rawould include (but not be limited to) tetrahydrofuryl, tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl.

[0106] The term “aryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (> 3 fused rings) hydrocarbon ring system. One or more ring atoms can be optionally substituted by one or more substituents for example. Aryl moi eties include groups such as phenyl and naphthyl.

[0107] The term “heteroaryl” refers to an aromatic monocyclic, bicyclic (2 fused rings), tricyclic (3 fused rings), or polycyclic (> 3 fused rings) hydrocarbon groups having one or more heteroatom ring atoms independently selected from O, N (it is understood that one or two additional groups may be present to complete the nitrogen valence and / or form a salt), or S. One or more ring atoms can be optionally substituted, e.g., by one or more substituents. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, P-carbolinyl, carbazolyl, coumarinyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl.

[0108] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0109] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated or synthesized as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the / / / ^-configuration. In some embodiments, the compound has the / / / / -configuration.

[0110] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0111] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0112] As used herein, the term “subject” refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0113] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0114] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e., reversing the pathology and / or symptomatology).

[0115] EXAMPLES

[0116] The general methods for the preparation of the compounds of Formula (I) and are described herein in an illustrative manner and is intended to be description, rather than of limitation. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof.

[0117] All commercially available reagents were used without further purification unless otherwise stated.JH and13C NMR spectra were recorded on a Bruker AV-III- 400 MHz NMR spectrometer. Chemical shifts are reported as 5 values in ppm downfield from TMS as the internal standard. 'H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, b= broad, m = multiplet), coupling constant (Hz), integration. Low resolution mass spectra were obtained on Waters Acquity Ultra Performance LC with electrospray ionization and SQ detector by injecting sample in a steady flow of 1 mM ammonium acetate in 20% water- acetonitrile at the rate of 0.2 mL min'1. The purity of compounds were determined by analytical HPLC, performed on a Shimadzu Prominence-HPLC with ELSD PDA multi, and a Gemini NX C-18 column (250 x 4.6 mm, 5p) with mobile phase (A) 0.1% Formic Acid in water and mobile phase (B) 0.1% Formic Acid in Acetonitrile using following gradient of B / A (0 min, 10%), (5 min, 90%), (6 min, 95%), (10 min, 95%), (10 min, 10%) and (14 min, 10%) at 1.0 mL min'1flow rate. Analytical thin layer chromatography was performed on 250 pM silica gel F254 plates. Preparative thin layer chromatography was performed on 1000 pM silica gel F254 plates. Flash column chromatography was performed employing 230-400 mesh silica gel. Preparative HPLC was performed using a WePure Biotech XP Cl 8 150 um X 40 um X 10 pm column; mobile phase: A=10 mM aq. NH4HCO3; B=ACN.

[0118] Synthesis of intermediates

[0119] Synthesis of intermediate 9- butyl ) 3-ethyl 6-(benzyloxy)-4-(methoxymethyl)-9H- pyridol3,4-b1indole-3,9-dicarboxylate

[0120] Step 1 : Preparation of 2-Methoxyacetaldehyde

[0121] A solution of 1,1,2-trimethoxy ethane (110 g, 582.62 mmol, 75.11 mL) in HC1 (1 M, 120 mL) was stirred at 75 °C overnight. To the reaction mixture was added portion wise NaHCCL till pH= 7-8, and the mixture was extracted with di chloromethane (3 x 1500 mL). The combined organic phases were dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure to give 2-methoxyacetaldehyde as a colorless oil (60 g).

[0122] Step 2: Preparation of Ethyl 3-hydroxy-4-methoxy-2-nitrobutanoate

[0123] To a solution of 2-methoxyacetaldehyde (50 g, 675 mmol) in ethanol (75 mL) was added a solution of sodium acetate (664 mg, 8.10 mmol) in water (5.35 g, 297 mmol, 5.35 mL), then ethyl 2-nitroacetate (89.84 g, 675 mmol, 74.87 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at 0 °C for 1 h and stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate (500 mL) and the mixture was washed with 10% NaLBPCU (3 x 500 mL). The organic phase was dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure and gave ethyl 3-hydroxy-4-methoxy-2-nitro- butanoate as a yellow oil (120 g).

[0124] Step 3 : Preparation of Ethyl 3-(5-benzyloxy-lH-indol-3-yl)-4-methoxy-2-nitro- butanoate

[0125] A mixture of 5-benzyloxy-lH-indole (32 g, 143.5 mmol) and ethyl 3-hydroxy- 4-methoxy-2-nitro-butanoate (120 g, 579 mmol) in toluene (300 mL) and acetic acid (30 mL) was stirred at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica (elution with petroleum ether and ethyl acetate, 0-30% gradient) and gave ethyl 3-(5-benzyloxy-lH-indol-3-yl)-4-methoxy-2-nitro-butanoate as a dark brown oil (30 g)-

[0126] Step 4: Preparation of Ethyl 2-amino-3-(5-benzyloxy-lH-indol-3-yl)-4- methoxy-butanoate

[0127] To a solution of ethyl 3-(5-benzyloxy-lH-indol-3-yl)-4-methoxy-2-nitro- butanoate (43 g, 104 mmol) in ethanol (200 mL) was added Raney -Ni (18.46 g, 215.48 mmol) under argon atmosphere. The mixture was degassed, charged with hydrogen and stirred under H2 (balloon pressure) at 25 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (elution with di chloromethane and ethanol, 0-10% gradient) and gave ethyl 2-amino-3-(5-benzyloxy-lH-indol-3-yl)-4- methoxy-butanoate as a brown oil (32 g).

[0128] Step 5: Preparation of Ethyl 3-(5-(benzyloxy)-lH-indol-3-yl)-2-formamido-4- methoxybutanoate

[0129] A mixture of acetic anhydride (14.69 g, 143.9 mmol) and formic acid (19.85 g, 431.4 mmol) was stirred at 0 °C for 1 h. To the mixture was added a solution of ethyl 2-amino-3-(5-benzyloxy-lH-indol-3-yl)-4-methoxy-butanoate (27.5 g, 71.90 mmol) in dichloromethane (150 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with water (100 mL) and extracted with di chloromethane (3 x 200 mL). The combined organic phases were dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure and gave ethyl 3-(5-(benzyloxy)-lH-indol-3- yl)-2-formamido-4-methoxybutanoate as a brown solid (25 g). MS (ESI): m / z 411.1 [M+H]+.

[0130] Step 6: Preparation of Ethyl 6-(benzyloxy)-4-(methoxymethyl)-4,9-dihydro-3H- pyrido[ 3, 4-b ] indole-3-carboxylate

[0131] To a solution of ethyl 3-(5-(benzyloxy)-lH-indol-3-yl)-2-formamido-4- methoxybutanoate (25 g, 61mmol) in acetonitrile (250 mL) was added POCI3 (18 g, 122 mmol). The mixture was stirred at room temperature overnight and concentrated. Water and acetonitrile were added to the residue and extracted with dichloromethane. The organic phases were washed with water, dried over Na2SO4, and concentrated to give the desired product ethyl 6-(benzyloxy)-4-(methoxymethyl)-4,9-dihydro-3H- pyrido[3,4-b] indole-3 -carboxylate as HC1 salt (20 g). MS (ESI): m / z 393.3[M+H]+.

[0132] Step 7: Preparation of ethyl 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0133] To a solution of 6-benzyloxy-3-ethoxycarbonyl-4-(methoxymethyl)-2, 3,4,9- tetrahydro-lH-pyrido[3,4-b] indole- 1 -carboxylic acid (30 g, 68.42 mmol) in dimethyl sulfoxide (200 mL) was added IBX (60 g, 214.19 mmol). The solution was heated to 45 °C for 3 h. The mixture was purified by silica gel column chromatography and gave ethyl 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3 -carboxylate as a brown solid (10 g). MS (ESI): m / z 391.2 [M+H]+. 'HNMR (400 MHz, CD3OD) 5 8.74 (s, 1H), 7.79 (d, J= 2.4 Hz, 1H), 7.51 (dd, J= 17.9, 8.1 Hz, 3H), 7.42 - 7.24 (m, 4H), 5.22 (d, J= 14.6 Hz, 4H), 4.44 (q, J= 7.1 Hz, 2H), 3.42 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0134] Step 8: Preparation of 9 -(tert-butyl) 3-ethyl 6-(benzyloxy)-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0135] To a solution of ethyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (10 g, 25.6 mmol) in dichloromethane (100 mL) was added diisopropyl ethylamine (6.6 g, 51.2 mmol) and BOC2O (7.2 g, 33.3 mmol). The solution was heated to 60 °C for 3 h and then partitioned between water and ethyl acetate. The organic phase was washed with water, dried over ISfeSCU, concentrated, and the crude product was purified by silica gel column chromatography to give the desired product ethyl 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4-b] indole-3 -carboxylate as a brown solid (10 g).

[0136] Synthesis of intermediate isopropyl 5-(benzyloxy)-4-(methoxymethyl)-9H-pyridof3,4- b]indole-3-carboxylate

[0137] Step 1 : Preparation of isopropyl 3-hydroxy-4-methoxy-2-nitrobutanoate

[0138] To a solution of 2-methoxyacetaldehyde (50 g, 674.96 mmol) in ethanol (75 mL) was added a solution of NaOAc (664 mg, 8.10 mmol) in water (5.35 g, 296.98 mmol, 5.35 mL), then isopropyl 2 -nitroacetate (89.84 g, 674.96 mmol, 74.87 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred at 0 °C for 1 h and stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate (500 mL) and the mixture was washed with 10% of NaLLPCU (3 x 500 mL). The organic phase was dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure and gave ethyl 3-hydroxy-4-methoxy- 2-nitro-butanoate as a yellow oil (120 g, crude).

[0139] Step 2: Preparation of isopropyl 3-(4-(benzyloxy)-lH-indol-3-yl)-4-methoxy-2- nitrobutanoate

[0140] A solution of 5-benzyloxy-lH-indole (7.0 g, 30 mmol) and isopropyl 3- hydroxy-4-methoxy-2-nitrobutanoate (50g, 121 mmol) in toluene (140 mL) and acetic acid (14 mL) was stirred at 110 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica (elution with petroleum ether and ethyl acetate 0-30% gradient) and gave isopropyl 3-(4-(benzyloxy)-lH-indol-3-yl)-4-methoxy-2-nitrobutanoate as a dark brown oil (8.0 g).

[0141] Step 3: Preparation of isopropyl 2-amino-3-(4-(benzyloxy)-lH-indol-3-yl)-4- methoxybutanoate

[0142] To a solution of isopropyl 3-(4-(benzyloxy)-lH-indol-3-yl)-4-methoxy-2- nitrobutanoate (8 g, 18.7 mmol) in ethanol (40 mL) was added Raney-Ni (8 g, 215.48 mmol) under Ar2 atmosphere. The mixture was degassed, charged with hydrogen and stirred under H2 (20 Psi) at 25 °C for 8 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (elution with di chloromethane and ethanol 0-10% gradient) and gave isopropyl 2-amino-3-(4-(benzyloxy)-lH-indol-3-yl)-4-methoxybutanoate as a brown oil (5.5 g).

[0143] Step 4: Preparation of isopropyl 3-(4-(benzyloxy)-lH-indol-3-yl)-2-formamido- 4-methoxybutanoate

[0144] A mixture of acetic anhydride (2.8 g, 27.8 mmol) and formic acid (3.8 g, 83.4 mmol) was stirred at 0 °C for 1 h. To the mixture was added a solution of isopropyl 2- amino-3-(4-(benzyloxy)-lH-indol-3-yl)-4-methoxybutanoate (5.5 g, 13.8 mmol) in dichloromethane (50 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with di chloromethane (3 x 100 mL). The combined organic phase was dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure and gave isopropyl 3-(4-(benzyloxy)-lH-indol-3- yl)-2-formamido-4-methoxybutanoate as a brown solid (6.0 g). MS (ESI): m / z 425.2 [M+H]+.

[0145] Step 5 : Preparation of isopropyl 5-(benzyloxy)-4-(methoxymethyl)-4, 9-dihydro- 3H-pyrido[ 3, 4-b ]indole-3-carboxylate

[0146] To a solution of isopropyl 3-(4-(benzyloxy)-lH-indol-3-yl)-2-formamido-4- methoxybutanoate (6 g, 14.1mmol) in acetonitrile (60 mL) was added POCI3 (4.3 g, 28.2 mmol). The mixture was stirred under at room temperature overnight and concentrated. Water and acetonitrile were added to the residue. The mixture was extracted with dichloromethane. The organic phases were washed by water, dried over Na2SO4, and concentrated to give isopropyl 5-(benzyloxy)-4-(methoxymethyl)-4,9- dihydro-3H-pyrido[3,4-b]indole-3 -carboxylate as the HC1 salt (6 g). MS (ESI): m / z 407[M+H]+.

[0147] Step 6: Preparation of isopropyl 5-(benzyloxy)-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0148] To a solution of isopropyl 5-(benzyloxy)-4-(methoxymethyl)-4,9-dihydro-3H- pyrido[3,4-b]indole-3 -carboxylate (6 g, 14.8 mmol) in dimethyl sulfoxide (12 mL) was added IBX (16.5 g, 59.1 mmol). The solution was heated to 45 °C for 3 h. The mixture was purified by silica gel column and gave isopropyl 5-(benzyloxy)-4- (methoxymethyl)-9H-pyrido[3,4-b]indole-3 -carboxylate as a brown solid (2.0 g).JH NMR (400 MHz, CDCI3): 8 8.78 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 7.55-7.52 (m, 2H), 7.48-7.37 (m, 4H), 7.14-7.12 (d, J= 8.0 Hz, 1H), 5.32-5.19 (m, 5H), 3.02(s, 3H), 1.42- 1.40 (d, 6H). MS (ESI): m / z 405 [M+H]+.

[0149] Example 1. Synthesis of 6-(benzyloxy)-4-(methoxymethyl)-7V-methyl-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 43)

[0150] To a mixture of ethyl 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (50 mg) in methanamine (4.78 g, 46.17 mmol, 30% purity in MeOH). The mixture was stirred at 25 °C for 12 h. The reaction mixture (combined with another batch at same scale) was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100 mm x 30 mm xlO pm; mobile phase: [water (10 mM lSELHCCLj-ACN]; B%: 25%-55%, 8 min) and gave 6-benzyloxy-4-(methoxymethyl)-N-methyl-9H-pyrido[3,4-b]indole-3 -carboxamide as a white solid (25.4 mg).XH NMR (400 MHz, CDC13) A 8.70 (s, 1H), 8.45 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.51 (d, 2H, J= 7.57 Hz), 7.41 (m, 3H), 7.32 (m, 2H), 5.71 (s, 2H), 5.21 (s, 2H), 3.52 (s, 3H), 3.05 (s, 3H).

[0151] Example 2. Synthesis of 6-(benzyloxy)-4-(methoxymethyl)-A,A-dimethyl-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 42)

[0152] Step 1 : Preparation of 6f Benzyloxy) -4 f methoxymethyl) -9H-pyrido[ 3,4- b]indole-3-carboxylic acid

[0153] To a solution of ethyl 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (500 mg, 1.28 mmol) in 10% aqueous NaOH (10 mL). The mixture was stirred at 100 °C for 1.5 h. The reaction mixture was cooled to 0 °C and the pH adjusted to 4 with IN HC1. The yellow solid which formed was filtered from the mixture and washed with H2O (20 mL). The solid was dried under reduced pressure and gave 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid as a yellow solid (430 mg).

[0154] Step 2: Preparation of 6-(Benzyloxy)-4-(methoxymethyl)-N,N-dimethyl-9H- pyrido[ 3, 4-b ]indole-3-carboxamide

[0155] To a mixture of 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (50 mg) and dimethylamine HC1 salt (13.50 mg) in dimethyl formamide (0.5 mL) was added EDCI (31.74 mg), HOBt (22.37 mg) and diisopropyl ethylamine (53.50 mg). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100 mm x 30 mm x 10 pm; mobile phase: [water (10 mM NELHCChj-ACN]; B%: 25%-50%, 8 min) and gave 6- benzyloxy-4-(methoxymethyl)-N,N-dimethyl-9H-pyrido[3,4-b]indole-3-carboxamide as a white solid (26.7 mg). 'H NMR (400 MHz, CDCI3) b 10.22 (s, 1H), 9.04 (s, 1H), 7.75 (d, 1H, J= 2.09 Hz), 7.57 (d, 1H, J= 9.09 Hz), 7.49 (m, 2H), 7.40 (m, 3H), 7.34 (m, 1H), 5.18 (s, 2H), 4.92 (s, 2H), 3.41 (s, 3H), 3.25 (s, 3H), 2.92 (s, 3H).

[0156] Example 3. Synthesis of 2-(6-(benzyloxy)-4-(methoxymethyl)-9J7-pyrido[3,4-Z>]indol- 3-yl)oxazole (Compound 41)

[0157] Step 1 : Preparation of 6f Benzyloxy) -4 f methoxymethyl) -9H-pyrido[ 3,4- b ]indole-3-carboxamide

[0158] To a solution of 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (50 mg) and NH4CI (11.07 mg) in dimethyl formamide (1 mL) was added EDCI (39.68 mg), HOBt (27.97 mg) and diisopropyl ethylamine (53.50 mg). The mixture was stirred at 25 °C for 12 h. The reaction mixture (combined with another batch at the same scale) was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX Cl 8 75 mm x 30 mm x 3 pm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) and gave 6-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxamide as a white solid (31 mg). 'HNMR (400 MHz, CDCI3) b 8.71 (s, 1H), 8.41 (s, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.41 (m, 8H), 5.67 (s, 2H), 5.24 (s, 2H), 3.50 (s, 3H)

[0159] Step 2: Preparation of 2-(6-(Benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indol-3-yl)oxazole

[0160] To a solution of 6 - benzyloxy- 4 - (methoxymethyl)- 9H - pyrido[3,4 - b]indole - 3 -carboxamide (80 mg) in NMP (1 mL) was added 2 -bromo- 1,1 -di ethoxy-ethane (65.44 mg) and p-TsOH (3.81 mg). The mixture was stirred at 110 °C for 12 h. The mixture (combined with another batch at 50 mg scale) was cooled to 25 °C, the yellow solid was separated out, filtered and washed with ethyl acetate (20 mL). The solid was dried under reduced pressure. The solid was purified by prep-HPLC (column: Phenomenex Luna C18 80 mm x 40 mm x 3 pm; mobile phase: [water (0.04% HC1)- ACN]; B%: 23%-53%, 7 min) and gave 2-[6-benzyloxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indol-3-yl]oxazole as a yellow solid (31.4 mg). MS (ESI): m / z 386.2 [M+H]+. Example 4. Synthesis of ethyl 4-(methoxymethyl)-6-(pyridin-2-ylmethoxy)-97 / - pyrido[3,4-Z>]indole-3 -carboxylate (Compound 40)

[0161] Step 1 : Preparation of 9-(Tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(pyridin-2- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0162] To a 10 mL scintillation vial was added 9-(te / 7-butyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (75 mg, 0.19 mmol), potassium carbonate (140 mg, 1.0 mmol), and dimethylformamide (2 mL). To this suspension was added 2-(chloromethyl)pyridine (52 mg, 0.40 mmol) and the reaction mixture was heated at 55 °C and monitored by LCMS. After heating overnight, the reaction was complete and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous brine (3 x 25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified via silica column running 0-60% ethyl acetate / hexanes to give 39 mg of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(pyridin-2- ylmethoxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate.

[0163] Step 2: Preparation of Ethyl 4-(methoxymethyl)-6-(pyridin-2-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0164] To a 10 mL scintillation vial was added 9-( / c77-butyl) 3-ethyl 4- (methoxymethyl)-6-(pyridin-2-ylmethoxy)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (40 mg, 0.09 mmol) and dichloromethane (3 mL) followed by trifluoracetic acid (1 ml). The reaction was stirred at 40 °C and was complete after 12 hours as monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with dichloromethane (3 x 25 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was recrystallized with 1 : 1 ethyl acetate: hexanes to yield the title compound (25 mg). MS (ESI): m / z 392.2 [M+H]+.JH NMR (CD3OD) 8 8.84 (s, 1H), 8.59 (d, 1H, J= 5.0 Hz), 7.93 (m, 1H), 7.84 (d, 1H, J= 2.38 Hz), 7.71 (d, 1H, J= 7.99 Hz), 7.63 (d, 1H, J= 8.84 Hz), 7.44 (m, 2H), 5.35 (s, 2H), 5.30 (s, 2H), 4.49 (q, 2H, J= 7.15 Hz), 3.44 (s, 3H), 1.47 (t, 3H, J= 7.15 Hz). Example 5. Synthesis of ethyl 4-(methoxymethyl)-6-(pyridin-3-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 39)

[0165] Step 1 : Preparation of 9-(Tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(pyridin-3- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0166] To a 10 mL scintillation vial was added 9-(te / 7-butyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (90 mg, 0.22 mmol), potassium carbonate (155 mg, 1.10 mmol), and dimethylformamide (5 mL). To this suspension was added 3-(chloromethyl)pyridine (60 mg, 0.44 mmol) and the reaction mixture was heated at 30 °C and monitored by LCMS. After heating overnight, the reaction was complete and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with saturated aqueous brine (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-60% ethyl acetate / hexanes (61 mg).

[0167] Step 2: Preparation of Ethyl 4-(methoxymethyl)-6-(pyridin-3-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0168] To a 10 mL scintillation vial was added 9-( / c77-butyl) 3-ethyl 4- (methoxymethyl)-6-(pyri din-3 -ylmethoxy)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (60 mg, 0.12 mmol) and di chloromethane (2 mL) followed by trifluoracetic acid (1 mL). The reaction was stirred at 45 °C for 2 days until completion monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with dichloromethane (3 x 25 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified via silica column running 0-5% methanol / dichloromethane to yield the title compound (16 mg). MS (ESI): m / z 392.2 [M+H]+. 'H NMR (CD3OD) 8 8.74 (d, 1H, J= 3.52 Hz), 8.69 (s, 1H), 8.50 (dd, 1H, J= 1.33, 4.94 Hz), 7.99 (m, 1H), 7.81 (d, 1H, J= 2.42 Hz), 7.53 (d, 1H, J= 8.85 Hz), 7.47 (dd, 1H, J= 4.71, 7.67 Hz), 7.35 (dd, 1H, J= 2.18, 7.34 Hz), 5.25 (m, 4H), 4.55 (q, 2H, J= 4.45 Hz), 3.98 (s, 2H), 3.42 (s, 3H), 1.44 (t, 3H, J= 7.12 Hz). Example 6. Synthesis of ethyl 4-(methoxymethyl)-6-(pyridin-4-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 38)

[0169] Step 1 : Preparation of 9 -(Tert-butyl) 3-ethyl 6-(pyridin-4-ylmethoxy)-9H- pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0170] To a 10 mL scintillation vial was added 9-(te / 7-butyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (90 mg, 0.23 mmol), potassium carbonate (175 mg, 1.25 mmol), and dimethylformamide (5 mL). To this suspension was added 4-(chloromethyl)pyridine (100 mg, 0.50 mmol) and the reaction mixture was heated at 55 °C overnight and monitored by LCMS. Upon completion, the reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous brine (3 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-60% ethyl acetate / hexanes (99 mg).

[0171] Step 2: Preparation of Ethyl 4-(methoxymethyl)-6-(pyridin-4-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0172] To a 10 mL scintillation vial was added 9-( / c77-butyl) 3-ethyl 4- (methoxymethyl)-6-(pyridin-4-ylmethoxy)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (115 mg, 0.23 mmol) and dichloromethane (3 mL) followed by trifluoracetic acid (1 mL). The reaction was stirred for 12 hours at 45 °C until completion as monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to give the title compound (10 mg). MS (ESI): m / z 392.2 [M+H]+. 'H NMR (CD3OD) 8 8.82 (s, 1H), 8.64 (s, 2H), 7.86 (d, 1H, J= 2.34 Hz), 7.78 (m, 2H), 7.63 (d, 1H, J= 8.96 Hz), 7.46 (dd, 1H, J= 2.50, 8.96 Hz), 5.42 (m, 3H), 5.32 (s, 2H), 4.48 (q, 2H, J= 7.10 Hz), 3.40 (s, 3H), 1.46 (t, 3H, J= 7.10 Hz). Example 7. Synthesis of ethyl 4-(methoxymethyl)-6-(pyridazin-3-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 37)

[0173] To a 10 mL scintillation vial was added 9-(tert-butyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (90 mg, 0.17 mmol), cesium carbonate (450 mg, 1.5 mmol), and dimethylformamide (12 mL). To this suspension was added 3-(chloromethyl)pyridazine (110 mg, 0.85 mmol) and the reaction mixture was heated at 90 °C overnight and monitored by LCMS. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and washed with saturated aqueous (3 x 25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column chromatography running 0-8% methanol / di chloromethane (41 mg). MS (ESI): m / z 393.2 [M+H]+. 'HNMR (400 MHz, CD3OD) 3 9.14 (dd, 1H, J= 1.60, 4.90 Hz), 8.74 (s, 1H), 7.95 (dd, 1H, J= 1.50, 8.40), 7.81 (d, 1H, J= 2.50 Hz), 7.76 (dd, 1H, J= 5.0, 8.50 Hz), 7.56 (d, 1H, J= 9.10 Hz), 7.41 (ddd, 1H, J= 2.50, 9.10, 11.40 Hz), 5.52 (s, 2H), 5.47 (s, 2H), 5.22 (s, 3H), 4.45 (q, 2H, J= 7.14 Hz), 1.44 (t, 3H, J= 7.14 Hz). Example 8. Synthesis of ethyl 4-(methoxymethyl)-6-(oxazol-2-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 36)

[0174] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(oxazol-2- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0175] To a 10 mL scintillation vial was added 9-(terLbutyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (75 mg, 0.19 mmol), potassium carbonate (265 mg, 1.9 mmol), and dimethylformamide (7 mL). To this suspension was added 2-(chloromethyl)oxazole (90 pL, 1 mmol) and the reaction mixture was heated at 90 °C and monitored by LCMS. After heating overnight, the reaction was complete and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous brine (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-50% ethyl acetate / hexanes (81 mg).

[0176] Step 2: Preparation of ethyl 4-(methoxymethyl)-6-(oxazol-2-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0177] To a 10 mL scintillation vial was added 9-( / c / 7-butyl) 3-ethyl 4- (methoxymethyl)-6-(oxazol-2-ylmethoxy)-9J7-pyrido[3,4-Z>]indole-3, 9-dicarboxylate (85 mg, 0.18 mmol) and di chloromethane (3 mL) followed by trifluoracetic acid (1 mL). The reaction was stirred overnight at 40 °C until completion as monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound (46 mg). MS (ESI): m / z 382.1 [M+H]+. 'H NMR (400 MHz, CDC13) b 9.54 (s, 1H), 9.00 (s, 1H), 7.94 (d, 1H, J= 2.15 Hz), 7.71 (d, 1H, J= 0.8 Hz), 7.51 (d, 1H, J= 8.70 Hz), 7.35 (dd, 1H, J= 2.15, 8.70 Hz), 7.18 (s, 1H), 5.35 (s, 2H), 5.29 (s, 2H), 4.52 (q, 2H, J= 7.06 Hz), 3.52 (s, 3H), 1.48 (t, 3H, J= 7.10 Hz).

[0178] Example 9. Synthesis of ethyl 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 35)

[0179] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0180] To a 10 mL scintillation vial was added 9-(terLbutyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (67 mg, 0.17 mmol), potassium carbonate (230 mg, 1.7 mmol), and dimethylformamide (5 mL). To this suspension was added 2-(chloromethyl)thiazole (87 pL, 0.84 mmol) and the reaction mixture was heated at 90 °C overnight and monitored by LCMS. Upon completion, the reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous brine (3 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-60% ethyl acetate / hexanes (66 mg).

[0181] Step 2: Preparation of ethyl 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-97 / - pyrido[3,4-Z>]indole-3 -carboxylate

[0182] To a 10 mL scintillation vial was added 9-( / c / 7-butyl) 3-ethyl 4- (methoxymethyl)-6-(thi azol -2 -ylmethoxy)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (66 mg, 0.13 mmol) and di chloromethane (3 mL) followed by trifluoracetic acid (1 mL). The reaction was stirred overnight at room temperature until completion as monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted di chloromethane (3 x 75 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-5% methanol / dichloromethane (13 mg). MS (ESI): m / z 398.1 [M+H]+.

[0183] Example 10. Synthesis of ethyl 4-(methoxymethyl)-6-(thiazol-5-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 34)

[0184] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(thiazol-5- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0185] To a 10 mL scintillation vial was added 9-(terLbutyl) 3-ethyl 6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (85 mg, 0.22 mmol), potassium carbonate (150 mg, 1.07, mmol), and dimethylformamide (5 mL). To this suspension was added 5-(chloromethyl)thiazole (88 mg, 0.66 mmol) and the reaction mixture was heated at 65 °C, stirred overnight, and monitored by LCMS. Upon completion, the reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous brine (3 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column elution with 0-60% ethyl acetate / hexanes (95 mg). Step 2: Preparation of ethyl 4-(methoxymethyl)-6-(thiazol-5-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0186] To a 10 mL scintillation vial was added 9 -(tert-butyl) 3-ethyl 4- (methoxymethyl)-6-(thiazol-5-ylmethoxy)-9JH-pyrido[3,4-Z>]indole-3,9-dicarboxylate (95 mg, 0.20 mmol) and di chloromethane (3 mL) followed by trifluoracetic acid (1 mL). The reaction was stirred overnight at room temperature until completion as monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with di chloromethane (3 x 75 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound (72 mg). MS (ESI): m / z 398.1 [M+H]+. *H NMR (400 MHz, CDC13) b 9.07 (s, 1H), 8.86 (d, 1H, J= 2.02 Hz), 8.02 (s, 1H), 7.93 (d, 1H, J= 2.35 Hz), 7.55 (d, 1H, J= 8.90 Hz), 7.48 (m, 1H), 7.38 (dd, 1H, J= 2.49, 8.90 Hz), 5.42 (s, 2H), 5.38 (s, 2H), 4.53 (q, 2H, J= 7.15 Hz), 3.47 (s, 3H), 1.49 (t, 3H, J= 7.15 Hz).

[0187] Example 11. Synthesis of 6-(benzyloxy)-4-(methoxymethyl)-7V-propyl-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 33)

[0188] To a 10 mL scintillation vial was added 6-(benzyloxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (30 mg, 0.083 mmol) and propylamine (10 pL, 0.124 mmol) followed by dimethylformamide (4mL). To this stirring solution was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20 mg, 0.124 mmol), hydroxybenzotriazole (19 mg, 0.124 mmol), and diisopropylethylamine (43 pL, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and then at 50 °C for three hours the next morning until all starting material had been consumed as monitored by LCMS. Subsequently, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and the organic layer was washed with saturated brine solution (2 x 25mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-7% methanol in dichloromethane (21 mg). MS (ESI): m / z 404.2 [M+H]+. 'H NMR (CDCI3) 5 8.93 (s, 1H), 8.59 (s, 1H), 8.21 (t, 1H, J= 5.74 Hz), 7.85 (d, 1H, 2.07 Hz), 7.50 (d, 2H, 7.44 Hz), 7.37 (m, 4H), 7.25 (dd, 1H, J= 2.21, 8.73 Hz), 5.67 (s, 2H), 5.19 (s, 2H), 3.52 (s, 3H), 3.44 (q, 2H, J= 6.98 Hz), 1.67 (m, 2H), 1.00 (t, 3H, J= 7.94 Hz).

[0189] Example 12. Synthesis of 6-(benzyloxy)-7V-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 32)

[0190] To a 10 mL scintillation vial was added 6-(benzyloxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (25 mg, 0.07 mmol) and 2.5 M ethylamine / THF (40 pL, 0.10 mmol) followed by dimethylformamide (2 mL). To this stirring solution was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (15.5 mg, 0.10 mmol), hydroxybenzotriazole (15.3 mg, 0.10 mmol), and diisopropylethylamine (36 pL, 0.21 mmol). The reaction mixture was stirred at room temperature overnight and then at 50 °C for three hours the next morning until all starting material had been consumed as monitored by LCMS. Subsequently, the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), and the organic layer was washed with saturated brine solution (2 x 25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-7% methanol in dichloromethane (19 mg). MS (ESI): m / z 390.1 [M+H]+. 'H NMR (CDC13) 8 8.78 (s, 1H), 8.62 (s, 1H), 8.16 (t, 1H, J= 5.08 Hz), 7.88 (d, 1H, J= 2.32 Hz), 7.50 (m, 2H), 7.37 (m, 4H), 7.27 (dd, 1H, J= 2.47, 8.85 Hz), 5.68 (s, 2H), 5.20 (s, 2H), 3.52 (m, 5H), 1.29 (t, 3H, J= 7.35 Hz).

[0191] Example 13. Synthesis of 7V-isopropyl-4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)- 9J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 30) Step 1 : Preparation of tert-butyl-6-(benzyloxy)-3-(isopropylcarbamoyl)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-9-carboxylate

[0192] To a 10 mL scintillation vial was added 6-(benzyloxy)-7V-isopropyl-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (172 mg, 0.43 mmol), dichloromethane (4 mL), followed by BOC2O (294 pL, 1.28 mmol) and diisopropyl ethylamine (223 pL, 1.28 mmol). The solution was cooled to 0 °C and DMAP (50 mg, 0.43 mmol) was added to the stirring solution. The solution was warmed to room temperature and stirred overnight. Upon completion, as monitored by LCMS, the reaction mixture was concentrated under vacuum and the title compound was purified via silica column running 0-60% ethyl acetate / hexanes (197 mg).

[0193] Step 2: Preparation of tert-butyl 6-hydroxy-3-(isopropylcarbamoyl)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-9-carboxylate

[0194] To a 10 mL scintillation vial was added tert-butyl 6-(benzyloxy)-3- (isopropylcarbamoyl)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (195 mg, 0.39 mmol), Pd / C (146 mg, 75% w / w), and ethanol (3 mL). The reaction mixture was purged with argon for 20 minutes prior to hydrogenation (balloon pressure). After 1 hour of hydrogenation, LCMS showed completion of the reaction. The mixture was filtered over a pad of celite, and the filtrate was concentrated under vacuum. The title compound was purified via silica column running 0-7% methanol / di chloromethane (161 mg).

[0195] Step 3: Preparation of tert-butyl 3-(isopropylcarbamoyl)-4-(methoxymethyl)-6- ( oxazol-2-ylmethoxy)-9H-pyrido[ 3, 4-b ]indole-9-carboxylate

[0196] To a 10 mL scintillation vial was added tert-butyl 6-hydroxy-3- (isopropylcarbamoyl)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (30 mg, 0.061 mmol), potassium carbonate (100 mg, 0.61 mmol), and dimethylformamide (3 mL). To this suspension was added 2-(chloromethyl)thiazole (30 pL, 0.122 mmol) and the reaction mixture was heated at 55 °C, stirred overnight, and monitored by LCMS. Upon completion, the reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous brine (3 x 25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-50% ethyl acetate / hexanes (20 mg). Step 4: Preparation of N-isopropyl-4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0197] To a 10 mL scintillation vial was added tert-butyl 3-(isopropylcarbamoyl)-4- (methoxymethyl)-6-(thiazol-2-ylmethoxy)-9JH-pyrido[3,4-Z>]indole-9-carboxylate (24 mg, 0.047 mmol) and dichloromethane (2 mL) followed by trifluoroacetic acid (100 pL). The reaction was complete after 12 hours as monitored by LCMS. The reaction was neutralized with a dropwise addition of saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with di chloromethane (3 x 50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-10% methanol / di chloromethane (4 mg). MS (ESI): m / z 411.1 [M+H]+.JH NMR (CDCh) 8 8.72 (s, 2H), 8.02 (d, 1H, J= 7.64), 7.93 (d, 1H, J= 1.88 Hz), 7.83 (d, 1H, J= 3.38 Hz), 7.46 (d, 1H, J= 8.64), 7.38 (d, 1H, J= 3.19 Hz), 7.34 (dd, 1H, J= 2.39, 8.81 Hz), 5.64 (s, 2H), 5.53 (s, 2H), 4.29 (septet, 1H, J= 6.70 Hz), 3.56 (s, 3H), 1.31 (d, 6H, J= 6.36 Hz).

[0198] Example 14. Synthesis of 6-(isopentyloxy)-7V-isopropyl-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 29)

[0199] Step 1 : Preparation of tert-butyl-6-(isopentyloxy)-3-(isopropylcarbamoyl)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-9-carboxylate

[0200] To a 10 mL scintillation vial containing tert-butyl 6-hydroxy-3- (isopropylcarbamoyl)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (25 mg, 0.061 mmol) was added potassium carbonate (84 mg, 0.61 mmol), l-bromo-3- methylbutane (30 pL, 0.242 mmol) followed by dimethyl formamide (2 mL). The solution was stirred for one hour at 90 °C at which point LCMS analysis showed full conversion to the title compound. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL) and washed with saturated aqueous brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-60% ethyl acetate / hexanes (20 mg). Step 2: Preparation of 6-(isopentyloxy)-N-isopropyl-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3-carboxamide

[0201] To a solution of tert-butyl 6-(isopentyloxy)-3-(isopropylcarbamoyl)-4- (methoxymethyl)-9JH-pyrido[3,4-Z>]indole-9-carboxylate (19 mg, 0.04 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (79 pL, 0.8 mmol) and the solution was stirred at room temperature for 1.5 hours at which point LCMS showed full conversion to the title compound. The reaction mixture was neutralized to pH=7 with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with DCM (3 x 50 mL) and the organic layers were combined, dried over sodium sulfate, and concentrated under vacuum. The title compound was purified via silica column running 0-10% methanol / di chloromethane (12 mg). MS (ESI): m / z 384.2 [M+H]+.JH NMR (CDC13) 8 8.75 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.82 (d, 1H, J= 2.32 Hz), 7.44 (d, 1H, J= 8.75 Hz), 7.25 (m, 1H), 5.70 (s, 2H), 4.29 (m, 1H), 4.14 (t, 2H, J= 6.63), 3.58 (s, 3H), 1.91 (m, 1H), 1.76 (q, 2H, J= 6.72), 1.32 (d, 6H, J= 6.35 Hz), 1.01 (d, 6H, J= 6.63 Hz).

[0202] Example 15. Synthesis of 5-(benzyloxy)-4-(methoxymethyl)-7V-methyl-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 28)

[0203] To a solution of 5-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (130 mg, 0.35 mmol), diisopropyl ethylamine (92 mg, 0.7 mmol) in 2 mL of dimethylformamide were added HATU (204.6 mg, 0.53 mmol) and methanamine hydrochloride (133 mg, 1.75 mmol). The mixture was stirred at room temperature for 2 h, quenched with water and extracted with ethyl acetate. The organic solvent was concentrated, the residue was purified by prep-HPLC to give 5- (benzyloxy)-4-(methoxymethyl)-N-methyl-9H-pyrido[3,4-b]indole-3 -carboxamide (42.3 mg).XH NMR (400 MHz, CDCI3) 8 8.75 (s, 1H), 8.61 (s, 1H), 7.73 (s, 1H), 7.54 (t, J = 6.1 Hz, 2H), 7.48 - 7.31 (m, 4H), 7.08 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.64 (s, 2H), 5.38 (s, 2H), 3.16 (s, 3H), 3.03 (d, J = 4.8 Hz, 3H).

[0204] Example 16. Synthesis of isopropyl 5-methoxy-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxylate (Compound 27)

[0205] Step 1 : Preparation of 9-(tert-butyl) 3-isopropyl -5-(benzyloxy)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0206] To a solution of isopropyl 5-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (1.0 g, 2.5 mmol) in dichloromethane (100 mL) was add diisopropylamine (0.7 g, 5.1 mmol) and BOC2O (0.7 g, 3.33 mmol). The solution was heated to 60 °C for 3 h. The reaction was partitioned between water and ethyl acetate, washed by water, dried over Na2SO4 and concentrated. The crude product was purified by silica gel column to give the desired product 9-(tert-butyl) 3-isopropyl 5- (benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate as solid (1.0 g).

[0207] Step 2: Preparation of 9-(tert-butyl) 3-isopropyl 5-hydroxy-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0208] To a solution of 9-(tert-butyl) 3-isopropyl 5-(benzyloxy)-4-(methoxymethyl)- 9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (100 mg, 0.2 mmol) in 2 mL of isopropyl alcohol was added 20 mg of Pd(OH)2. The mixture was degassed and purged with H2 gas and stirred for 1 h. The mixture was filtered and concentrated to give the desired product 9-(tert-butyl) 3-isopropyl 5-hydroxy-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3, 9-dicarboxylate as solid (80 mg).

[0209] Step 3 : Preparation of 9-(tert-butyl) 3-isopropyl 5-methoxy-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0210] To a suspension of 9-(tert-butyl) 3-isopropyl 5 -hydroxy -4-(m ethoxymethyl)- 9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (60 mg, 0.14 mmol) and K2CO3 (20 mg) in 1.0 mL dimethylformamide was added iodomethane (30 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h, quenched with water and extracted with ethyl acetate. The organic solvents were concentrated, the residue was purified by silica gel column to give the desired product 9-(tert-butyl) 3-isopropyl 5-methoxy-4- (methoxymethyl)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate as a solid (60 mg).

[0211] Step 4: Preparation of isopropyl 5-methoxy-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate To a solution of 9-(tert-butyl) 3-isopropyl 5-methoxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (60 mg, 0.14 mmol) in 1.0 mL dioxane was added 1.5 ml of HCl / dioxane (4N). The mixture was stirred at room temperature for 1 h, concentrated and the residue was purified by silica gel column to give the desired product isopropyl 5-methoxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylate (35 mg). 'H NMR (400 MHz, CDC13) 8 8.78 (s, 2H), 7.51 (dd, J = 11.3, 4.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.74 (d, J= 8.0 Hz, 1H), 5.52 (s, 2H), 5.37 (m, 1H), 4.08 (s, 3H), 3.39 (s, 3H), 1.46 (d, J = 9.5 Hz, 6H).

[0212] Example 17. Synthesis of isopropyl-4-(methoxymethyl)-6-(pyridin-4-ylmethoxy)-9H- pyrido[3,4-b]indole-3 -carboxylate (Compound 26)

[0213] Step 1 : Preparation of 9-(Ttert-butyl)-3-isopropyl-4-(methoxymethyl)-6- (pyridin-4-ylmethoxy)-9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0214] To a solution of 9-(tert-butyl) 3-isopropyl 6-hydroxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (35 mg, 0.085 mmol) in dimethylformamide (3 mL) were added 4-(chloromethyl)pyridine hydrochloride (28 mg, 0.17 mmol) and cesium carbonate (83 mg, 0.26 mmol) and potassium iodide (3 mg, 0.02 mmol). The mixture was stirred at room temperature for 5 h. Upon completion, the mixture was purified by pre-HPLC (10 mmol / L aq. NH4HCO3) to obtain 9-(tert-butyl) 3-isopropyl 4-(methoxymethyl)-6-(pyridin-4-ylmethoxy)-9H-pyrido[3,4-b]indole-3,9- dicarboxylate as a colorless oil (20 mg). MS (ESI): m / z 506 [M+H]+.

[0215] Step 2: Preparation of isopropyl 4-(methoxymethyl)-6-(pyridin-4-ylmethoxy)~ 9H-pyrido[ 3, 4-b ]indole-3-carboxylate

[0216] A solution of 9-(tert-butyl) 3-isopropyl 4-(methoxymethyl)-6-(pyridin-4- ylmethoxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (15 mg, 0.03 mmol) in dichloromethane (5 mL) and trifluoracetic acid (1 mL) was stirred at room temperature for 2 h. Then the mixture was concentrated and purified by prep-HPLC and gave isopropyl 4-(methoxymethyl)-6-(pyridin-4-ylmethoxy)-9H-pyrido[3,4-b]indole-3- carboxylate as a white solid (9.2 mg). MS (ESI): m / z 406 [M+H]+.1H NMR (400 MHz, CDCI3): 6 8.93 (s, 1H), 8.67 (q, J= 3.2 Hz, 3H), 7.89 (d, J= 2.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.46 (d, J= 6.0 Hz, 2H), 7.35 (q, J= 6.8 Hz, 1H), 5.41 (t, J= 6.4 Hz, 1H), 5.31 (s, 2H), 5.28 (s, 2H), 3.43 (d, 3H), 1.49 (t, 3.6 Hz, 6H).

[0217] Example 18. Synthesis of isopropyl-4-(methoxymethyl)-5-(thiazol-2-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 23)

[0218] Step 1 : Preparation of 9-(tert-butyl)-3-isopropyl-4-(methoxymethyl)-5-(thiazol- 2-ylmethoxy)-9H-pyrido [ 3, 4-b ]indole-3, 9-dicarboxylate

[0219] To a suspension of 9-(tert-butyl) 3-isopropyl 5 -hydroxy -4-(m ethoxymethyl)- 9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (60 mg, 0.14 mmol), CS2CO3 (136.5 mg, 0.42 mmol) and KI (10 mg) in 1.0 mL dimethylformamide was added 2- (chloromethyl)thiazole (27.7 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 h, quenched with water and extracted with ethyl acetate. The organic solvents were concentrated, the residue was purified by silica gel column to give the desired product 9-(tert-butyl) 3-isopropyl 5-methoxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (65 mg).

[0220] Step 2: Preparation of isopropyl 4-(methoxymethyl)-5-(thiazol-2-ylmethoxy)~ 9H-pyrido[ 3, 4-b ]indole-3-carboxylate

[0221] To a solution of 9-(tert-butyl) 3-isopropyl 5-methoxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (65 mg, 0.14 mmol) in 1.0 mL of dioxane was added 1.5 mL HCl / Dioxane (4 N). The mixture was stirred at room temperature for 1 h, concentrated and the residue was purified by silica gel column to give the desired product isopropyl 4-(methoxymethyl)-5-(thiazol-2-ylmethoxy)-9H-pyrido[3,4- b]indole-3 -carboxylate (16 mg).

[0222] Example 19. Synthesis of 4-(methoxymethyl)-7V-propyl-6-(thiazol-2-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 25) Step 1 : Preparation of 4f methoxymethyl) -6 fthiazol-2-y lmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylic acid

[0223] To a mixture of 9-(tert-butyl) 3-isopropyl 4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[3,4-b]indole-3,9-dicarboxylate (60 mg, 0.12 mmol) in methanol (10 mL) was added NaOH (10 mg, 0.24 mmol). The mixture was heated to 80 °C for 2 h. Upon the completion, the solvent was removed and then water (20 mL) was added, HC1 (2 N) solution was added to adjust pH= 5 and then the mixture was extracted with dichloromethane (50 mL). The combined organic solvents were dried and concentrated to give the desired product (40 mg), which was used for next step without further purification. MS (ESI): m / z 370 [M+H]+.

[0224] Step 2: Preparation of 4-(methoxymethyl)-N-propyl-6-(thiazol-2-ylmethoxy)- 9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0225] To a solution of 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9H-pyrido[3,4- b]indole-3 -carboxylic acid (0.03 g, 0.08 mmol) in dimethylformamide (3 mL) were added propan- 1 -amine (14.2 mg, 0.24 mmol), HATU (46 mg, 0.12 mmol) and diisopropylethylamine (46.44 mg, 0.36 mmol). The mixture was stirred at room temperature for 1 h. Upon the completion, the mixture was purified by prep-HPLC and gave 4-(methoxymethyl)-N-propyl-6-(thiazol-2-ylmethoxy)-9H-pyrido[3,4-b]indole- 3-carboxamide as a white solid (24.07 mg). MS (ESI): m / z 411 [M+H]+.JH NMR (400 MHz, CD3OD) 5 8.74 (s, 1H), 7.86 (d, J = 3.2Hz, 1H), 7.83 (d, J = 3.2Hz, 1H), 7.63 (d, J = 3.6Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.37 (dd, Ji = 8.8Hz, J2= 2.4Hz, 1H), 5.52 (s, 2H), 5.28 (s, 2H), 3.47 (s, 3H), 3.41 (t, J = 7.2Hz, 2H), 1.73-1.64 (m, 2H), 1.04-1.0 (t, J = 7.2 Hz, 2H).

[0226] Example 20. Synthesis of 4-(methoxymethyl)-7V-propyl-6-(thiazol-5-ylmethoxy)-9J / - pyrido[3,4-Z>]indole-3 -carboxamide (Compound 24)

[0227] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(thiazol-5- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate To a solution of 9-(tert-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (100 mg, 0.25 mmol) in dimethylformamide (5 mL) were added 5-(chloromethyl)thiazole hydrochloride (64 mg, 0.38 mmol), cesium carbonate (245 mg, 0.75 mmol) and potassium iodide (8 mg, 0.05 mmol). The mixture was stirred at room temperature for 5 h. Upon the completion, the mixture was purified by pre-HPLC (10 mmol / L aq. NH4HCO3) to obtain 9-(tert-butyl) 3-ethyl 4- (methoxymethyl)-6-(thiazol-5-ylmethoxy)-9H-pyrido[3,4-b]indole-3,9-dicarboxylate as a light-yellow oil (100 mg). MS (ESI): m / z 498 [M+H]+.

[0228] Step 2: Preparation of 4-(methoxymethyl)-6-(thiazol-5-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylic acid

[0229] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(thiazol-5- ylmethoxy)-9H-pyrido[3,4-b]indole-3,9-dicarboxylate (100 mg, 0.20 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was added NaOH (200 mg, 1.00 mmol). Then the mixture was stirred at room temperature for 2 h. Upon the completion, the mixture was quenched with 100 mL of water and extracted with ethyl acetate (100 mL). The combined organic solvents were dried and concentrated under reduced pressure and gave 4-(methoxymethyl)-6-(thiazol-5-ylmethoxy)-9H-pyrido[3,4-b]indole-3- carboxylic acid as a yellow oil (70 mg). MS (ESI): m / z 370 [M+H]+.

[0230] Example 21. Synthesis of isopropyl 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 23)

[0231] Step 1 : Preparation of 9 -(tert-butyl) 3-isopropyl 6-(benzyloxy)-4-

[0232] (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0233] To a mixture of 9-(tert-butyl) 3-ethyl 6-(benzyloxy)-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (1.0 g, 2.0 mmol) in toluene (20 mL) was added titanium isopropoxide (5.68 g, 20 mmol) under nitrogen. The mixture was stirred at room temperature for 10 h. Upon the completion, the mixture was quenched with water (100 mL) and ethyl acetate (100 mL), filtered over diatomite to remove the solid and the filtrate was separated. The organic layer was dried and concentrated under reduced pressure to dryness. 9-(Tert-butyl) 3-isopropyl 6-(benzyloxy)-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate was obtained as an off-white solid, which was used directly to next step (940 mg). MS (ESI): m / z 505 [M+H]+.

[0234] Step 2: Preparation of 9-(tert-butyl) 3-isopropyl 6-hydroxy-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0235] To a mixture of 9-(tert-butyl) 3-isopropyl 6-(benzyloxy)-4-(methoxymethyl)- 9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (240 mg, 0.48 mmol) in isopropyl alcohol (20 mL) was added Pd / C (50 mg). The mixture was stirred at room temperature under H2 atmosphere for 2 h. Upon the completion, the mixture was filtered and the filtrate was concentrated to give the title compound as a white solid, which was used for next step without further purification (170 mg). MS (ESI): m / z 415 [M+H]+.

[0236] Step 3 : Preparation of 9-(tert-butyl)-3-isopropyl-4-(methoxymethyl)-6-(thiazol- 2-ylmethoxy)-9H-pyrido [ 3, 4-b ]indole-3, 9-dicarboxylate

[0237] To a solution of 9-(tert-butyl) 3-isopropyl 6-hydroxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (150 mg, 0.36 mmol) in dimethylformamide (60 mL) were added 2-(chloromethyl)thiazole (71.8 mg, 0.54 mmol), cesium carbonate (353 mg, 1.08 mmol) and potassium iodide (12 mg, 0.072 mmol). The mixture was stirred at room temperature for 5 h. Upon the completion, the mixture was purified by prep-HPCL to obtain 9-(tert-butyl) 3-isopropyl 4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate as a colorless oil (130 mg). MS (ESI): m / z 512 [M+H]+.

[0238] Step 4: Preparation of isopropyl 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)- 9H-pyrido[ 3, 4-b ]indole-3-carboxylate

[0239] To a solution of 9-(tert-butyl) 3-isopropyl 4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (50 mg, 0.098 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (30 mL) at 0 °C. Then the mixture was stirred at this temperature for 2 h. Upon the completion, the mixture was concentrated and purified by prep-HPLC and gave isopropyl 4-(methoxymethyl)-6- (thiazol-2-ylmethoxy)-9H-pyrido[3,4-b]indole-3-carboxylate as a white solid (19 mg). MS (ESI): m / z 412 [M+H]+. 'H NMR (400 MHz, CD3OD) 5 8.78 (s, 1H), 7.88-7.89 (d, J = 2.4Hz, 1H), 7.86-7.85 (d, J = 2.4Hz, 1H), 7.66-7.65 (d, J = 2.4Hz, 1H), 7.60-7.58 (d, J = 8.8 Hz, 1H), 7.42-7.40 (dd, Ji = 9.2Hz, J2= 2.4Hz, 1H), 5.55 (s, 2H), 5.37-5.31 (m, 1H), 5.27 (s, 2H), 3.5 (s, 3H), 1.47-1.46 (d, J = 6Hz, 6H). Example 22. Synthesis of 4-(methoxymethyl)-7V-propyl-6-(thiazol-4-ylmethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 21)

[0240] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(thiazol-4- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0241] To a solution of 9-(tert-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (100 mg, 0.25 mmol) in dimethylformamide (3 mL) were added 4-(chloromethyl)thiazole hydrochloride (64 mg, 0.38 mmol), cesium carbonate (245 mg, 0.75 mmol) and potassium iodide (9 mg, 0.05 mmol) at ambient temperature. The mixture was stirred at this temperature for 5 h. Upon the completion, the mixture was purified by prep-HPLC (10 mmol / L aq. NH4HCO3) to obtain 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(thiazol-4-ylmethoxy)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate as a colorless oil (50 mg). MS (ESI): m / z 498 [M+H]+.

[0242] Step 2: Preparation of 4-(methoxymethyl)-6-(thiazol-4-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylic acid

[0243] To a mixture of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(thiazol-4- ylmethoxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (50 mg, 0.10 mmol) in methanol / water (1 : 1, 5 mL) was added NaOH (40 mg, 1.0 mmol). The mixture was heated to 70 °C for 1 h. Upon the completion, the solvent was removed and then water (10 mL) was added. 2 N aq. HC1 was added to adjust pH= 4 and then extracted with dichloromethane (3 x 20 mL). The combined organic solvents were dried and concentrated to give 4-(methoxymethyl)-6-(thiazol-4-ylmethoxy)-9H-pyrido[3,4- b]indole-3 -carboxylic acid as a yellow oil which was used for next step without further purification (38 mg). MS (ESI): m / z 370 [M+H]+.

[0244] Step 3: Preparation of 4-(methoxymethyl)-N-propyl-6-(thiazol-4-ylmethoxy)- 9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0245] To a solution of 4-(methoxymethyl)-6-(thiazol-4-ylmethoxy)-9H-pyrido[3,4- b]indole-3 -carboxylic acid (38 mg, 0.1 mmol) in dimethylformamide (3 mL) were added HATU (76 mg, 0.2 mmol), diisopropylethylamine (44 mg, 0.3 mmol) and propan- 1 -amine (12 mg, 0.2 mmol) in ice bath. The mixture was then stirred at ambient temperature for 2 h. Upon the completion, the mixture was purified by prep-HPLC (10 mmol / L aq. NH4HCO3) to obtain 4-(methoxymethyl)-N-propyl-6-(thiazol-4- ylmethoxy)-9H-pyrido[3,4-b]indole-3 -carboxamide as a white solid (19 mg). MS (ESI): m / z 411 [M+H]+.1H-NMR (400 MHz, CD3OD) 59.06 (d, J = 2.0 Hz, 1 H), 8.75 (s, 1 H), 7.85 (d, J = 2.4 Hz, 1 H), 7.68 (d, J = 1.2 Hz, 1 H), 7.52 (d, J = 9.2 Hz, 1 H), 7.36-7.33 (m, 1 H), 5.39 (s, 2 H), 5.35 (s, 2 H), 3.46 (s, 3 H), 3.40 (t, J = 7.2 Hz, 2 H), 1.72-1.66 (m, 2 H), 1.03 (t, J = 7.2 Hz, 3 H).

[0246] Example 23. Synthesis of 5-(benzyloxy)-4-(methoxymethyl)-7V-propyl-9J / -pyrido[3,4-

[0247] Z>]indole-3 -carboxamide (Compound 20)

[0248] To a solution of 5-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (130 mg, 0.35 mmol), diisopropylethylamine (92 mg, 0.7 mmol) in 2 mL of dimethylformamide were added HATU (204.6 mg, 0.53 mmol) and propan-1- amine (103 mg, 1.75 mmol). The mixture was stirred at room temperature for 2 h, quenched with water (15 mL) and extracted with ethyl acetate (2 x 25 mL). The organic solvents were concentrated, the residue was purified by prep-HPLC to give 5- (benzyloxy)-4-(methoxymethyl)-N-propyl-9H-pyrido[3,4-b]indole-3-carboxamide (5.2 mg). 'H NMR (400 MHz, CD3OD) 5 8.70 (s, 1H), 7.59 (d, J = 7.1 Hz, 2H), 7.51 (t, J = 8.1 Hz, 1H), 7.46 - 7.33 (m, 3H), 7.19 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 5.38 (s, 4H), 3.36 (t, J = 7.1 Hz, 2H), 3.0 (s, 3H), 1.66 (m, 7.3 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0249] Example 24. Synthesis of 5-(benzyloxy)-4-(methoxymethyl)-A,A-dimethyl-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 19)

[0250] To a solution of 5-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (110 mg, 0.31 mmol), diisopropylethylamine (90 mg, 0.62 mmol) in 2 mL of dimethylformamide were added HATU (176.7 mg, 0.46mmol) and dimethylamine (45 mg, 0.93 mmol). The mixture was stirred at room temperature for 2 h, quenched with water and extracted with ethyl acetate. The organic solvents were concentrated, the residue was purified by prep-HPLC to give 5-(benzyloxy)-4- (methoxymethyl)-N,N-dimethyl-9H-pyrido[3,4-b]indole-3-carboxamide (9.5 mg, yield).1H NMR (400 MHz, CD3OD) 5 8.69 (s, 1H), 7.59 (d, J = 7.1 Hz, 2H), 7.53 (t, J = 8.1 Hz, 1H), 7.48 - 7.35 (m, 3H), 7.20 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.34 (m, 4H), 3.12 (s, 3H), 2.94 (s, 3H), 2.78 (s, 3H).

[0251] Example 25. Synthesis of 6-(benzyloxy)-4-(methoxymethyl)-7V-(2,2,2-trifluoroethyl)- 9 J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 18)

[0252] To a lOmL scintillation vial was added 6-(benzyloxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (12 mg, 0.033 mmol) and 2,2,2- triflouroethylamine (4 pL, 0.05 mmol) followed by dimethylformamide (2 mL). To this stirring solution was added l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (8 mg, 0.05 mmol), hydroxybenzotriazole (8 mg, 0.05 mmol), and diisopropylethylamine (18 pL, 0.10 mmol). The reaction mixture was stirred at 50 °C for three hours. Upon completion, as monitored by LCMS, the reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and washed with saturated aqueous brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-8% methanol in dichloromethane followed by a recrystallization in 1 : 1 dichloromethane: hexanes (13 mg) MS (ESI): m / z 444.1 [M+H]+. 'HNMR (CDCh) 8 8.72 (m, 2H), 7.89 (s, 1H), 7.40 (m, 7H), 7.27 (m, 1H), 5.64 (s, 2H), 5.22 (s, 2H), 4.14 (m, 2H), 3.52 (m, 3H).

[0253] Example 26. Synthesis of 6-(benzyloxy)-7V-(3,3-difluorocyclobutyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 17)

[0254] To a 10 mL scintillation vial was added 6-(benzyloxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (12 mg, 0.033 mmol) and 3,3- difluorocyclobutan-1 -amine hydrochloride (8 mg, 0.05 mmol) followed by dimethylformamide (3 mL). To this stirring solution was added l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (8 mg, 0.05 mmol), hydroxybenzotriazole (8 mg, 0.05 mmol), and diisopropylethylamine (28 pL, 0.165 mmol). The reaction mixture was stirred at 50 °C for three hours until all starting material had been consumed as monitored by LCMS. Subsequently, the reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated brine solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The title compound was purified via silica column running 0-8% methanol in dichloromethane (12 mg). MS (ESI): m / z 452.1 [M+H]+.JH NMR (CDCh) 8 9.09 (s, 1H), 8.81 (s, 1H), 8.61 (s, 1H), 7.84 (s, 1H), 7.41 (m, 7H), 5.58 (s, 2H), 5.20 (s, 2H), 4.48 (s, 1H), 3.50 (s, 3H), 3.1 (m, 2H), 2.70 (m, 2H).

[0255] Example 27. Synthesis of 9-(benzyloxy)-l,6-dihydro-3J / -furo[3',4':5,6]pyrido[3,4- Z>]indol-3-one (Compound 16)

[0256] 6-(Benzyloxy)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (15 mg, 0.04 mmol) was dissolved in 3 mL of dichloromethane. To this solution, at room temperature, was added oxalyl chloride (5 pL, 0.04 mmol) dropwise followed by one drop of dimethylformamide (catalytic). After 3 hours, LCMS indicated completion of the reaction. The reaction mixture was concentrated under vacuum. The title compound was purified via silica column chromatography running 0-10% methanol / dichloromethane (9 mg). MS (ESI): m / z 331.1 [M+H]+. 'H NMR (400 MHz, DMSO- tZ6) 8 9.06 (s, 1H), 7.74 (d, 1H, J= 2.55 Hz), 7.67 (d, 1H, J= 8.23 Hz), 7.51 (m, 2H), 7.38 (m, 4H), 5.90 (s, 2H), 5.22 (s, 2H).

[0257] Example 28. Synthesis of 2-(4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9JT- pyrido[3,4-Z>]indol-3-yl)-l,3,4-oxadiazole (Compound 15)

[0258] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0259] To a solution of 9-(tert-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (300 mg, 0.75 mmol) in dimethylformamide (6 mL) were added 2-(chloromethyl)thiazole (150 mg, 1.13 mmol), cesium carbonate (733 mg, 2.25 mmol) and potassium iodide (25 mg, 0.15 mmol) at ambient temperature. The mixture was stirred at this temperature for 5 h. Upon the completion, the mixture was purified by prep-HPLC (10 mmol / L aq. NH4HCO3) to obtain 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9H-pyrido[3,4-b]indole-3,9- dicarboxylate as a colorless oil (200 mg). MS (ESI): m / z 498 [M+H]+.

[0260] Step 2: Preparation of 4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carbohydrazide

[0261] To a mixture of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (180 mg, 0.36 mmol) in butan- l-ol (3 mL) was added hydrazine hydrate (80 % aq. 452 mg, 7.2 mmol) in a sealed tube. The mixture was heated to 150 °C with stirring under microwave for 1 h. Upon the completion, the solvent was removed in vacuo and the residue was triturated with 2- methoxy-2-methylpropane (5 mL) to yield 4-(methoxymethyl)-6-(thiazol-2- ylmethoxy)-9H-pyrido[3,4-b]indole-3 -carbohydrazide as an off-white solid (100 mg). MS (ESI): m / z 384 [M+H]+. Step 3: Preparation of N'-formyl-4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)~ 9H-pyrido[ 3, 4-b ]indole-3-carbohydrazide

[0262] A solution of acetic anhydride (1 mL) and HCOOH (98%, 3 mL) was stirred in ice bath at this temperature for 15 mins. To a mixture of 4-(methoxymethyl)-6-(thiazol- 2-ylmethoxy)-9H-pyrido[3,4-b]indole-3 -carbohydrazide (30 mg, 0.08 mmol) in dichloromethane (3 mL) was added the mixed anhydride above (0.25 mL) in an ice bath. The mixture was stirred at 0 °C for 1 h. Upon the completion, the reaction was quenched with 1 N aq. NaOH (5 mL) and stirred for another 15 min. The off-white solid was collected by filtration and concentrated under reduced pressure to give N'- formyl-4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9H-pyrido[3,4-b]indole-3- carbohydrazide (25 mg). MS (ESI): m / z 412 [M+H]+.

[0263] Step 4: Preparation of 2-(4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9H- pyrido[ 3, 4-b ]indol-3-yl)-l, 3, 4-oxadiazole

[0264] To a solution of N'-formyl-4-(methoxymethyl)-6-(thiazol-2-ylmethoxy)-9H- pyrido[3,4-b]indole-3 -carbohydrazide (25 mg, 0.06 mmol) in toluene (3 mL) was added POCI3 (46 mg, 0.3 mmol). The mixture was heated to 100 °C with stirring for 1 h. Upon the completion, the mixture was evaporated in vacuo and gave the residue which was diluted in dichloromethane (3 mL) and poured into 20 mL of cooled saturated NaHCCh aqueous solution. The mixture was then extracted with di chloromethane (2 x 15 mL). The organic layers were dried and evaporated in vacuo and the resultant residue was purified by prep- HPLC in 10 mmol / L aq. NH4HCO3 to obtain 2-(4-(methoxymethyl)- 6-(thiazol-2-ylmethoxy)-9H-pyrido[3,4-b]indol-3-yl)-l, 3, 4-oxadiazole as a white solid (8 mg, yield). MS (ESI): m / z 394 [M+H]+.1H-NMR (400 MHz, CD3OD+CDCI3) 88.92 (d, J= 8.0 Hz, 1 H), 7.90 (d, J = 2.0 Hz, 1 H), 7.82 (d, J = 3.2 Hz, 1 H), 7.59 (d, J= 9.2 Hz, 1 H), 7.52 (d, J = 3.2 Hz, 1 H), 7.42-7.40 (m, 1 H), 5.54 (s, 2 H), 5.50 (s, 2 H), 3.54 (s, 3 H).

[0265] Example 29. Synthesis of 3-(6-(benzyloxy)-4-(methoxymethyl)-9J7-pyrido[3,4- Z>]indol-3-yl)-5-(trifluoromethyl)-l, 2, 4-oxadiazole (Compound 14) Step 1 : Preparation of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxamide

[0266] To a solution of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (0.5 g, 1.38 mmol), diisopropylethylamine (0.36 g, 2.76 mmol) in dimethylformamide (5 mL) was added HATU (786.6 g, 2.07 mmol) and NH4CI (731.4 mg, 13.8 mmol). The mixture was stirred for 4 h, quenched with water (50 mL), then extracted DCM (3 x 30 mL). The combined organic solvents were washed with brine (50 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography on silica to give 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indol-3 -amine as yellow solid (300 mg). MS (ESI): m / z 334.1 [M+H]+.

[0267] Step 2: Preparation of 6-(Benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3-carbonitrile (Compound 13)

[0268] A solution of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indol-3- amine (180 mg, 0.5 mmol) in POCI3 (1 mL) was heated to reflux for 4 h. The mixture was concentrated and water (20 mL) was added, then the mixture was extracted with di chloromethane (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous ISfeSCU and concentrated under reduced pressure to afford 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3 -carbonitrile (160 mg). MS (ESI): m / z 334.1 [M+H]+. *H NMR (400 MHz, DMSO-t / 6) 8 12.26 (s, 1H), 8.97 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.67 (d, J= 8.9 Hz, 1H), 7.52 (d, J = 7.0 Hz, 2H), 7.47 - 7.30 (m, 4H), 5.24 (s, 2H), 5.11 (s, 2H), 3.41 (s, 3H).

[0269] Step 3 : Preparation of 6-(benzyloxy)-N-hydroxy-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3 carboximidamide

[0270] 8-hydroxyquinoline (1 mg, 0.0042 mmol) was added to a solution of 6- (benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carbonitrile (160 mg, 0.42 mmol) in 10 mL ethanol. To this reaction mixture were added first hydroxylamine hydrochloric acid (59 mg, 0.84 mmol) in water (2 mL) followed by sodium carbonate (56.4 mg, 0.67 mmol) in water (3 mL). The mixture was heated to reflux for 4 h. After removal of ethanol under reduced pressure, the residue was diluted with water, and the aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic solvents were dried over Na2SO4 and concentrated to give 6-(benzyloxy)-N-hydroxy- 4-(methoxymethyl) -9H-pyrido[3,4-b]indole-3 carboximidamide (110 mg). Step 4: Preparation of 3-(6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indol-3-yl)-5-(trifluoromethyl)-l, 2, 4-oxadiazole

[0271] The solution of 6-(benzyloxy)-N-hydroxy-4-(m ethoxymethyl) -9H-pyrido[3,4- b]indole-3 carboximidamide (110 mg, 0.3 mmol) in anhydrous pyridine (2.0 mL) was cooled to 0 °C and trifluoroacetic anhydride (189 mmol, 0.9 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature over 1 h. The reaction mixture was poured into ice-water and adjusted to pH= 4 by addition of 1.5 N HC1. The product was extracted with ethyl acetate (2 x 100 mL) and the combined organic solvents were concentrated under reduced pressure and purified by prep-HPLC to give 3-(6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indol-3-yl)-5- (trifhioromethyl)-l,2,4-oxadiazole (37 mg). 'H NMR (400 MHz, OMSO-ifc) 5 12.03 (s, 1H), 9.02 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.52 (d, J= 7.2 Hz, 2H), 7.39 (m, 4H), 5.25 (s, 2H), 5.15 (s, 2H), 3.36 (s, 3H).

[0272] Example 30. Synthesis of 6-(benzyloxy)-4-(methoxymethyl)-3-(pyridin-4-yl)-9H- pyrido[3,4-b]indole (Compound 12)

[0273] A mixture of 6-(benzyloxy)-3-bromo-4-(methoxymethyl)-9H-pyrido[3,4- b]indole (35 mg, 0.083 mmol), pyri din-3 -ylboronic acid (15 mg, 0.125 mmol), Pd(PPhs)4 (10 mg, 0.0083 mmol) and CS2CO3 (54 mg, 0.166 mmol) in dioxane / H2O (3 mL, 10: 1) was stirred at 110 °C for 5 h under Ar. The reaction was monitored by LCMS. The reaction mixture was quenched with water and was extracted dichloromethane (2 x 25 mL). The organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4.The mixture was concentrated by rotary evaporation under reduced pressure to give a residue. The residue was purified by basic Prep HPLC (FA), and dried on a lyophilizer to give to 6-(benzyloxy)-4-(methoxymethyl)-3-(pyridin-4-yl)-9H- pyrido[3,4-b]indole as yellow solid (12 mg). MS (ESI): m / z 396.1 [M+H]+. 'H NMR (400 MHz, DMSO- f,) b: 11.75 (s, 1 H), d: 8.96 (s, 1 H), 8.70-8.68 (d, 2 H), 7.68-7.63 (m, 4H), 8.04-8.00 (m, 2 H), 7.52-7.43 (d, m, 2H), 7.36 (m, 2 H), 5.24 (s, 2 H), 4.80 (s, 2 H), 3.45 (s, 3 H). Example 31. Synthesis of ethyl 4-(methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole- 3-carboxylate (Compound 11)

[0274] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-4-(methoxymethyl)-6- ((( trifluoromethyl)sulfonyl)oxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0275] To a solution of 9-(tert-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (0.91 g, 2.27 mmol) in di chloromethane (40 mL), was added N,N-dimethylaminopyridine (0.56 g, 4.58 mmol). The mixture was cooled to 0 °C, and a solution of trifluoromethanesulfonic anhydride (0.71 g, 2.52 mmol) in di chloromethane (5 mL) was added dropwise. The mixture was stirred for 2 hours, and LCMS indicated the completion of the reaction. The mixture was diluted with dichloromethane (50 mL) and washed with saturated NaHCCh (25 mL) and brine (25 mL). The organic phase was dried, filtered, and concentrated. The residue was chromatographed on silica gel with hexane: ethyl acetate (4: 1) to give 9-(tert-butyl) 3- ethyl 4-(methoxymethyl)-6-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole- 3, 9-dicarboxylate as a white solid (1.03 g). ESI MS: m / z 533.2

[0276] Step 2: Preparation of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-methyl-9H- pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0277] To a sealed tube, 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6- (((trifhioromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (82 mg), methyl boronic acid (40 mg), K3PO4 (100 mg) and Pd(PPhs)4 (20 mg) and tetrahydrofuran (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC with hexane: ethyl acetate (3 : 1) to give 9- (tert-butyl) 3-ethyl 4-(methoxymethyl)-6-methyl-9H-pyrido[3,4-b]indole-3,9- dicarboxylate (37 mg). ESI-MS: m / z 399.1.

[0278] Step 3 : Preparation of ethyl 4-(methoxymethyl)-6-methyl-9H-pyrido[3,4- b ]indole-3-carboxylate To a solution of 9-(tert-butyl)-3 -ethyl 4-(methoxymethyl)-6-methyl-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (37 mg) in DCM (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LC- MS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCCL, extracted with ethyl acetate. The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate to give ethyl 4-(methoxymethyl)-6-methyl-9H- pyrido[3,4-b]indole-3 -carboxylate as a solid after the trituration with hexane (15 mg). ESI MS: m / z 299.0 (M+l). 'H NMR (400 MHz, CDC13) d: 9.76 (s, 1H), 9.04 (s, 1H), 8.09 (s, 1H), 7.51 (d, 1H, J= 8.32 Hz), 7.43 (d, 1H, J= 8.32 Hz), 5.41 (s, 2H), 4.52 (q, 2H, 7.02 Hz), 3.51 (s, 3H), 2.56 (s, 3H), 1.46 (t, 3H, 7.01 Hz)

[0279] Example 32. Synthesis of ethyl 6-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carboxylate (Compound 10)

[0280] Boc

[0281] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 6-ethyl-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0282] To a sealed tube, 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (91 mg, 0.17 mmol), ethyl boronic acid (51 mg, 0.68 mmol), K3PO4 (HO mg, 0.51 mmol) and Pd(PPh3)4 (20 mg, 0.017 mmol) and THF (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with water (15 mL) and brine (15 mL). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC with hexane: ethyl acetate (3:1) to give 9-(tert-butyl) 3-ethyl 6-ethyl- 4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (39 mg). ESI MS: m / z 413.1 (M+l).

[0283] Step 2: Preparation of ethyl 6-ethyl-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0284] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-ethyl-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (39 mg, 0.095 mmol) in DCM (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LCMS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCO3, extracted with ethyl acetate (50 mL). The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate to give ethyl 6-ethyl-4- (methoxymethyl)-9H-pyrido[3,4-b]indole-3 -carboxylate as a white solid after the trituration with hexane (14 mg). ESI MS: m / z 313.0 (M+l).JH NMR (400 MHz, CDC13) <T 9.23 (s, 1H), 8.14 (s, 1H), 7.59 (d, 1H, J= 8.50 Hz), 7.51 (d, 1H, J= 8.50 Hz), 8.46 (s, 2H), 4.56 (q, 2H, J= 7.10 Hz), 3.53 (s, 3H), 2.88 (q, 2H, J= 7.50 Hz), 1.53 (t, 3H, J= 7.10 Hz), 1.37 (t, 3H, J= 7.50 Hz).

[0285] Example 33. Synthesis of ethyl 6-isopropyl-4-(methoxymethyl)-9J7-pyrido[3,4- Z>]indole-3 -carboxylate (Compound 9)

[0286] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(prop-l-en-2- yl)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0287] To a sealed tube, 9-( / c / 7-butyl) 3-ethyl 4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (95 mg, 0.18 mmol), 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane (50 mg, 0.27 mmol), K3PO4 (120 mg, 0.54 mmol) and Pd(PPh3)4 (30 mg, 0.018 mmol) and THF (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate (50 mL) and washed with water (15 mL) and brine (15 mL). The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC with hexane: ethyl acetate (3: 1) to give 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(prop-l-en-2-yl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (40 mg). ESI MS: m / z 425.1 (M+l).

[0288] Step 2: Preparation of 9 -(tert-butyl) 3-ethyl 6-isopropyl-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0289] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(prop-l-en-2-yl)- 9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (40 mg, 0.094 mmol) in ethyl acetate (15 mL), added palladium / carbon (4 mg, 10% by weight). The mixture was hydrogenated under balloon hydrogen pressure at room temperature until completion. The mixture was filtered through a Celite and washed with ethyl acetate (50 mL). The solvent was removed to give 9-(tert-butyl) 3-ethyl 6-isopropyl-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3,9-dicarboxylate (40 mg). ESI MS: m / z 427.1 (M+l).

[0290] Step 3: Preparation of ethyl 6-isopropyl-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0291] To a solution of 9-(tert-butyl) 3-ethyl 6-isopropyl-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3,9-dicarboxylate (40 mg, 0.094 mmol) in dichloromethane (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LC-MS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCCL, extracted with ethyl acetate (2 x 25 mL). The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate to give ethyl 6-isopropyl-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate as a solid after the trituration with hexane (12 mg). ESI MS: m / z 327.1 (M+l).JH NMR (400 MHz, CDC13) b: 9.83 (s, 1H), 9.12 (s, 1H), 8.17 (s, 1H), 7.55 (m, 2H), 5.44 (s, 2H), 4.54 (q, 2H, J= 7.18 Hz), 3.55 (s, 3H), 3.15 (septet, 1H, J= 6.80 Hz), 1.49 (t, 3H, J= 7.13 Hz), 1.38 (d, 6H, J= 6.80 Hz).

[0292] Example 34. Synthesis of 6-(benzyloxy)-4-(methoxymethyl)-3-(pyridin-2-yl)-9H- pyrido[3,4-b]indole (Compound 8)

[0293] Step 1 : Preparation of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3-carboxylic acid

[0294] Ethyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylate (2 g, 5.1 mmol) was dissolved in MeOH / H2O (30 mL / 8 mL) and NaOH (2 g, 51 mmol) was added. The mixture was stirred at room temperature for 3 h and the reaction was monitored by LCMS. After completion, the aqueous phase was washed with dichloromethane (2 x 30 mL) before acidified with 4 N HC1 until pH<3. The acidified aqueous phase was then extracted with isopropanol / dichloromethane (1 :2) (3 x 100 mL), the organic layers were dried over anhydrous ISfeSC The reaction was concentrated by rotary evaporation under reduced pressure to give 6-(benzyloxy)-4- (methoxymethyl)-9H-pyrido[3,4-b]indole-3 -carboxylic acid (1.3 g). MS (ESI): m / z 363.1 [M+H]+.

[0295] Step 2: Preparation of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indol-3-amine

[0296] To a solution of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylic acid (1.3 g, 3.59 mmol) in dimethylformamide (20 mL) was added triethylamine (1.1 g, 10.77 mmol), DPPA (1.48 g, 5.38 mmol), the mixture was heated to 80 °C and stirred for 4 h then 2-(trimethylsilyl)ethan-l-ol (2.12 g, 17.95 mmol) was added. The reaction mixture was added was quenched with water (50 mL), then was extracted dichloromethane (3 x 30 mL). The organic layers were washed with brine (50 mL) and dried over anhydrous ISfeSC The mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography on silica gel running 0-7% methanol / di chloromethane to give 6- (benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indol-3-amine as a yellow solid (520 mg). MS (ESI): m / z 334.1 [M+H]+.

[0297] Step 3 : Preparation of 6-(benzyloxy)-3-bromo-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ] indole

[0298] 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indol-3 -amine (400 mg, 1.2 mmol) was dissolved in CEhB (16 mL) and CuBr (171 mg, 1.2 mmol), HBr (0.8 mL), H(OCH2CH2)nOH (1.6 mL), isoamyl nitrite (280 mg, 2.4 mmol) were added at -9 °C. The mixture was warmed to room temperature and stirred for 4 h. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography on silica gel running 0-50% ethyl acetate in petroleum ether to give 6-(benzyloxy)-3-bromo-4-(methoxymethyl)-9H-pyrido[3,4- b]indole as a yellow solid (210 mg). MS (ESI): m / z 396.8 [M+H]+.

[0299] Step 4: Preparation of 6-(benzyloxy)-4-(methoxymethyl)-3-(pyridin-2-yl)-9H- pyrido[ 3, 4-b ] indole

[0300] A mixture of 6-(benzyloxy)-3-bromo-4-(methoxymethyl)-9H-pyrido[3,4- b]indole (40 mg, 0.1 mmol), 2-(tributylstannyl)pyridine (56 mg, 0.15 mmol), Pd(PPhs)4 (12 mg, 0.01 mmol), CuCl (20 mg, 0.2 mmol), LiCl (9 mg, 0.2 mmol) in dioxane (3 mL) was stirred at 110 °C for 5 h under Ar. The residue was purified by preparative HPLC (formic acid), and dried on lyophilizer to give the title compound (16 mg). The product was further purified by prep-HPLC (NH4HCO3) and dried on lyophilizer to give 6-(benzyloxy)-4-(methoxymethyl)-3-(pyridin-2-yl)-9H-pyrido[3,4-b]indole as white solid (4.8 mg). MS (ESI): m / z 396.1 [M+H]+. 'H NMR (400 MHz, DMSO-t / 6) d: 8.95 (s, 1 H), 8.78 (d, J= 4.8 Hz, 1 H), d: 8.52 (s, 1 H), 7.91-7.81 (m, 3 H), 7.56- 7.51 (m, 2 H), 7.48 (d, J= 8.8 Hz, 1 H), 7.45-7.40 (m, 2 H), 7.39-7.32 (m, 3 H), 5.24 (s, 2 H), 5.12 (s, 2 H), 3.41 (s, 3 H).

[0301] Example 35. Synthesis of 2-(6-(benzyloxy)-4-(methoxymethyl)-9J7-pyrido[3,4- Z>]indol-3-yl)-5-(trifluoromethyl)-l,3,4-oxadiazole (Compound 7)

[0302] Step 1 : Preparation of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carbohydrazide

[0303] To a solution of ethyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (150 mg, 1.06 mmol) in 1-butanol (2 mL) was added N2H4 (1 mL). The mixture was heated to 80 °C and stirred for 4 h under microwave condition. The reaction was monitored by LCMS. After completion, the mixture was filtered and concentrated to afford 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carbohydrazide as yellow solid. (135 mg). MS (ESI): m / z 377.4 [M+H]+.

[0304] Step 2: Preparation of 6-(benzyloxy)-4-(methoxymethyl)-N'-(2,2,2- trifluoroacetyl)-9H-pyrido[ 3, 4-b ] indole-3 -carbohydrazide

[0305] A solution of 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carbohydrazide (160 mg, 0.425 mmol) in THF (6 mL) was cooled to 0 °C, triethylamine (64 mg, 0.85 mmol), TFAA (267 mg, 1.275 mmol) were added. The mixture was stirred at 0 °C for 2 h, quenched with water (30 mL), then extracted di chloromethane (3 x 20 mL). The combined organic solvents were washed with brine (20 mL), dried over anhydrous ISfeSCU, concentrated by rotary evaporation under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel running 0- 10% methanol in di chloromethane to afford 6-(benzyloxy)-4-(methoxymethyl)-N'- (2, 2, 2-trifluoroacetyl)-9H-pyrido[3,4-b]indole-3 -carbohydrazide as a yellow solid (45 mg). MS (ESI): m / z 473.0 [M+H]+. Step 3 : Preparation of 2-(6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indol-3-yl)-5-(trifluoromethyl)-l, 3, 4-oxadiazole

[0306] To a suspension of 6-(benzyloxy)-4-(methoxymethyl)-N' -(2,2,2- trifluoroacetyl)-9H-pyrido[3,4-b]indole-3 -carbohydrazide (30 mg, 0.064 mmol) in dimethylformamide (2 mL) was added Burgess reagent (227 mg, 0.953 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (30 mL), then was extracted di chloromethane (3 x 15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous ISfeSCU, concentrated by rotary evaporation under reduced pressure to give a residue. The residue was purified by acidic preparative HPLC (formic acid) to give 2-(6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indol-3-yl)-5- (trifluorom ethyl)- 1,3, 4-oxadiazole as white solid (13.3 mg). MS (ESI): m / z 455.0 [M+H]+. ‘H NMR (400 MHz, DMSO-t / 6) b: 12.19 (s, 1 H), 9.05 (s, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 6.8 Hz, 2 H), 7.44-7.33 (m, 4 H), 5.43 (s, 2 H), 5.26 (s, 2 H), 3.42 (s, 3 H).

[0307] Example 36. Synthesis of ethyl 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole- 3-carboxylate (Compound 6)

[0308] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-phenyl-9H- pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0309] To a sealed tube, 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (1 eq), phenyl boronic acid (4 eq), K3PO4 (3 eq) and Pd(PPhs)4 (0.1 eq) and tetrahydrofuran (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC, elution with hexane: ethyl acetate (3: 1) and gave 9-(tert- butyl) 3-ethyl 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3,9- di carb oxy late. Step 2: Preparation of ethyl 4-(methoxymethyl)-6-phenyl-9H-pyrido[3,4- b ]indole-3-carboxylate

[0310] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-phenyl-9JT- pyrido[3,4-Z>]indole-3, 9-dicarboxylate (1 eq) in di chloromethane (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LCMS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCCL, extracted with ethyl acetate. The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate and gave ethyl 4-(methoxymethyl)-6-phenyl-9JT- pyrido[3,4-Z>]indole-3 -carboxylate as a solid after the trituration with hexane.JH NMR (400 MHz, CDC13) b 13.61 (s, 1H), 10.04 (s, 1H), 8.61 (s, 1H), 8.04 (m, 2H), 7.71 (d, 2H, J= 7.85 Hz), 7.52 (m, 2H), 7.41 (m, 1H), 5.64 (s, 2H), 4.69 (q, 2H, J= 7.0 Hz), 3.55 (s, 3H), 1.67 (t, 3H, J= 7.0 Hz).

[0311] Example 37. Synthesis of ethyl 6-((4-fluorobenzyl)oxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 5)

[0312] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-6-((4-fluorobenzyl)oxy)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0313] To a solution of 9-( / c / 7-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-97 / - pyrido[3,4-Z>]indole-3, 9-dicarboxylate (1 eq) and K2CO3 (10 eq) in dimethylformamide (2 mL) was added l-(chloromethyl)-4-fluorobenzene (2 eq). The solution was heated at 55 °C overnight until LCMS shows full conversion to product. The solution was diluted with ethyl acetate (25 mL) and the organic layer was washed with brine (2 x 50 mL). The resultant organic layer was dried over sodium sulfate and concentrated under vacuum to give the title compound.

[0314] Step 2: Preparation of ethyl 6-((4-fluorobenzyl)oxy)-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0315] To a solution of 9-( / c77-butyl) 3-ethyl 6-((4-fluorobenzyl)oxy)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (leq) in dichloromethane (3 mL) was added trifluoroacetic acid (10 eq). The solution was stirred at room temperature for 12 hours until completed as monitored by LCMS. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with di chloromethane (2 x 25 mL) and the resulting organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC with ethyl acetate and gave the title compound ethyl 6-((4-fluorobenzyl)oxy)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate.

[0316] 'H NMR (400 MHz, CDC13) b 10. 90 (s, 1H), 9.39 (s, 1H), 7.89 (s, 1H), 7.65 (d, 1H, J= 8.97 Hz), 7.48 (m, 2H), 7.41 (d, 1H, J= 9.0 Hz), 7.09 (m, 2H), 5.44 (s, 2H), 5.18 (s, 2H), 4.58 (q, 2H, J= 7.12 Hz), 3.47 (s, 3H), 1.55 (t, 3H, J= 7.12)

[0317] Example 38. Synthesis of ethyl 6-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 4)

[0318] Step 1 : Preparation of 9-(tert-butyl)-3-ethyl-6-((3-fluorobenzyl)oxy)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0319] To a solution of 9-( / c / 7-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-97 / - pyrido[3,4-Z>]indole-3, 9-dicarboxylate (1 eq) and K2CO3 (10 eq) in dimethylformamide (2 mL) was added 1 -(chi oromethyl)-3 -fluorobenzene (2 eq). The solution was heated at 55 °C overnight until LCMS shows full conversion to product. The solution was diluted with ethyl acetate (25 mL) and the organic layer was washed with brine (2 x 50 mL). The resultant organic layer was dried over sodium sulfate and concentrated under vacuum.

[0320] Step 2: Preparation of ethyl 6-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0321] To a solution of 9-( / c77-butyl) 3-ethyl 6-((3-fluorobenzyl)oxy)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (1 eq) in di chloromethane (3 mL) was added trifluoroacetic acid (10 eq). The solution was stirred at room temperature for 12 hours until completed as monitored by LCMS. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate until pH=7. The aqueous layer was extracted with dichloromethane (2 x 25 mL) and the resulting organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC with ethyl acetate and gave the title compound ethyl 6-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-97 / -pyrido[3,4- / i]indole-3 -carboxylate.

[0322] 'HNMR (400 MHz, CDCh) d: 12.57 (s, 1H), 9.61 (s, 1H), 7.89 (m, 1H), 7.77 (d, 1H, J= 9.05 Hz), 7.49 (m, 1H), 7.37 (m, 1H), 7.26 (m, 2H), 7.03 (m, 1H), 5.48 (s, 2H), 5.22 (s, 2H), 4.61 (q, 2H, J= 7.11 Hz), 3.46 (s, 3H), 1.58 (t, 3H, J= 7.11 Hz).

[0323] Example 39. Synthesis of ethyl 5-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carboxylate (Compound 3)

[0324] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 5-ethyl-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0325] To a sealed tube, 9-tert-butyl) 3-ethyl 4-(methoxymethyl)-5- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (1 eq), ethyl boronic acid (4 eq), K3PO4 (3 eq) and Pd(PPh3)4 (0.1 eq) and THF (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC with hexane: ethyl acetate (3: 1) to give 9-(terLbutyl) 3-ethyl 5-ethyl- 4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate.

[0326] Step 2: Preparation of ethyl 5-ethyl-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0327] To a solution of 9-( / c / 7-butyl) 3-ethyl 5-ethyl-4-(methoxymethyl)-97 / - pyrido[3,4-Z>]indole-3, 9-dicarboxylate in DCM (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LC-MS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCCh, extracted with ethyl acetate. The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate to give ethyl 5-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carboxylate as a white solid after the trituration with hexane. 'H NMR (400 MHz, CDCh) b 11.92 (s, 1H), 9.37 (s, 1H), 7.61 (m, 2H), 7.29 (m, 1H), 5.29 (s, 2H), 4.56 (q, 2H, J= 7.25 Hz), 3.39 (s, 3H), 3.36 (q, 2H, J= 7.47 Hz), 1.51 (t, 3H, J= 7.25 Hz), 1.42 (t, 3H, J= 7.47 Hz).

[0328] Example 40. Synthesis of ethyl 4-(methoxymethyl)-5-phenyl-9J / -pyrido[3,4-Z>]indole- 3-carboxylate (Compound 2)

[0329] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-phenyl-9H- pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0330] To a sealed tube, 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (1 eq), phenyl boronic acid (4 eq.), K3PO4 (3 eq) and Pd(PPhs)4 (0.1 eq) and THF (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC with hexane: ethyl acetate (3: 1) to give 9-( / c 7-butyl) 3-ethyl 4- (methoxymethyl)-5-phenyl-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate.

[0331] Step 2: Preparation of ethyl 4-(methoxymethyl)-5-phenyl-9H-pyrido[3,4- b ]indole-3-carboxylate

[0332] To a solution of 9-( / c 7-butyl) 3-ethyl 4-(methoxymethyl)-5-phenyl-9JT- pyrido[3,4-Z>]indole-3, 9-dicarboxylate (1 eq) in di chloromethane (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LCMS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCCL, extracted with ethyl acetate. The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC elution with ethyl acetate and gave ethyl 4-(methoxymethyl)-5- phenyl-9J / -pyrido[3,4-Z>]indole-3-carboxylate as a solid after trituration with hexane. ‘H NMR (400 MHz, CDCI3) b 11.17 (s, 1H), 9.16 (s, 1H), 7.67 (m, 2H), 7.48 (m, 5H), 7.23 (d, 1H, J= 6.82 Hz), 4.42 (q, 2H, J= 7.20 Hz), 4.04 (s, 2H), 2.83 (s, 3H), 1.38 (t, 3H, J= 7.20 Hz).

[0333] Example 41. Synthesis of ethyl 5-cyano-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole- 3-carboxylate (Compound 1)

[0334] To a sealed tube, 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (92 mg), Zn(CN)2 (23 mg), and Pd(PPhs)4 (20 mg, 0.1 eq) and DMF (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 90 °C overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate to give ethyl 5-cyano-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate. 'H NMR (400 MHz, CDCh) 8: 11.25 (s, 1H), 9.15 (s, 1H), 7.95 (d, 1H, J= 8.08 Hz), 7.79 (d, 1H, J= 7.22 Hz), 7. 65 (m, 1H), 5.57 (s, 2H), 4.52 (q, 2H, J= 7.11), 3.51 (s, 3H), 1.44 (t, 3H, J= 7.11 Hz).

[0335] Example 42. Synthesis of Ethyl 5-(piperidinyl)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (Compound 44)

[0336] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 5-piperidinyl-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0337] To a sealed tube, 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-3, 9-dicarboxylate (1 eq), piperidine (2 eq), CsCCL (1.5 eq), Pd(CHsCO2)2 (0.10 eq) and BINAP (0.15 eq) and dioxane (4 mL) were added. The mixture was degassed for 5 min. The tube was sealed and heated at 100 °C overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried, filtered, and concentrated. The residue was purified by preparative TLC, elution with hexane: ethyl acetate (3: 1) and gave 9-(tert-butyl) 3-ethyl 5-piperidinyl-4-(methoxymethyl)-9H-pyrido[3,4-b]indole- 3, 9-dicarboxylate. Step 2: Preparation of ethyl 5-(piperidinyl)-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0338] To a solution of 9-(tert-butyl) 3-ethyl 5-piperidinyl-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3,9-dicarboxylate (1 eq) in di chloromethane (5 mL), was added trifluoro acetic acid (0.5 mL). The mixture was stirred at room temperature overnight, and LCMS indicated the completion of the reaction. The solvents were removed. The residue was basified by saturated NaHCCL, extracted with ethyl acetate. The organic phase was washed by brine, dried, filtered, and concentrated. The residue was purified by preparative TLC with ethyl acetate and gave ethyl 4-(methoxymethyl)-5- piperidinyl-9J / -pyrido[3,4-Z>]indole-3 -carboxylate as a solid after the trituration with hexane. 'HNMR (400 MHz, CD3OD) 5: 8.71 (s, 1H), 7.56 (t, 1H, J= 7.9 Hz), 7.31 (d, 1H, J= 7.9 Hz), 7.1 (d, 1H, 7.9 Hz), 6.01 (s, 2H), 4.45 (q, 2H, J= 7.2 Hz), 3.29 (s, 3H), 2.7 (m, 2H), 1.94 (m, 3H), 1.80 (m, 2H), 1.45 (m, 4H), 1.3 (m, 2H).

[0339] Example 43. Synthesis of ethyl 4-(methoxymethyl)-6-(3-methoxyphenyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 45)

[0340] To a stirred mixture of 9-( / c / 7-butyl) 3-ethyl 4-(methoxymethyl)-6-(3- methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (210 mg, 0.43 mmol) in dichloromethane (24 mL) was added trifluoracetic acid (1.4 mL, 17.2 mmol). The solution was stirred for 3 hours at room temperature and then neutralized with saturated aqueous sodium bicarbonate to yield a residue. The resultant residue was washed with water and hexanes, recrystallized in 1 : 1 hexanes: ethyl acetate, and then purified via silica column running 0-7% methanol / dichloromethane to give the title compound ethyl 4-(methoxymethyl)-6-(3-methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (190 mg). MS (ESI): m / z 391.1 [M+H]+. 'H NMR (CD3OD) <5: 9.64 (s, 1H), 8.58 (s, 1H), 7.97 (dd, 1H, J= 1.5, 8.6 Hz), 7.85 (m, 1H), 7.43 (m, 1H), 7.29 (d, 1H, J= 7.9 Hz), 7.24 (m, 1H), 6.94 (dd, 1H, J= 2.5, 7.9 Hz), 5.55 (s, 2H), 4.63 (q, 2H, J= 7.3 Hz), 3.90 (s, 3H), 3.56 (s, 3H), 1.60 (t, 3H, J= 7.3 Hz).

[0341] Example 44. Synthesis of ethyl 4-(methoxymethyl)-6-(2-methoxyphenyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 46)

[0342] To a stirred mixture of 9-(tert-butyl) 3 -ethyl 4-(methoxymethyl)-6-(2- methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (512 mg, 1.04 mmol) in dichloromethane (10 mL) was added trifluoracetic acid (2.8 mL, 36.6 mmol). The solution was stirred for 1.5 hours at room temperature, then neutralized with saturated aqueous sodium bicarbonate and extracted with di chloromethane (3 x 25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-5% methanol / di chloromethane to give the title compound ethyl 4-(methoxymethyl)-6-(2- methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (189 mg). MS (ESI): m / z 391.2 [M+H]+. 'HNMR (CDC13) <5: 9.17 (s, 1H), 8.50 (s, 1H), 7.84 (dd, 1H, J= 1.4, 8.6 Hz), 7.67 (d, 1H, J= 8.6 Hz), 7.44 (dd, 1H, J= 1.4, 7.5 Hz), 7.36 (m, 1H), 7.07 (m, 2H), 5.42 (s, 2H), 4.54 (q, 2H, J= 7.1 Hz), 3.86 (s, 3H), 3.50 (s, 3H), 1.49 (t, 3H, J= 7.1 Hz).

[0343] Example 45. Synthesis of ethyl 6-(4-fluorophenyl)-4-(methoxyrnethyl)-9J / - pyrido[3,4-Z>]indole-3 -carboxylate (Compound 47)

[0344] To a stirred mixture of 9-( / c / 7-butyl) 3 -ethyl 6-(4-fluorophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (340 mg, 0.74 mmol) in dichloromethane (10 mL) was added trifluoracetic acid (1.7 mL, 30 mmol). The solution was stirred for 3 hours at room temperature, neutralized with saturated aqueous sodium bicarbonate, and extracted with dichloromethane (4 x 25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-4% methanol / dichloromethane to give the title compound ethyl 6-(4-fluorophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (236 mg). MS (ESI): m / z 379.1 [M+H]+. 'HNMR (CDCI3) <5: 8.49 (s, 1H), 7.86 (d, 1H, J= 8.9 Hz), 7.75 (d, 1H, J= 8.9 Hz), 7.64 (m, 3H), 7.19 (m, 2H), 5.50 (s, 2H), 4.58 (q, 2H, J= 7.2 Hz), 3.52 (s, 3H), 1.54 (t, 3H, J= 7.2 Hz).

[0345] Example 46. Synthesis of ethyl-6-(4-fluorophenyl)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 48)

[0346] To an oven-dried 20 mL scintillation vial was added 6-(4-fluorophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (10 mg, 0.03 mmol) and HATU (22 mg, 0.06 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (2 mL) and anhydrous DIPEA (21 pL, 0.12 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M ethylamine in tetrahydrofuran (30 pL, 0.06 mmol) was added, and the solution was stirred at room temperature overnight. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (20 mL) and was then washed with brine (2 x 15 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-5% methanol / dichloromethane to yield the title compound N-ethyl-6-(4-fluorophenyl)-4- (methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxamide (6 mg). MS (ESI): m / z 378.1 [M+H]+. 'HNMR (CDC13) 6 8.75 (s, 1H), 8.46 (s, 1H), 7.75 (d, 1H, J= 9.0 Hz), 7.60 (m, 3H), 7.17 (t, 2H, J= 9.0 Hz), 5.73 (s, 2H), 3.58 (s, 3H), 3.54 (q, 2H, J= 6.9 Hz), 1.30 (t, 3H, J= 6.9 Hz).

[0347] Example 47. Synthesis of 6-(4-fluorophenyl)-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 49)

[0348] A solution of 6-(4-fluorophenyl)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole- 3-carboxamide (66 mg, 0.19 mmol) in phosphorus oxychloride (1 mL) was refluxed at 105C for 4 hours and then cooled to room temperature. The reaction mixture was diluted with dichloromethane (20 mL) and then quenched with saturated aqueous sodium bicarbonate. The aqueous was washed with dichloromethane (2 x 25 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-5% methanol / dichloromethane to yield the title compound 6-(4-fluorophenyl)-4-(methoxymethyl)- 9 J / -pyrido[3,4-Z>]indole-3 -carbonitrile (7 mg). MS (ESI): m / z 332.1 [M+H]+. 'H NMR (pyridine-t / s) <5: 9.17 (s, 1H), 8.74 (s, 1H), 7.96 (d, 1H, J= 8.4 Hz), 7.82 (m, 3H), 7.29 (m, 2H), 5.43 (s, 2H), 3.51 (s, 3H).

[0349] Example 48. Synthesis of 9-(4-fluorophenyl)-l,6-dihydro-3JT- furo[3',4':5,6]pyrido[3,4-Z>]indol-3-one (Compound 50)

[0350] A suspension of 6-(4-fluorophenyl)-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxylic acid (35 mg, 0.1 mmol) in dichloromethane (3 mL) was treated with a 2M solution of oxalyl chloride in dichloromethane (100 pL, 0.2 mmol). The reaction mixture was then treated with one drop of dimethylformamide (catalytic). The reaction was stirred overnight at room temperature and refluxed for 2 hours. The reaction was cooled to room temperature, and a precipitate formed. The resultant solid was washed with water and dried to yield the title compound 9-(2-methoxyphenyl)-l,6- dihydro-3J / -furo[3',4':5,6]pyrido[3,4-Z>]indol-3-one (26 mg). MS (ESI): m / z 319.1 [M+H]+. 'H NMR (DMSO- e) <5: 9.13 (s, 1H), 8.37 (s, 1H), 7.95 (d, 1H, J= 8.1 Hz), 7.83 (m, 3H), 7.33 (t, 2H, J= 8.6 Hz), 6.00 (s, 2H).

[0351] Example 49. Synthesis of 6-(4-fluorophenyl)-4-(methoxymethyl)-9J / -pyrido[3,4-

[0352] Z>]indole-3 -carboxylic acid (Compound 51)

[0353] To a 20 mL scintillation vial was added ethyl 6-(4-fluorophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (148 mg, 0.39 mmol) and a 10% (w / w) sodium hydroxide solution in water (5 mL). The reaction mixture was heated at 100 °C for 1 hour. The vessel was then cooled to room temperature and acidified with aqueous 2M hydrochloric acid until a precipitate formed. The solid was filtered over a glass frit to yield the title compound 6-(4-fluorophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid as a bright orange solid (140 mg). MS (ESI): m / z 351.1 [M+H]+. ‘H NMR (DMSO ) <5: 12.38 (s, 1H), 8.97 (s, 1H), 8.45 (s, 1H), 7.94 (dd, 1H, J= 1.9 Hz), 7.79 (m, 3H), 7.34 (m, 2H), 5.42 (s, 2H), 3.37 (s, 3H).

[0354] Example 50. Synthesis of A-ethyl-4-(methoxymethyl)-6-(2-methoxyphenyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 52)

[0355] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6-(2- methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (43 mg, 0.12 mmol) and HATU (92 mg, 0.24 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (2 mL) and anhydrous DIPEA (84 pL, 0.48 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M ethylamine in tetrahydrofuran (180 pL, 0.36 mmol) was added, and the solution was stirred at room temperature for 3 hours. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with brine (2 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via solid load onto a silica column running 0-5% methanol / dichloromethane to yield the title compound N-ethyl-4-(methoxymethyl)-6-(2- methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (19 mg). MS (ESI): m / z 390.2 [M+H]+. ‘H NMR (CDC13) <5: 10.86 (s, 1H), 9.21 (s 1H), 8.41 (s, 1H), 8.30 (m, 1H), 7.82 (m, 1H), 7.66 (d, 1H, J= 8.5 Hz), 7.35 (m, 3H), 7.05 (m, 3H), 5.37 (s, 2H), 3.84 (s, 3H), 3.54 (s, 3H), 1.53 (q, 2H, J= 7.7 Hz), 1.32 (t, 3H, J= 7.7 Hz).

[0356] Example 51. Synthesis of 9-(2-methoxyphenyl)-l,6-dihydro-3JT- furo[3',4':5,6]pyrido[3,4-Z>]indol-3-one (Compound 53)

[0357] A suspension of 4-(methoxymethyl)-6-(2-methoxyphenyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxylic acid (40 mg, 0.11 mmol) in dichloromethane (5 mL) was treated with a 2M solution of oxalyl chloride in dichloromethane (50 pL, 0.55 mmol). The reaction mixture was then treated with one drop of dimethylformamide (catalytic). The reaction was stirred for 1 hour at room temperature and then refluxed for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane to yield the title compound 9-(2-methoxyphenyl)-l,6-dihydro-3JT- furo[3',4':5,6]pyrido[3,4-Z>]indol-3-one (12 mg). MS (ESI): m / z 331.1 [M+H]+.

[0358] Example 52. Synthesis of / ' -ethyl-4-(methoxymethyl)-6-(3-methoxyphenyl)-97 / - pyrido[3,4-Z>]indole-3 -carboxamide (Compound 54)

[0359] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6-(3- methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (20 mg, 0.06 mmol) and HATU (45 mg, 0.18 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (3 mL) and anhydrous DIPEA (47 pL, 0.27 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M ethylamine in tetrahydrofuran (90 uL, 0.18 mmol) was added, and the solution was stirred at room temperature for 3 hours. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (2 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-5% methanol / dichloromethane to yield the title compound N-ethyl-4-(methoxymethyl)-6-(3- methoxyphenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (14 mg). MS (ESI): m / z 390.2 [M+H]+. 'H NMR (CD3OD) 8 12.22 (s, 1H), 8.93 (s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 7.92 (d, 1H, J= 8.8 Hz), 7.74 (d, 1H, J= 8.3 Hz), 7.40 (m, 1H), 7.28 (m, 2H), 6.93 (m, 1H), 5.46 (s, 2H), 3.83 (s, 3H), 3.38 (s, 3H), 1.25 (q, 2H, J= 6.5 Hz), 1.16 (t, 2H, J= 6.5 Hz).

[0360] Example 53. Synthesis of A-ethyl-4-(methoxymethyl)-6-(4-methoxyphenyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 55)

[0361] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6-(4- methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (20 mg, 0.055 mmol) and HATU (41 mg, 0.011 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (3 mL) and anhydrous DIPEA (43 pL, 0.025 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M ethylamine in tetrahydrofuran (90 pL, 0.17 mmol) was added, and the solution was stirred at room temperature for 2 hours. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with brine (3 x 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 50-100% ethyl acetate / hexanes to yield the title compound A-ethyl-4-(methoxymethyl)-6-(4-methoxyphenyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (10 mg). MS (ESI): m / z 390.2 [M+H]+

[0362] Example 54. Synthesis of ethyl 4-(methoxymethyl)-6-(pyridin-2-yl)-9J / -pyrido[3,4- Z>]indole-3 -carboxylate (Compound 56)

[0363] An oven-dried vial containing 9-( / c / 7-butyl) 3 -ethyl 4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (190 mg, 0.38 mmol) and palladium tetrakis (88 mg, 0.076 mmol) was sparged with argon gas and then anhydrous tetrahydrofuran (8 mL) was added. To this solution was added 0.5M 2-pyridyl zinc bromide (0.5 M) in tetrahydrofuran at room temperature. The reaction mixture was then heated at 60 °C for 1.5 hours, at which point LCMS indicated completion. The reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and then washed with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-70% ethyl acetate / hexanes to yield the title compound 9-(te / 7-butyl) 3 -ethyl 4- (methoxymethyl)-6-(pyridin-2-yl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (86 mg). Example 55. Synthesis of 4-(methoxymethyl)-6-(4-methoxyphenyl)-9J7-pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 57)

[0364] Prepared analogous to Example 47. MS (ESI): m / z 344.1 [M+H]+.JH NMR (pyridine-t / s) <5: 13.68 (s, 1H), 9.16 (s, 1H), 8.78 (s, 1H), 8.01 (d, 1H, J= 9.0 Hz), 7.83 (m, 3H), 7.15 (s, 1H), 5.43 (s, 2H), 3.76 (s, 3H), 3.53 (s, 3H).

[0365] Example 56. Synthesis of ethyl 6-(4-cyanophenyl)-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxylate (Compound 58)

[0366] To a stirred mixture of 9-( / c77-butyl) 3-ethyl 6-(4-cyanophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (40 mg, 0.08 mmol) in di chloromethane (2.5 mL) was added trifluoracetic acid (252 pL mL, 3.3 mmol). The solution was stirred for 3 hours and then neutralized with saturated aqueous sodium bicarbonate to yield a solid. The solid was filtered over a glass frit and washed with water and hexanes, yielding the title compound ethyl 6-(4-cyanophenyl)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (20 mg). MS (ESI): m / z 386.1 [M+H]+

[0367] Example 57. Synthesis of 4-(methoxymethyl)-6-(2-methoxyphenyl)-9J / -pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 59)

[0368] A solution of 4-(methoxymethyl)-6-(2-methoxyphenyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (20 mg, 0.06 mmol) in pyridine (1 mL) was cooled to 0 °C and treated with trifluoracetic anhydride (34 pL, 0.24 mmol) dropwise and stirred at 0 °C for 1 hour until full conversion to the title compound as monitored by LC-MS. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 15 mL). The organics were combined and dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-6-(2-methoxyphenyl)-9J / -pyrido[3,4-Z>]indole-3- carbonitrile (17 mg). MS (ESI): m / z 344.2 [M+H]+. 'H NMR (Pyridine-t / s) <5: 10.65 (s, 1H), 10.29 (d, 1H, J= 1.6 Hz), 9.50 (dd, 1H, J= 1.6, 8.5 Hz), 9.28 (dd, 1H, J= 0.6, 8.5 Hz), 9.15 (dd, 1H, J= 1.6, 7.5 Hz), 8.92 (m, 1H), 8.64 (m, 2H), 6.87 (s, 2H), 5.27 (s, 3H), 4.97 (s, 3H).

[0369] Example 58. Synthesis of 4-(methoxymethyl)-6-(pyridin-2-yl)-9J / -pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 60)

[0370] A solution of 4-(methoxymethyl)-6-(pyri din-2 -yl)-9J / -pyrido[3,4-Z>]indole-3- carboxamide (69 mg, 0.21 mmol) in pyridine (2 mL) was cooled to 0 °C and treated with trifluoracetic anhydride (60 pL, 0.42 mmol) dropwise and stirred at 0 °C for 1 hour until complete conversion to the title compound as monitored by LC-MS. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 20 mL). The organics were combined and dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-6% methanol / dichloromethane to yield the title compound 4- (methoxymethyl)-6-(pyridin-2-yl)-9J / -pyrido[3,4-Z>]indole-3-carbonitrile (22 mg). MS (ESI): m / z 314.1 [M+H]+. *H NMR (CD3OD) <5: 8.91 (s, 1H), 8.88 (d, 1H, J= 1.6 Hz), 8.66 (m, 1H), 8.26 (dd, 1H, J= 1.6, 8.6 Hz), 7.94 (m, 2H), 7.76 (d, 1H, J= 8.57 Hz), 7.37 (m, 1H), 5.30 (s, 2H), 3.55 (s, 3H).

[0371] Example 59. Synthesis of ethyl 4-(methoxymethyl)-6-(pyridin-2-yl)-9H-pyrido[3,4- b]indole-3 -carboxylate (Compound 61)

[0372] To a stirred mixture of 9-( / c / 7-butyl) 3-ethyl 4-(methoxymethyl)-6-(pyridin-2- yl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (86 mg, 0.19 mmol) in dichloromethane (5 mL) was added trifluoracetic acid (225 pL mL, 2.85 mmol). The solution was stirred overnight, neutralized with saturated aqueous sodium bicarbonate (15 mL), and extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-7% methanol / dichloromethane to give the title compound ethyl 4-(methoxymethyl)-6-(pyridin-2-yl)-9J / -pyrido[3,4-Z>]indole-3- carboxylate (48 mg). MS (ESI): m / z 181.6, 362.1.

[0373] Example 60. Synthesis of 7V-ethyl-4-(methoxymethyl)-6-(pyridin-2-yl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 62)

[0374] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6- (pyridin-2-yl)-9J / -pyrido[3,4-Z>]indole-3-carboxylic acid (30 mg, 0.045 mmol) and HATU (35 mg, 0.09 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (3 mL) and anhydrous DIPEA (80 uL, 0.45 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M ethylamine in tetrahydrofuran (225 pL, 0.45 mmol) was added and the solution was stirred at room temperature overnight. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (3 x 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane to yield the title compound / ' -ethyl-4-(methoxymethyl)-6-(pyridin-2-yl)-97 / -pyrido[3,4- Z>]indole-3 -carboxamide (18 mg). MS (ESI): m / z 181.1, 361.2 [M+H]+. H NMR

[0375] (CD3OD) <5: 8.87 (d, 1H, J= 1.6 Hz), 8.81 (s, 1H), 8.64 (m, 1H), 8.20 (dd, 1H, J= 1.6, 8.5 Hz), 7.9 (m, 2H), 7.71 (d, 1H, J= 8.5 Hz), 7.35 (m, 1H), 5.53 (s, 2H), 3.52 (s, 3H), 3.49 (q, 2H, J= 7.5 Hz), 1.29 (t, 3H, J= 7.5 Hz).

[0376] Example 61. Synthesis of 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3- carboxamide (Compound 63)

[0377] To a 10 mL scintillation vial was added 4-(methoxymethyl)-6-methyl-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (50 mg, 0.15 mmol), ammonium chloride (16 mg, 0.30 mmol), HOBt (41 mg, 0.30 mmol), EDCI (57 mg, 0.30 mmol) and then dimethylformamide (2 mL). After stirring the solution for 5 minutes, DIPEA (80 pL, 0.45 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (25 mL), and washed with brine (3 x 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane to yield the title compound 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3- carboxamide (29 mg). MS (ESI): m / z 332.1 [M+H]+. 'H NMR (CD3OD) <5: 8.77 (s, 1H), 8.46 (d, 1H, J= 1.6 Hz), 7.84 (dd, 1H, J= 1.6, 8.5 Hz), 7.69 (m, 2H), 7.65 (d, 1H, J= 8.5 Hz), 7.46 (m, 2H), 7.32 (m, 1H), 5.50 (s, 2H), 3.51 (s, 3H),

[0378] Example 62. Synthesis of 4-(methoxymethyl)-A-methyl-6-phenyl-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 64)

[0379] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6- phenyl-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (20 mg, 0.06 mmol) and HATU (46 mg, 0.12 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (3 mL) and anhydrous DIPEA (42 pL, 0.24 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M methylamine in tetrahydrofuran (90 pL, 0.18 mmol) was added, and the solution was stirred at room temperature for 4 hours. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-8% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-N-methyl-6-phenyl- 9H-pyrido[3,4-b]indole-3-carboxamide (19 mg). MS (ESI): m / z 346.2 [M+H]+.JH NMR (CD3OD) 8 8.44 (s, 1H), 8.46 (d, 1H, J= 1.6 Hz), 7.85 (dd, 1H, J= 1.6, 8.4 Hz), 7.69 (m, 2H), 7.64 (d, 1H, J= 8.4 Hz), 7.46 (m ,2H), 7.33 (m, 1H), 5.48 (s, 2H), 3.51 (s, 3H), 2.99 (s, 3H).

[0380] Example 63. Synthesis of 7V-ethyl-4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 65)

[0381] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6- phenyl-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (20 mg, 0.06 mmol) and HATU (46 mg, 0.12 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (3 mL) and anhydrous DIPEA (42 pL, 0.24 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M ethylamine in tetrahydrofuran (90 pL, 0.18 mmol) was added, and the solution was stirred at room temperature for 2.5 hours. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-8% methanol / di chloromethane to yield the title compound / ' / -ethyl-4-(methoxymethyl)-6-phenyl-97 / - pyrido[3,4-Z>]indole-3 -carboxamide (13 mg). MS (ESI): m / z 360.1 [M+H]+. 'H NMR (CD3OD) 8 8.79 (s, 1H), 8.49 (d, 1H, J= 1.6 Hz), 7.87 (dd, 1H, J= 1.6, 8.4 Hz), 7.68 (m, 3H), 7.47 (m, 2H), 7.33 (m, 1H), 5.48 (s, 2H), 3.51 (s, 3H), 3.48 (q, 2H, J= 7.3 Hz), 1.28 (t, 3H, J= 7.3 Hz). Example 64. Synthesis of 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3- carbonitrile (Compound 66)

[0382] A solution of 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3- carboxamide (21 mg, 0.06 mmol) in pyridine (3 mL) was cooled to 0 °C and treated with trifluoracetic anhydride (52 pL, 0.36 mmol) dropwise and stirred at 0 °C for 2 hours until full conversion to the title compound as monitored by LC-MS. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 15 mL). The organics were combined and dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via silica column running 0-5% methanol / dichloromethane to yield the title compound 4- (methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3-carbonitrile (14 mg). MS (ESI): m / z 314.1 [M+H]+. 'H NMR (DMSO-de) <5: 9.02 (s, 1H), 8.45 (s, 1H), 7.95 (dd, 1H, J= 1.8, 8.4 Hz), 7.80 (d, 1H, J= 8.4 Hz), 7.75 (m, 2H), 7.50 (m, 2H), 7.36 (m, 1H), 5.21 (s, 2H), 3.43 (s, 2H).

[0383] Example 65. Synthesis of 4-(methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole-3- carbonitrile (Compound 67)

[0384] A solution of 4-(methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole-3- carboxamide (21 mg, 0.074 mmol) in pyridine (20 mL) was cooled to 0 °C and treated with trifluoracetic anhydride (156.4 pL, 1.11 mmol) dropwise and stirred at 0 °C for 1 hour until full conversion to the title compound as monitored by LC-MS. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 20 mL). The organics were combined and dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4- (methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole-3-carbonitrile (15 mg). MS (ESI): m / z 252.2 [M+H]+. ^NMR fTDsOD) <5: 8.81 (s, 1H), 8.03 (s, 1H), 7.53 (d, 1H, J= 8.4 Hz), 7.47 (dd, 1H, J= 1.6, 8.4 Hz), 5.16 (s, 2H), 3.50 (s, 3H), 2.53, (s, 3H).

[0385] Example 66. Synthesis of 9-phenyl-l,6-dihydro-3J / -furo[3',4':5,6]pyrido[3,4-Z>]indol- 3 -one (Compound 68)

[0386] To a suspension of 4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3- carboxylic acid (20 mg, 0.06 mmol) in dichloromethane (3 mL) was added 2M oxalyl chloride in dichloromethane (26 pL, 0.3 mmol) and one drop of dimethylformamide (catalytic). The reaction mixture was stirred overnight at room temperature. The resultant solid was then filtered over a glass frit to yield the title compound 9-phenyl- l,6-dihydro-3J / -furo[3',4':5,6]pyrido[3,4-Z>]indol-3-one (15 mg). MS (ESI): m / z 301.1 [M+H]+.1HNMR (DMSO-6) <5: 9.13 (s, 1H), 8.39 (s, 1H), 7.97 (dd, 1H, J= 1.7, 8.6 Hz), 7.82 (m, 3H), 7.50 (m, 2H), 7.37 (m, 2H), 6.02 (s, 2H).

[0387] Example 67. Synthesis of 4-(methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole-3- carboxamide (Compound 69)

[0388] To a 10 mL scintillation vial was added 4-(methoxymethyl)-6-methyl-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (35 mg, 0.13 mmol), ammonium chloride (15 mg, 0.26 mmol), HOBt (35 mg, 0.26 mmol), EDCI (50 mg, 0.26 mmol) and then dimethylformamide (2 mL). After stirring the solution for 5 minutes, DIPEA (68 pL, 0.39 mmol) was added. The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (25 mL), and washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane to yield the title compound 4-(methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole-3- carboxamide (30 mg). MS (ESI): m / z 270.2 [M+H]+*HNMR (CD3OD) <5: 8.72 (s, 1H), 8.02 (s, 1H), 7.46 (d, 1H, J= 8.3 Hz), 7.39 (m, 1H), 5.44 (s, 2H), 3.49 (s, 3H), 2.51 (s, 3H).

[0389] Example 68. Synthesis of 9-methyl-l,6-dihydro-3J / -furo[3',4':5,6]pyrido[3,4-Z>]indol- 3 -one (Compound 70)

[0390] A suspension of 4-(methoxymethyl)-6-methyl-9J / -pyrido[3,4-Z>]indole-3- carboxylic acid (13 mg, 0.05 mmol) in dichloromethane (2 mL) was treated with a 2M solution of oxalyl chloride in dichloromethane (170 pL, 0.34 mmol). The reaction mixture was then treated with 1 drop of dimethylformamide (catalytic). The reaction was stirred for two hours at room temperature, diluted with di chloromethane, and neutralized with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2 x 25 mL), and then the organics were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was recrystallized in 100% methanol to yield the title compound 9-methyl-l,6- dihydro-3J / -furo[3',4':5,6]pyrido[3,4-Z>]indol-3-one (10 mg). MS (ESI): m / z 239.1 [M+H]+. 'H NMR (CD3OD) <5: 9.21 (s, 1H), 8.02 (s, 1H), 7.72 (d, 1H, J= 8.1 Hz), 7.66 (d, 1H, J= 8.1 Hz), 6 ,01( s, 2H), 2.59 (s, 3H).

[0391] Example 69. Synthesis of 9-isopropyl-l,6-dihydro-3J / -furo[3',4':5,6]pyrido[3,4- Z>]indol-3-one (Compound 71)

[0392] A suspension of 6-isopropyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carboxylic acid (20 mg, 0.067 mmol) in dichloromethane (2 mL) was treated with a 2M solution of oxalyl chloride in dichloromethane (230 pL, 0.47 mmol). The reaction mixture was then treated with 1 drop of dimethylformamide (catalytic). The reaction was stirred overnight at room temperature, diluted with dichloromethane, and neutralized with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2 x 25 mL), and then the organics were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was recrystallized in 100% methanol to yield the title compound 9-isopropyl- l ,6-dihydro-3 / / -furo[3',4':5,6]pyrido[3,4-A]indol-3-one (12 mg). MS (ESI): m / z 267.1 [M+H]+. 'H NMR (CD3OD) <5: 8.99 (s, 1H), 7.92 (s, 1H), 7.63 (m, 2H), 5.90 (s, 2H), 3.15 (sextet, 1H, J= 6.9 Hz), 1.37 (d, 6H, J= 6.9 Hz).

[0393] Example 70. Synthesis of 6-isopropyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carbonitrile (Compound 72)

[0394] To a stirred solution of 6-isopropyl-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (17 mg, 0.057 mmol) in pyridine (1.5 mL) at 0 °C was added trifluoracetic anhydride (80 pL, 0.57 mmol) dropwise. After 2 hours of stirring at 0 °C, the reaction was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-3% methanol / dichloromethane to yield the title compound 6-isopropyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3-carbonitrile (12 mg). MS (ESI): m / z 280.1 [M+H]+. 'H NMR (CD3OD) <5: 8.80 (s, 1H), 8.08 (s, 1H), 7.56 (s, 2H), 5.14 (s, 2H), 3.53 (s, 3H), 3.11 (sextet, 1H, J= 6.9 Hz), 1.36 (d, 6H, J= 6.9 Hz).

[0395] Example 71. Synthesis of 6-isopropyl-4-(methoxymethyl)-7V-methyl-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 73)

[0396] To an oven-dried 20 mL scintillation vial was added 6-isopropyl-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (25 mg, 0.08 mmol) and HATU (61 mg, 0.16 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (4 mL) and anhydrous DIPEA (56 pL, 0.32 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M methylamine in tetrahydrofuran (125 pL, 0.25 mmol) was added, and the solution was stirred at room temperature overnight. LCMS indicated reaction completion. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-7% methanol / dichloromethane to yield the title compound 6-isopropyl-4-(methoxymethyl)-7V- methyl-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (16 mg). MS (ESI): m / z 312.2 [M+H]+. 'H NMR (CD3OD) <5: 8.73 (s, 1H), 8.10 (s, 1H), 7.50 (m ,2H), 5.44 (s, 2H), 3.53 (s, 3H), 3.10 (sextet, 1H, J= 6.9 Hz), 2.98 (s, 3H), 1.36 (d, 6H, J= 6.9 Hz).

[0397] Example 72. Synthesis of A-methoxy-4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4- Z>]indole-3 -carboxamide (Compound 74)

[0398] To a 20 mL scintillation vial was added 4-(methoxymethyl)-6-phenyl-9JT- pyrido[3,4-Z>]indole-3 -carboxylic acid (90 mg, 0.27 mmol), triethylamine (150 pL, 1.08 mmol), HATU (103 mg, 0.27 mmol) and dimethylformamide (2.5 mL). The reaction mixture was stirred at room temperature overnight. Upon reaction completion, the solution was diluted with water (18 mL) and stirred for 1 hour. The resultant precipitate was isolated via vacuum filtration and purified via a silica column running 0-25% methanol + 0.1% ammonium hydroxide / dichloromethane to yield the title compound 7V-methoxy-4-(methoxymethyl)-6-phenyl-9J / -pyrido[3,4-Z>]indole-3-carboxamide (32 mg). MS (ESI): m / z 362.2 [M+H]+. 'H NMR (CDCI3) <5: 9.99 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 7.67 (d, 1H, J= 8.2 Hz), 7.56 (m, 2H), 7.47 (d, 1H, J= 8.2 Hz), 7.42 (m, 2H), 7.34 (m, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.53 (s, 3H).

[0399] Example 73. Synthesis of 4-(methoxymethyl)-6-(U / -pyrazol-4-yl)-9J7-pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 75)

[0400] To a 15 mL seal tube was added tert-butyl 3-cyano-4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9-carboxylate (80 mg, 0.16 mmol), (U / -pyrazol-4-yl)boronic acid (159 mg, 0.82 mmol), tripotassium phosphate (135 mg, 0.64 mmol), palladium tetrakis (20 mg, 0.016 mmol), and 7 mL of 4: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was suspended in di chloromethane where the title compound 4-(methoxymethyl)-6-(l -methyl- 1H- pyrazol-4-yl)-9J / -pyrido[3,4-Z>]indole-3 -carbonitrile (25 mg) precipitated as a brown solid. MS (ESI): m / z 304.1 [M+H]+. 'H NMR (CD3OD) 8 8.98 (s, 1H), 8.33 (s, 1H), 8.09 (s, 2H), 7.89 (dd, 1H, J= 1.6, 8.5 Hz), 7. 69 (d, 1H, J= 8.5 Hz), 5.19 (s, 2H), 3.49 (s, 3H).

[0401] Example 74. Synthesis of 6-(2-(dimethylamino)ethoxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 76)

[0402] To a stirred mixture of tert-butyl 3-cyano-6-(2-(dimethylamino)ethoxy)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (22 mg, 0.052 mmol) in dichloromethane (5 mL) was added trifluoracetic acid (200 pL, 2.5 mmol). The solution was stirred for 3 hours, then neutralized with saturated aqueous sodium bicarbonate (5 mL), and extracted with dichloromethane (2 x 25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was recrystallized in 1 : 1 methanol: di chloromethane to yield the title compound 6-(2-(dimethylamino)ethoxy)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-

[0403] 3 -carbonitrile (10 mg). MS (ESI): m / z 325.1 [M+H]+. 'H NMR (CD3OD) <5: 8.99 (s, 1H), 7.71 (d, 1H, J= 2.4 Hz), 7.60 (d, 1H, J= 8.7 Hz), 7.27 (dd, 1H, J= 2.4, 8.7 Hz), 5.17 (s, 2H), 4.63 (t, 2H, J= 7.0 Hz), 3.53 (s, 3H), 2.79 (t, 2H), 2.33 (s, 6H), 2.15 (s,

[0404] 3H).

[0405] Example 75. Synthesis of ethyl 4-(methoxymethyl)-6-(U7-pyrazol-4-yl)-9J7- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 77)

[0406] To a stirred mixture of 9-(tert-butyl) 3 -ethyl 4-(methoxymethyl)-6-(UT- pyrazol-4-yl)-9J / -pyrido[3,4-Z>]indole-3,9-dicarboxylate (100 mg, 0.23 mmol) in dichloromethane (10 mL) was added trifluoracetic acid (874 pL, 11.5 mmol). The solution was stirred overnight, neutralized with saturated aqueous sodium bicarbonate (15 mL), and extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was resuspended in DCM, and the title compound ethyl 4- (methoxymethyl)-6-(U7-pyrazol-4-yl)-9J / -pyrido[3,4-Z>]indole-3-carboxylate precipitated out at as bright orange crystals (77 mg). MS (ESI): m / z 176.1, 351.2 [M+H]+. 'H NMR (CD3OD) <5: 8.95 (s, 1H), 8.51 (s, 1H), 8.06 (s, 2H), 7.99 (d, 1H, J= 8.8 Hz), 7.75 (d, 1H, J= 8.8 Hz), 5.5 (s, 2H), 4.57 (q, 2H, J= 7.2 Hz), 3.57 (s, 3H), 1.5 (t, 3H, J= 7.2 Hz).

[0407] Example 76. Synthesis of 4-(methoxymethyl)-6-(l-methyl-l,2,3,6-tetrahydropyridin- 4-yl)-9J / -pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 78)

[0408] To a 15 mL seal tube was added tert-butyl 3-cyano-4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9-carboxylate (100 mg, 0.21 mmol), (l-methyl-l,2,3,6-tetrahydropyridin-4-yl)boronic acid (229 mg, 1.03 mmol), tripotassium phosphate (179 mg, 0.84 mmol), palladium tetrakis (25 mg, 0.021 mmol), and 7 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-6-(l -methyl- 1, 2,3,6- tetrahydropyridin-4-yl)-97 / -pyrido[3,4- / i]indole-3-carbonitrile (35 mg). MS (ESI): m / z 333.1 [M+H]+. 'H NMR (CD3OD) <5: 8.89 (s, 1H), 8.34 (s, 1H), 7.83 (dd, 1H, J= 1.8, 8.6 Hz), 7.65 (d, 1H, J= 8.6 Hz), 6. 23(m, 1H), 5.24 (s, 2H), 3.63 (m, 2H), 3.52 (s, 3H), 3.24 (t, 2H, J= 6.2 Hz), 2.92 (m, 2H), 2.76 (s, 3H).

[0409] Example 77. Synthesis of 4-(methoxymethyl)-6-(l -methyl- lf / -pyrazol-4-yl)-9ZZ- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 79)

[0410] To a 15 mL seal tube was added tert-butyl 3-cyano-4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9-carboxylate (60 mg, 0.12 mmol), (1 -methyl- IT / -pyrazol-4-yl)boronic acid (129 mg, 0.62 mmol), tripotassium phosphate (102 mg, 0.48 mmol), palladium tetrakis (28 mg, 0.024 mmol), and 7 mL of 4: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4- (methoxymethyl)-6-(l -methyl- l / / -pyrazol-4-yl)-9Z / -pyrido[3,4-Z>]indole-3- carbonitrile (33 mg). MS (ESI): m / z 318.1 [M+H]+. 'H NMR. (CD3OD) <5: 8.87 (s, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.85 (dd, 1H, J= 1.6, 8.5 Hz), 7.65 (d, 1H, J= 8.6 Hz), 5.25 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H).

[0411] Example 78. Synthesis of 4-(methoxymethyl)-7V-methyl-6-(lZ / -pyrazol-4-yl)-9Z7- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 80)

[0412] To a 15 mL seal tube was added tert-butyl 4-(methoxymethyl)-3- (methylcarbamoyl)-6-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9- carboxylate (57 mg, 0.14 mmol), (17 / -pyrazol-4-yl)boronic acid (134 mg, 0.69 mmol), tripotassium phosphate (119 mg, 0.56 mmol), palladium tetrakis (15 mg, 0.014 mmol), and 7 mL of 4: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-7V-methyl-6-(177-pyrazol-4-yl)-977-pyrido[3,4- Z>]indole-3 -carboxamide (22 mg). MS (ESI): m / z 336.1 [M+H]+. *H NMR (CD3OD) <5: 8.77 (s, 1H), 8.43 (s, 1H), 7.99 (s, 2H), 7.82 (dd, 1H, J= 1.6, 8.4 Hz), 7.61 (d, 1H, J= 8.5 Hz), 5.55 (s, 2H), 3.53 (s, 3H), 2.99 (s, 3H).

[0413] Example 79. Synthesis of 4-(methoxymethyl)-7V-methyl-6-(l -methyl- IT / -pyrazol -4- yl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 81)

[0414] To a 15 mL seal tube was added tert-butyl 4-(methoxymethyl)-3- (methylcarbamoyl)-6-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9- carboxylate (54 mg, 0.15 mmol), (1 -methyl- IT / -pyrazol-4-yl)boronic acid (135 mg, 0.65 mmol), tripotassium phosphate (110 mg, 0.52 mmol), palladium tetrakis (15 mg, 0.013 mmol), and 7 mL of 4: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with water (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane to yield the title compound 4-(methoxymethyl)-7V-methyl-6-(l -methyl- lJT-pyrazol-4-yl)- 9J / -pyrido[3,4-Z>]indole-3 -carboxamide (18 mg). MS (ESI): m / z 350.1 [M+H]+.JH NMR (CD3OD) <5: 8.77 (s, 1H), 8.39 (d, 1H, J= 1.5 Hz), 7.97 (s, 1H), 7.85 (s, 1H), 7.78 (dd, 1H, J= 1.5, 8.5), 7.59 (d, 1H, J= 8.5 Hz), 5.55 (s, 2H), 3.96 (s, 3H), 3.52 (s, 3H), 2.99 (s, 3H).

[0415] Example 80. Synthesis of A-ethyl-4-(methoxymethyl)-6-(l-methylpiperidin-4-yl)-9J7- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 82)

[0416] A solution of ethyl 4-(methoxymethyl)-6-(l-methyl-l,2,3,6-tetrahydropyridin- 4-yl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (75 mg, 0.2 mmol) in methanol (10 mL) was sparged with argon gas for 15 minutes and then Pd / C (10 mg, 15% by weight) was added. The solution was then sparged with H2 gas (balloon pressure) and stirred for 2 hours. LC-MS indicated full conversion to the product species. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated under vacuum to yield the title compound 7V-ethyl-4-(methoxymethyl)-6-(l-methylpiperidin-4-yl)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (69 mg). MS (ESI): m / z 191.6, 382.2 [M+H]+. 'H NMR (CD3OD) <5: 8.77 (s, 1H), 8.15 (s, 1H), 7.56 (m, 2H), 5.33 (s, 2H), 4.47 (q, 2H, J= 7.4 Hz), 3.52 (s, 3H), 3.11 (m, 2H), 2.78 (m, 1H), 2.42 (s, 3H), 2.33 (m, 2H), 1.96 (m, 4H), 1.45 (t, 3H, J= 7.4 Hz).

[0417] Example 81. Synthesis of 4-(methoxymethyl)-7V-methyl-6-(l-methylpiperidin-4-yl)- 9J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 83) Step 1 : Preparation of 4-(methoxymethyl)-6-(l-methylpiperidin-4-yl)-9H- pyrido[ 3, 4-b ]indole-3-carboxylic acid

[0418] To a 20 mL scintillation vial was added ethyl 4-(methoxymethyl)-6-(l- methylpiperidin-4-yl)-9J7-pyrido[3,4-Z>]indole-3 -carboxylate (56 mg, 0.15 mmol) and a 10% (w / w) sodium hydroxide solution in water (2 mL). The reaction mixture was heated at 100 °C for 3 hours. The vessel was then cooled to room temperature and acidified with aqueous 2M hydrochloric acid. The entire reaction mixture was then concentrated under vacuum and moved directly to the next step as a crude residue.

[0419] Step 2: Preparation of 4-(methoxymethyl)-N-methyl-6-(l-methylpiperidin-4- yl)-9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0420] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6-(l- methylpiperidin-4-yl)-9J7-pyrido[3,4-Z>]indole-3 -carboxylic acid (50 mg, 0.15 mmol) and HATU (114 mg, 0.30 mmol). The vessel was purged with argon gas and then anhydrous dimethylformamide (3 mL) and anhydrous DIPEA (132 pL, 0.75 mmol) were added and the reaction mixture was stirred 5 minutes. Next, 2M methylamine in tetrahydrofuran (225 pL, 0.45 mmol) was added and the solution was stirred at room temperature for 1 hour. Reaction completion was indicated by LCMS. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via basic alumina column running 0-10% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-A-methyl- 6-(l-methylpiperidin-4-yl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (13 mg). MS (ESI): m / z 184.1 [M+H]+. 'H NMR (CD3OD) <5: 8.76 (s, 1H), 8.14 (s, 1H), 7.53 (m, 2H), 5.46 (s, 2H), 3.52 (s, 3H).

[0421] Example 82. Synthesis of 6-cyclohexyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole- 3 -carbonitrile (Compound 84)

[0422] A solution of 6-(cyclohex-l-en-l-yl)-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carbonitrile (67 mg, 0.21 mmol) in methanol (10 mL) was sparged with argon gas for 15 minutes and then Pd / C (17 mg, 25% by weight) was added. The solution was then sparged with H2 gas (balloon pressure) and stirred for 1 week. LC- MS indicated full conversion to the product species. The reaction mixture was filtered over a pad of celite and the filtrate was concentrated under vacuum. The resultant residue was then purified via a silica column running 0-50% ethyl acetate / hexanes to yield the title compound 6-cyclohexyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carbonitrile (9 mg). 'HNMR (CD3OD) 8 8.84 (s, 1H), 8.11 (s, 1H), 7.57 (m, 2H), 5.21 (s, 2H), 3.55 (s, 3H), 1.89 (m, 8H). MS (ESI): m / z 320.2 [M+H]+

[0423] Example 83. Synthesis of 4-(methoxymethyl)-7V-methyl-6-(2-morpholinoethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 85)

[0424] To an oven-dried 20 mL scintillation vial was added 4-(methoxymethyl)-6-(2- morpholinoethoxy)-9J / -pyrido[3,4-Z>]indole-3 -carboxylic acid (65 mg, 0.17 mmol) and HATU (160 mg, 0.42 mmol). The vessel was purged with argon gas, and then anhydrous dimethylformamide (4 mL) and anhydrous DIPEA (146 pL, 0.85 mmol) were added, and the reaction mixture was stirred for 5 minutes. Next, 2M methylamine in tetrahydrofuran (5.1 mL, 10.2 mmol) was added, and the solution was stirred at room temperature for 4 hours. Reaction completion was indicated by LCMS. The reaction mixture was diluted with ethyl acetate (25 mL) and was then washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-A-methyl- 6-(2-morpholinoethoxy)-9J / -pyrido[3,4-Z>]indole-3-carboxamide (3 mg). MS (ESI): m / z 200.1, 399.2 [M+H]+. 'H NMR (CD3OD) 8 8.74 (s, 1H), 7.8 (d, 1H, J= 2.6 Hz), 7.51 (d, 1H, J= 8.7 Hz), 7.28 (dd, 1H, J= 2.6, 8.7), 5.45 (s, 2H), 4.27 (t, 2H, J= 5.5 Hz), 3.74 (m, 4H), 3.49 (s, 3H), 2.98 (s, 3H), 2.89 (m, 3H), 2.67 (m, 3H).

[0425] Example 84. Synthesis of 4-(methoxymethyl)-6-(tetrahydro-2J / -pyran-4-yl)-9JT- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 86)

[0426] A solution of 6-(3,6-dihydro-2Z / -pyran-4-yl)-4-(rnethoxyrnethyl)-9J / - pyrido[3,4-Z>]indole-3 -carbonitrile (20 mg, 0.062 mmol) in dimethylformamide (3 mL) was sparged with argon gas for 15 minutes and then Pd / C (5 mg, 25% by weight) was added. The solution was then sparged with H2 gas (balloon pressure) and stirred for 1 hour. LC-MS indicated full conversion to the product species. The reaction mixture was filtered over a pad of celite, and the filtrate was diluted with ethyl acetate (25 mL) and washed with water (2 x 100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was then purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4- (methoxymethyl)- / ' / -methyl-6-(tetrahydro-27 / -pyran-4-yl)-97 / -pyrido[3,4- / i]indole-3- carboxamide (10 mg). MS (ESI): m / z 322.1 [M+H]+. ^NMR CDCh) <5: 8.90 (s, 1H), 8.73 (s, 1H), 8.16 (s, 1H), 7.55 (m, 2H), 5.25 (s, 2H), 4.15 (m, 2H), 3.61 (m, 2H), 3.55 (s, 3H), 2.99 (m, 1H), 1.92 (m, 4H),

[0427] Example 85. Synthesis of 4-(methoxymethyl)- / ' / -methyl-6-(tetrahydro-27 / -pyran-4- yl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 87)

[0428] A solution of 6-(3,6-dihydro-2J / -pyran-4-yl)-4-(methoxymethyl)-A-methyl- 9 J / -pyrido[3,4-Z>]indole-3 -carboxamide (39 mg, 0.11 mmol) in dimethylformamide (5 mL) was sparged with argon gas for 15 minutes and then Pd / C (14 mg, 35% by weight) was added. The solution was then sparged with H2 gas (balloon pressure) and stirred for 1 day. LC-MS indicated full conversion to the product species. The reaction mixture was filtered over a pad of celite and the filtrate was diluted with ethyl acetate (25 mL) and washed with water (2 x 100 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was then purified via a silica column running 0-6% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-7V-methyl-6-(tetrahydro-277-pyran-4-yl)-977-pyrido[3,4-Z>]indole- 3-carboxamide (18 mg). MS (ESI): m / z 354.2 [M+H]+. 'H NMR (CDCh) <5: 8.69 (s, 1H), 8.58 (s, 1H), 8.18 (s, 2H), 7.47 (2H), 5.77 (s, 2H), 4.14 (m, 2H), 3.60 (m, 5H), 3.05 (d, 3H, J= 5.1 Hz), 1.92 (m, 2H), 1.57 (s, 1H).

[0429] Example 86. Synthesis of ethyl 6-(2-(dimethylamino)ethoxy)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 88)

[0430] Step 1 : Preparation of 9 -(tert-butyl) 3-ethyl 6-(2-(dimethylamino)ethoxy)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0431] To a solution of 9-( / c / 7-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-97 / - pyrido[3,4-Z>]indole-3, 9-dicarboxylate (100 mg, 0.25 mmol) and potassium carbonate (207 mg, 1.5 mmol) in dimethylacetamide (4 mL) was added 2-chloro-7V,7V- dimethylethan-1 -amine (144 mg, 1 mmol) at room temperature. The mixture was heated at 75C overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (3 x 25 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 9-( / c77-butyl) 3-ethyl 6-(2-(dimethylamino)ethoxy)-4-(methoxymethyl)- 9 J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (76 mg).

[0432] Step 2: Preparation of ethyl 6-(2-(dimethylamino)ethoxy)-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3-carboxylate

[0433] To a stirred mixture of 9-( / c77-butyl) 3-ethyl 6-(2-(dimethylamino)ethoxy)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (76 mg, 0.16 mmol) in dichloromethane (5 mL) was added trifluoracetic acid (613 pL, 8.07 mmol). The solution was stirred for 3 hours and then neutralized with saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane (2 x 25 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-9% methanol / dichloromethane to give the title compound ethyl 6-(2-(dimethylamino)ethoxy)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxylate (50 mg). MS (ESI): m / z 186.6, 372.2 [M+H]+. 'H NMR (CDCh) 6 8.89 (s, 1H), 8.67 (s, 1H), 7.83 (d, 1H, J= 2.5 Hz), 7.43 (d, 1H, J= 8.8 Hz), 7.26 (dd, 1H, J= 2.5, 8.8 Hz), 5.36 (s, 2H), 4.51 (q, 2H, J= 6.6 Hz), 4.22 (t, 2H, J= 5.6 Hz), 3.51 (s, 3H), 2.83 (t, 2H, J= 5.6 Hz), 2.39 (s, 6H), 1.47 (t, 3H, 6.6 Hz).

[0434] Example 87. Synthesis of 6-(3,6-dihydro-2J / -pyran-4-yl)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 89)

[0435] To a 15 mL seal tube was added tert-butyl 3-cyano-4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9-carboxylate (87 mg, 0.18 mmol), (3,6-dihydro-2J / -pyran-4-yl)boronic acid (187 mg, 0.89 mmol), tripotassium phosphate (153 mg, 0.72 mmol), palladium tetrakis (21 mg, 0.018 mmol), and 7 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via silica column running 0-7% methanol / dichloromethane followed by a silica column running 0-60% ethyl acetate / hexanes to yield the title compound 6-(3,6-dihydro-2J / -pyran-4-yl)-4-(methoxymethyl)-9J / -pyrido[3,4- Z>]indole-3 -carbonitrile (23 mg). MS (ESI): m / z 320.1 [M+H]+. ' H NMR (CDCh) <5: 8.91 (s, 1H), 8.64 (s, 1H), 8.32 (s, 1H), 7.74 (dd, 1H, J= 1.9, 8.8 Hz), 7.55 (d, 1H, J= 8.8 Hz), 6.22 (m, 1H), 5.25 (s, 2H), 4.39 (m, 2H), 4.02 (t, 2H, J= 5.4 Hz), 3.54 (s, 3H), 2.67 (m, 2H).

[0436] Example 88. Synthesis of 6-(2-chloropyridin-3-yl)-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 90)

[0437] To a 10 mL seal tube was added tert-butyl 3-cyano-4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9-carboxylate (60 mg, 0.12 mmol), (2-chl oropyri din-3 -yl)boronic acid (97 mg, 0.62 mmol), tripotassium phosphate (102 mg, 0.48 mmol), palladium tetrakis (14 mg, 0.012 mmol), and 5 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane followed by a basic alumina column 0-6% methanol / dichloromethane to yield the title compound 6-(2-chl oropyri din-3 -yl)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carbonitrile (5 mg). MS (ESI): m / z 349.1 [M+H]+. *H NMR (CDC13) <5: 8.96 (s, 1H), 8.91 (s, 1H), 8.46 (d, 1H, J= 1.9, 4.7 Hz), 8.42 (m, 1H), 7.78 (m, 2H), 7.69 (d, 1H, J= 8.4 Hz), 7.39 (dd, 1H, J= 4.7, 7.6 Hz), 5.23 (s, 2H), 3.51 (s, 3H).

[0438] Example 89. Synthesis of 4-(methoxymethyl)-6-(pyridin-3-yl)-9J / -pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 91)

[0439] To a 10 mL seal tube was added tert-butyl 3-cyano-4-(methoxymethyl)-6- (((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9-carboxylate (60 mg, 0.12 mmol), pyri din-3 -ylboronic acid (77 mg, 0.62 mmol), tripotassium phosphate (102 mg, 0.48 mmol), palladium tetrakis (14 mg, 0.012 mmol), and 5 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC- MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (25 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 4-(methoxymethyl)-6-(pyri din-3 -yl)-9J / -pyrido[3,4-Z>]indole-3 -carbonitrile (19 mg). MS (ESI): m / z 315.1 [M+H]+. *HNMR (CDC13) 8 8.96 (s, lH7.8 Hz), ), 8.89 (s, 1H), 8.64 (d, 1H, J= 4.4 Hz), 8.54 (s, 1H), 7.99 (d, 1H, J= 7.8 Hz), 7.88 (d, 1H, J= 8.7 Hz), 7.71 (d, 1H, J= 8.7 Hz), 7.44 (m, 1H), 5.28 (s, 1H), 3.55 (s, 3H),

[0440] Example 90. Synthesis of 4-(methoxymethyl)-6-(l-methylpiperidin-4-yl)-9J7- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 92)

[0441] A solution of 4-(methoxymethyl)-6-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)- 9 J / -pyrido[3,4-Z>]indole-3 -carbonitrile (25 mg, 0.075 mmol) in methanol (5 mL) was sparged with argon gas for 15 minutes and then Pd / C (13 mg, 50% by weight) was added. The solution was then sparged with H2 gas (balloon pressure) and stirred for 6 days hours. LC-MS indicated full conversion to the product species. The reaction mixture was filtered over a pad of celite, and the filtrate was concentrated under vacuum. The resultant residue was then recrystallized in 9: 1 ethyl acetate: methanol and the resultant solid was then purified on a basic alumina column running 0-6% methanol / di chloromethane to yield the title compound 4-(methoxymethyl)-6-(l- methylpiperidin-4-yl)-9J7-pyrido[3,4-Z>]indole-3 -carbonitrile (12 mg). MS (ESI): m / z 335.2 [M+H]+. 'H NMR (CDCI3) 8 8. 89 (s, 1H), 8.72 (s, 1H), 8.15 (s, 1H), 7.53 (m, 2H), 5.23 (s, 2H), 3.53 (s, 3H), 3.04 (m, 2H), 2.71 (m, 1H), 2.37 (s, 3H), 2.13 (m, 2H), 1.95 (m, 2H).

[0442] Example 91. Synthesis of 6-(3,6-dihydro-27 / -pyran-4-yl)-4-(methoxymethyl)- / ' / - methyl-9J / -pyrido[3,4-Z>]indole-3 -carboxamide (Compound 93)

[0443] To a 15 mL seal tube was added tert-butyl 4-(methoxymethyl)-3- (methylcarbamoyl)-6-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9- carboxylate (100 mg, 0.24 mmol), (3,6-dihydro-2J / -pyran-4-yl)boronic acid (253 mg, 1.2 mmol), tripotassium phosphate (203 mg, 0.96 mmol), palladium tetrakis (28 mg, 0.024 mmol), and 7 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with saturated aqueous sodium bicarbonate (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-6% methanol / di chloromethane to yield the title compound 6-(3,6-dihydro-27 / -pyran-4-yl)- 4-(methoxymethyl)-7V-methyl-9J / -pyrido[3,4-Z>]indole-3-carboxamide (46 mg). MS (ESI): m / z 352.1 [M+H]+. *HNMR (CDC13) 8 8.71 (s, 1H), 8.35 (s, 1H), 7.67 (dd, 1H, J= 2.0, 8.4 Hz), 7.48 (d, 1H, J= 8.4 Hz), 6.21 (m, 1H), 5.76 (s, 2H), 4.39 (m, 2H), 4.01 (t, 2H, J= 5.3 Hz), 3.58 (s, 3H), 3.05 (d, 3H, J= 5.3 Hz), 2.68 (m, 2H).

[0444] Example 92. Synthesis of 4-(methoxymethyl)-6-(2-morpholinoethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 94)

[0445] To a 20 mL scintillation vial was added / c / 7-butyl 3-cyano-6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (70 mg, 0.20 mmol), potassium carbonate (165 mg, 1.2 mmol), dimethylacetamide (3 mL) and then 4-(2- chloroethyl)morpholine (118 pL, 0.79 mmol). The reaction mixture was stirred at 75C overnight, and the next morning, LCMS indicated full conversion to the product. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (25 mL), and then washed with water (25 mL). The organics were then dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was then diluted with dichloromethane and treated with 2 mL of trifluoracetic acid for 2 hours. This solution was then neutralized with saturated aqueous sodium bicarbonate, and the organics were dried and concentrated. The resultant residue was then purified via a silica column running 0-5% methanol / dichloromethane to yield the title compound 4- (methoxymethyl)-6-(2-morpholinoethoxy)-9Z / -pyrido[3,4-Z>]indole-3 -carbonitrile (24 mg). MS (ESI): m / z 367.1 [M+H]+.1H NMR (CD3OD) <5: 8.99 (s 1H), 7.70 (d, 1H, J= 2.4 Hz), 7.61 (d, 1H, J= 8.9 Hz), 7.26 (dd, 1H, J= 2.4, 8.9 Hz), 5.16 (s, 2H), 4.63 (t, 2H, J= 5.8 Hz), 3.54 (m, 7H), 2.79 (t, 2H, J= 5.8 Hz), 2.47 (m, 4H).

[0446] Example 93. Synthesis of 6-(difluoromethoxy)-4-(methoxymethyl)-9Z / -pyrido[3,4- Z>]indole-3 -carbonitrile (Compound 95)

[0447] To a 10 mL seal tube was added terLbutyl 3-cyano-6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (100 mg, 0.28 mmol), potassium carbonate (1,352 mg, 9.8 mmol) followed by acetonitrile (2 mL) and water (2 mL) and then 2-chloro-2,2-difluoro-l-phenylethan-l-one (250 pL, 1.68 mmol). The reaction vessel was sealed and heated at 75C overnight. The next morning, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL). Upon addition of ethyl acetate, a precipitate formed, and the suspension was filtered over a glass frit. The filtrate was isolated and washed with water (2 x 25 mL), and the organics were then dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane, where the title compound co-eluted with an impurity. The resultant solid was recrystallized in 100% methanol to yield the title compound 6- (difluoromethoxy)-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carbonitrile (9 mg). MS (ESI): m / z 304.1 [M+H]+. 'HNMR (CD3OD) <5: 8.92 (s 1H), 8.08 (d, 1H, J= 2.43 Hz), 7.69 (d, 1H, J= 8.89 Hz), 7.49 (dd, 1H, J= 2.4, 8.8 Hz), 5.48 (s, 1H), 5.20 (s, 2H), 3.53 (s, 3H).

[0448] Example 94. Synthesis of 6-(4-fluorophenyl)-4-(methoxymethyl)-7V-methyl-9Z7- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 96)

[0449] To a 15 mL seal tube was added tert-butyl 4-(methoxymethyl)-3- (methylcarbamoyl)-6-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[3,4-b]indole-9- carboxylate (75 mg, 0.18 mmol), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (127 mg, 0.90 mmol), tripotassium phosphate (153 mg, 0.72 mmol), palladium tetrakis (22 mg, 0.018 mmol), and 7 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with water (100 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 6-(4-fluorophenyl)-4- (methoxymethyl)-7V-methyl-9J / -pyrido[3,4-Z>]indole-3-carboxamide (31 mg). MS (ESI): m / z 364.1 [M+H]+. *H NMR (CD3OD) <5: 8.79 (s, 1H), 8.5 (d, 1H, J= 1.8 Hz), 7.83 (dd, 1H, J= 1.7, 8.5), 7.69 (m, 3H), 7.2 (m, 2H), 5.50 (s, 2H), 3.50 (s 3H), 2.99 (s, 3H).

[0450] Example 95. Synthesis of 6-(2-fluorophenyl)-4-(methoxymethyl)-7V-methyl-9JT- pyrido[3,4-Z>]indole-3 -carboxamide (Compound 97)

[0451] To a 15 mL seal tube was added tert-butyl 4-(methoxymethyl)-3- (methylcarbamoyl)-6-(((trifhioromethyl)sulfonyl)oxy)-9JH-pyrido[3,4-Z>]indole-9- carboxylate (75 mg, 0.18 mmol), 2-(2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (127 mg, 0.90 mmol), tripotassium phosphate (153 mg, 0.72 mmol), palladium tetrakis (22 mg, 0.018 mmol), and 7 mL of 2: 1 tetrahydrofuran: water mixture. The solution was sparged with argon gas (balloon pressure) for 15 minutes before the vessel was sealed and stirred at 90 °C overnight. The next morning, reaction progress indicated full conversion to the title compound as monitored by LC-MS. The reaction mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with water (100 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The resultant residue was purified via a silica column running 0-10% methanol / dichloromethane to yield the title compound 6-(2-fluorophenyl)-4- (methoxymethyl)-7V-methyl-9J / -pyrido[3,4-Z>]indole-3-carboxamide (36 mg). MS (ESI): m / z 364.1 [M+H]+. *H NMR (CD3OD) <5: 8.81 (s, 1H), 8.46 (m, 1H), 7.79 (m, 1H), 7.68 (d, 1H, J= 8.36 Hz), 7.59 (m, 1H), 7.37 (m, 1H), 7.25 (m, 2H), 5.48 (s, 1H), 5.47 (s, 2H), 3.49 (s, 3H), 2.99 (s, 3H).

[0452] Example 96. Synthesis of 6-(3 -hydroxy-3 -methylbutoxy)-4-(m ethoxymethyl)-97 / - pyrido[3,4-Z>]indole-3 -carbonitrile (Compound 98)

[0453] To a 20 mL scintillation vial was added tert-butyl 3-cyano-6-hydroxy-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-9-carboxylate (70 mg, 0.2 mmol), 4-bromo- 2-methylbutan-2-ol (135 pL, 0.8 mmol), potassium carbonate (166 mg, 1.2 mmol), and dimethylformamide (4 mL) and the mixture was allowed to stir at 70 °C overnight. LC- MS monitored the reaction. Upon full conversion to the product, the reaction mixture was diluted with ethyl acetate (25 mL) and washed with water (3 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-80% ethyl acetate / hexanes to yield the title compound 6-(3 -hydroxy-3 -methylbutoxy)-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carbonitrile (27 mg). MS (ESI): m / z 340.1 [M+H]+. 'H NMR (CD3OD) <5: 8.83 (s, 1H), 7.76 (d, 1H, J= 2.5 Hz), 7.57 (d, 1H, J= 8.9 Hz), 7.31 (dd, 1H, J= 2.5, 8.9 Hz), 5.20 (s, 2H), 4.26 (t, 2H, J= 6.9 Hz), 3.53 (s, 3H), 2.04 (t, 2H, 6.9 Hz).

[0454] Example 97. Synthesis of ethyl 4-(methoxymethyl)-6-(2-morpholinoethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (Compound 99)

[0455] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-6-(2- morpholinoethoxy)-9H-pyrido [ 3, 4-b ] indole-3, 9-dicarboxylate

[0456] To a solution of 9-(tert-butyl) 3-ethyl 6-hydroxy-4-(methoxymethyl)-9JT- pyrido[3,4-Z>]indole-3, 9-dicarboxylate (205 mg, 0.52 mmol) and potassium carbonate (420 mg, 3.12 mmol) in dimethylacetamide (6 mL) was added 4-(2- chloroethyl)morpholine (305 pL, 2.05 mmol) at room temperature. The mixture was heated at 75C for 4 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (3 x 50 mL). The organics were dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-3% methanol / dichloromethane to yield the title compound 9-( / c77-butyl) 3-ethyl 4-(methoxymethyl)-6-(2- morpholinoethoxy)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (200 mg).

[0457] Step 2: Preparation of ethyl 4-(methoxymethyl)-6-(2-morpholinoethoxy)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0458] To a stirred mixture of 9-( / c / 7-butyl) 3-ethyl 4-(methoxymethyl)-6-(2- morpholinoethoxy)-9J / -pyrido[3,4-Z>]indole-3, 9-dicarboxylate (200 mg, 0.39 mmol) in dichloromethane (2 mL) was added trifluoracetic acid (2.2 mL, 29 mmol). The solution was stirred overnight, neutralized with saturated aqueous sodium bicarbonate (15 mL), and extracted with dichloromethane (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resultant residue was purified via a silica column running 0-10% methanol / di chloromethane to give the title compound ethyl 4-(methoxymethyl)-6-(2-morpholinoethoxy)-9JT- pyrido[3,4-Z>]indole-3 -carboxylate (170 mg). MS (ESI): m / z 2.07.1, 414.2 [M+H]+.JH NMR (CD3OD) <5: 8.73 (s, 1H), 7.74 (d, 1H, J= 2.5 Hz), 7.51 (d, 1H, J= 9.1 Hz), 7.28 (dd, 1H, J=2.41, 8.90 Hz), 5.27 (s, 2H), 4.45 (q, 2H, J= 7.2 Hz), 4.24 (t, 2H, J= 5.7 Hz), 3.73 (m, 4H), 3.47 (s, 3H), 2.87 (t, 2H, J= 5.7 Hz), 2.64 (m, 4H), 1.45 (t, 3H, J= 7.2 Hz).

[0459] Example 98. Synthesis of 5-[(2-fhiorophenyl)methoxy]-4-(methoxymethyl)-N- methyl-9H-pyrido[3,4-b]indole-3 -carboxamide (Compound 105)

[0460] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 5-(benzyloxy)-4-(methoxymethyl)- 9H-pyrido[ 3, 4-b ]indole-3, 9-dicarboxylate

[0461] To a solution of ethyl 5-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (1 g, 2.56 mmol, 1 eq) in DCM (15 mL) was added tertbutoxycarbonyl tert-butyl carbonate (670.79 mg, 3.07 mmol, 1.2 eq) and DMAP (62.58 mg, 512.25 pmol, 0.2 eq). The mixture was stirred at 25 °C for 2 h. The mixture was added water (20 mL) and extracted with DCM (20 mLx3). The combined organic phase was dried with anhydrous ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 3 / 1) to get 9-(tert-butyl) 3-ethyl 5-(benzyloxy)-4-(methoxymethyl)-9H- pyrido[3,4-b]indole-3, 9-dicarboxylate (1 g, 2.04 mmol, 79.59% yield) as a yellow solid.

[0462] 'H NMR (400 MHz, CDC13) 8 = 9.53 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.59 - 7.56 (m, 1H), 7.55 - 7.51 (m, 2H), 7.47 - 7.39 (m, 3H), 6.96 (d, J = 8.2 Hz, 1H), 5.29 (s, 2H), 5.16 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.00 (s, 3H), 1.77 (s, 9H), 1.42 (t, J = 7.2 Hz, 3H).

[0463] Step 2: Preparation of 9 -(tert-butyl) 3-ethyl 5-hydroxy-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0464] To a solution of 9-tert-butyl 3-ethyl 5 -benzyloxy -4-

[0465] (methoxymethyl)pyrido[3,4-b]indole-3,9- dicarboxylate (1 g, 2.04 mmol, 1 eq) in MeOH (10 mL) was added Pd / C (0.5 g, 10% load) under Ar atmosphere. The mixture was stirred under H2 (15 psi) at 25 °C for 6 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 9-tert-butyl 3-ethyl 5- hydroxy-4-(methoxymethyl)pyrido[3,4-b]indole-3, 9-dicarboxylate (700 mg, 1.75 mmol, 85.75% yield) as a gray solid. 'H NMR (400 MHz, CDCI3) 6 = 10.49 (s, 1H), 9.68 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 5.29 (s, 2H), 4.55 (q, J = 7.1 Hz, 2H), 3.60 (s, 3H), 1.77 (s, 9H), 1.50 (t, J = 7.2 Hz, 3H) Step 3 : Preparation of 9-tert-butyl 3-ethyl 5-((2-fluorobenzyl)oxy)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ] -indole-3, 9-dicarboxylate

[0466] A mixture of 9-tert-butyl 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b]indole-3,9- dicarboxylate (250 mg, 624.34 pmol, 1 eq), 1 -(bromomethyl)-2-fluoro- benzene (141.6 mg, 749.21 pmol, 90.38 pL, 1.2 eq), K2CO3 (189.83 mg, 1.37 mmol, 2.2 eq) in DMF (0.5 mL), the mixture was stirred at 60 °C for 4 h under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 3 / 1) to get 9-tert-butyl 3-ethyl 5-[(2- fluorophenyl)methoxy]-4-(methoxymethyl) pyrido[3,4-b]indole- 3, 9-dicarboxylate (0.25 g, 491.61 pmol, 78.74% yield) as a yellow solid. 'H NMR (400 MHz, CDCI3) 8 = 9.53 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 8.3 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.23 - 7.13 (m, 3H), 6.98 (d, J = 8.1 Hz, 1H), 5.36 (s, 2H), 5.17 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 3.05 (s, 3H), 1.77 (s, 9H), 1.42 (t, J = 7.1 Hz, 3H)

[0467] Step 4: Preparation of ethyl 5-[(2-fluorophenyl)methoxy]-4-(methoxymethyl)- 9H-pyrido [ 3, 4-b ]indole-3-carboxylate

[0468] A mixture of 9-tert-butyl 3-ethyl 5-[(2-fluorophenyl)methoxy]-4- (methoxymethyl)pyrido [3, 4-b]indole-3, 9-dicarboxylate (0.25 g, 491.61 pmol, 1 eq) in DCM (3 mL) and TFA (0.6 mL), then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. The mixture was treated with saturated NaHCCL (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chomatography (SiCL, petroleum ether / ethyl acetate=3 / l to 1 / 1) to get ethyl 5- [(2-fluorophenyl)methoxy]-4-(methoxymethyl)-9H-pyrido [3,4-b]indole-3- carboxylate (150 mg, 367.27 pmol, 74.71% yield) as a yellow solid. 'H NMR (400 MHz, CDCI3) 6 = 9.29 (s, 1H), 8.76 (s, 1H), 7.56 (dt, J = 1.7, 7.6 Hz, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.21 - 7.14 (m, 3H), 6.80 (d, J = 7.9 Hz, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 3.08 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H.

[0469] Step 5: Preparation of 5-[(2-fluorophenyl)methoxy]-4-(methoxymethyl)-N- methyl-9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0470] To a solution of ethyl 5-[(2-fluorophenyl)methoxy]-4-(methoxymethyl)-9H- pyrido[3,4-b] indole-3 -carboxylate (150 mg, 367.27 pmol, 1 eq) in toluene (3 mL) was added MeNH2(2 M in THF, 275.45 pL, 1.5 eq) and AlMe3(2 M, 367.27 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: WePure Biotech XP tC18 150 pm x 40 pm xlO pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient:25%-55% B over 8.0 min) to get 5-[(2-fluorophenyl)methoxy]-4- (methoxymethyl)-N-methyl-9H-pyrido[3,4-b]indole-3-carboxamide (66 mg, 160.78 pmol, 43.78% yield, 95.84% purity) as a white solid.JH NMR (400 MHz, CD3OD) 5 = 8.69 (s, 1H), 7.64 (dt, J = 1.7, 7.5 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.26 - 7.19 (m, 3H), 6.92 (d, J = 7.9 Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 3.01 (s, 3H), 2.94 (s, 3H). LC-MS (ES+, m / z): 394.1 [(M+H)+]; Rt= 1.987 min.

[0471] Example 99. Synthesis of 5-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-N-methyl-9H- pyrido[3,4-b]indole-3 -carboxamide (Compound 106)

[0472] Step 1 : Preparation of 9 -tert-butyl 3-ethyl 5-[(3-jluorophenyl)methoxy]-4- (methoxymethyl)pyrido [ 3, 4-b ] indole-3, 9-dicarboxylate

[0473] A mixture of 9-tert-butyl 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b]indole-3, 9-dicarboxylate (250 mg, 624.34 pmol, 1 eq), 1 -(brom omethyl)-3 -fluorobenzene (141.62 mg, 749.21 pmol, 91.90 pL, 1.2 eq), K2CO3 (189.83 mg, 1.37 mmol, 2.2 eq) in DMF (5 mL), then the mixture was stirred at 60 °C for 4 h under N2 atmosphere. The mixture (combined with another batch at 20 mg scale) was filtered by celite and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 3 / 1) to get 9-tert-butyl 3-ethyl 5 -[(3 -fluorophenyl) methoxy]-4- (methoxymethyl)pyrido [3, 4-b]indole-3, 9-dicarboxylate (250 mg, 72.9% yield) as a yellow solid. 'H NMR (400 MHz, CDCI3) 8 = 9.46 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.32 (dd, J = 2.2, 7.8 Hz, 1H), 7.22 (br d, J = 7.8 Hz, 1H), 7.17 (br d, J = 9.9 Hz, 1H), 7.01 (dt, J = 1.9, 8.4 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 5.22 (s, 2H), 5.12 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.00 (s, 3H), 1.69 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H).

[0474] Step 2: Preparation of ethyl 5-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0475] A mixture of 9-tert-butyl 3-ethyl 5-[(3-fluorophenyl)methoxy]-4- (methoxymethyl)pyrido [3,4-b]indole-3,9-dicarboxylate (0.25 g, 491.61 pmol, 1 eq) in DCM (3 mL) and TFA (0.6 mL), then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. Saturated NaHCCL (10 mL) was added to the mixture and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate=3 / l to 1 / 1) to get ethyl 5- ((3-fluorobenzyl)oxy)-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (150 mg, 367.27 pmol, 74.71% yield) as a yellow solid.1H NMR (400 MHz, CDCI3) 8 = 9.29 (br s, 1H), 8.79 (s, 1H), 7.49 - 7.44 (m, 1H), 7.40 (dt, J = 5.8, 7.9 Hz, 1H), 7.34

[0476] - 7.30 (m, 1H), 7.28-7.25 (m, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.08 (dt, J = 2.1, 8.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H), 5.33 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 3.13 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0477] Step 3: Preparation of 5-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-N-methyl- 9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0478] To a solution of ethyl 5-[(3-fluorophenyl)methoxy]-4-(methoxymethyl)-9H- pyrido[3,4- b]indole-3 -carboxylate (150 mg, 367.27 pmol, 1 eq) in toluene (3 mL) was added MeNH2in THF (2 M, 275.4 pL, 1.5 eq) and AlMe3(2 M, 367.2 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. The reaction mixture was added water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: WePure Biotech XP tC18 150 pm x 40 pm x 10 pm; mobile phase: [H2O (10 mM lSTLHCCL)- ACN]; gradient: 25%- 55% B over 8.0 min) to get 5-((3-fluorobenzyl)oxy)-4-(methoxymethyl)-N-methyl-9H- pyrido[3,4-b]indole-3 -carboxamide (43 mg, 106.62 pmol, 29.03% yield, 97.55% purity) as a white solid. 'H NMR (400 MHz, CD3OD) 5 = 8.71 (s, 1H), 7.50 (t, J = 8.1 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.36 (br d, J = 9.8 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.13

[0479] - 7.07 (m, 1H), 6.84 (d, J = 8.1 Hz, 1H), 5.43 (s, 2H), 5.42 (s, 2H), 3.10 (s, 3H), 2.96 (s, 3H). LC-MS (ES+, m / z): 394.1 [(M+H)+]; Rt= 1.999 min. Example 100. Synthesis of 5-((4-fluorobenzyl)oxy)-4-(methoxymethyl)-N-methyl- 9H-pyrido[3,4-b]indole-3-carboxamide (Compound 107)

[0480] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 5-((4-fluorobenzyl)oxy)-4- (methoxymethyl)-9H-pyrido[ 3, 4-b ] indole-3, 9 -dicarboxylate

[0481] A mixture of 9-tert-butyl 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b]indole-3,9 -di carb oxy late (200 mg, 499.47 pmol, 1 eq), 1 -(bromomethyl)-4-fluoro- benzene (113.29 mg, 599.36 pmol, 73.86 pL, 1.2 eq), K2CO3 (151.87 mg, 1.10 mmol, 2.2 eq) in DMF (0.4 mL), then the mixture was stirred at 60 °C for 4 h under N2 atmosphere. The mixture was filtered by celite and the filtrate was concentrated under reduced pressure to get 9-(tert-butyl) 3-ethyl5-[(4-fluorophenyl)methoxy]-4- (methoxymethyl)pyrido[3,4-b]indole-3,9-dicarboxylate (220 mg, 432.61 pmol, 86.61% yield) as a brown solid. 'HNMR (400 MHz, CDCI3) 8 = 9.53 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.3 Hz, 1H), 7.51 (dd, J = 5.4, 8.4 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 5.26 (s, 2H), 5.15 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 3.03 (s, 3H), 1.77 (s, 9H), 1.43 (t, J = 7.2 Hz, 3H).

[0482] Step 2: Preparation of ethyl 5-((4-fluorobenzyl)oxy)-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3- carboxylate

[0483] A mixture of 9-(tert-butyl) 3-ethyl 5-[(4-fluorophenyl)methoxy]-4- (methoxymethyl)pyrido [3,4-b]indole-3,9-dicarboxylate (0.22 g, 432.61 pmol, 1 eq) in DCM (2.5 mL) and TFA (0.5 mL), then the mixture was stirred at 25 °C for 1 h under N2 atmosphere. Saturated NaHCCL solution (10 mL) was added to the mixture and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography ( Si O2, petroleum ether / ethyl acetate=3 / l to 1 / 1) to get ethyl 5-[(4-fluorophenyl)methoxy]-4-(methoxymethyl)-9H-pyrido [3,4-b]indole-3- carboxylate (0.13 g, 318.30 pmol, 73.58% yield) as a yellow solid.1HNMR (400 MHz, CDCI3) 6 = 9.47 (s, 1H), 8.65 (s, 1H), 7.44 (dd, J = 5.4, 8.4 Hz, 2H), 7.38 (t, J = 8.1 Hz, 1H), 7.09 - 7.01 (m, 3H), 6.67 (d, J = 8.1 Hz, 1H), 5.26 (s, 2H), 5.20 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.99 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). Step 3: Preparation of 5-((4-fluorobenzyl)oxy)-4-(methoxymethyl)-N-methyl- 9H-pyrido[ 3, 4-b ] indole-3- carboxamide

[0484] To a solution of ethyl 5-[(4-fluorophenyl)methoxy]-4-(methoxymethyl)-9H- pyrido[3,4-b] indole-3 -carboxylate (0.13 g, 318.30 pmol, 1 eq) in toluene (2.6 mL) was added MeNH2in THF (2 M, 238.7 pL, 1.5 eq) and AlMe3(2 M, 318.3 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. Water (10 mL) was added and the resulting solution was extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: WePure Biotech XPtC18 150 pm x 40 pm x 7 pm; mobile phase: [H2O(10mM NH4HCO3)- ACN]; gradient:25%-55% B over 8.0 min) to get 5-[(4-fhiorophenyl)methoxy]-4- (methoxymethyl)-N-methyl-9H-pyrido[3,4-b]indole-3-carboxamide (67.2 mg, 166.41 pmol, 52.28% yield, 97.42% purity) as a white solid.JH NMR (400 MHz, CD3OD) 5 = 8.70 (s, 1H), 7.64 - 7.59 (m, 2H), 7.51 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.18 - 7.13 (m, 2H), 6.88 (d, J = 8.0 Hz, 1H), 5.39 (s, 2H), 5.37 (s, 2H), 3.05 (s, 3H), 2.95 (s, 3H). LC-MS (ES+, m / z): 394.1 [(M+H)+]; Rt= 1.999 min.

[0485] Example 101. Synthesis of 4-(methoxymethyl)-N-methyl-5-(pyridin-2-ylmethoxy)- 9H-pyrido[3,4-b]indole-3-carboxamide (Compound 108)

[0486] Step 1 : Preparation of 9 -(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(pyridin-2- ylmethoxy)-9H-pyrido [ 3, 4-b ] indole-3, 9-dicarboxylate

[0487] To a solution of 9-(tert-butyl) 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b] indole-3, 9-dicarboxylate (0.23 g, 574.39 pmol, 1 eq) in DMF (4.6 mL) was added K2CO3(261.98 mg, 1.90 mmol, 3.3 eq) and 2-(bromomethyl)pyridine hydrobromide (174.34 mg, 689.27 pmol, 1.2 eq). The mixture was stirred at 60 °C for 4 h. The mixture (combined with 20 mg scale) was poured into H2O (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 3 / 1) to get 9-(tert-butyl) 3-ethy 4-(methoxymethyl)-5-(2- pyridylmethoxy)pyrido[3,4-b]indole-3,9-dicarboxylate (220 mg) as a yellow oil. 'H NMR (400 MHz, DMSO-t / 6) 8 = 9.42 (s, 1H), 8.67 (dd, J = 0.8, 4.8 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.89 (dt, J = 1.7, 7.7 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.43 (ddd, J = 1.0, 4.9, 7.5 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 5.47 (s, 2H), 5.05 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.96 (s, 3H), 1.74 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H).

[0488] Step 2: Preparation of ethyl 4-(methoxymethyl)-5-(pyridin-2-ylmethoxy)-9H- pyrido[ 3, 4-b ] indole-3- carboxylate

[0489] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(2- pyridylmethoxy)pyrido [3,4-b]indole-3,9-dicarboxylate (0.22 g, 447.58 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into saturated NaHCCh (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 9) to get ethyl 4-(methoxymethyl)-5-(2-pyridylmethoxy)-9H-pyrido[3,4-b]indole-3- carboxylate (0.15 g, 383.22 pmol, 85.62% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-t / 6) 6 = 12.10 (s, 1H), 8.77 (s, 1H), 8.65 (br d, J = 4.3 Hz, 1H), 7.86 (dt, J = 1.6, 7.7 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.40 (dd, J = 5.2, 6.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.45 (s, 2H), 5.21 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.96 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0490] Step 3: Preparation of 4-(methoxymethyl)-N-methyl-5-(pyridin-2-ylmethoxy)- 9H-pyrido[ 3, 4-b ] indole-3- carboxamide

[0491] To a mixture of ethyl 4-(methoxymethyl)-5-(2-pyridylmethoxy)-9H- pyrido[3,4-b]indole-3 -carboxylate (0.15 g, 383.22 pmol, 1 eq) in toluene (3 mL) was added MeNH2in THF (2 M, 287.42 pL, 1.5 eq) and AlMe3(2 M, 383.22 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3 condition column: WePure Biotech XPtC18 150 pm x 40 pm x 7 pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 10%-50% B over 8.0 min) to get 4-(methoxymethyl)-N- methyl-5-(2-pyridylmethoxy)-9H-pyrido[3,4-b]indole-3-carboxamide (75.9 mg, 201.00 pmol, 52.45% yield, 99.68% purity) as a white solid. 'H NMR (400 MHz, DMSO- f,) 8 = 12.00 (s, 1H), 8.76 (s, 1H), 8.66 - 8.61 (m, 1H), 8.33 (br d, J = 4.8 Hz, 1H), 7.83 (dt, J = 1.7, 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.37 (ddd, J = 0.9, 4.9, 7.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.48 (s, 2H), 5.42 (s, 2H), 2.99 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H). LC-MS (ES+, m / z): 377.1 [(M+H)+]; Rt= 1.490 min.

[0492] Example 102. Synthesis of 4-(methoxymethyl)-N-methyl-5-(pyridin-3-ylmethoxy)- 9H-pyrido[3,4-b]indole-3-carboxamide (Compound 109)

[0493] Step 1 : Preparation of 9 -(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(pyridin-3- ylmethoxy)-9H-pyrido[ 3, 4-b ] indole-3, 9-dicarboxylate

[0494] To a solution of 9-tert-butyl 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b]indole- 3, 9-dicarboxylate (0.23 g, 574.39 pmol, 1 eq) in DMF (4.6 mL) was added K2CO3 (261.98 mg, 1.90 mmol, 3.3 eq) and 3-(bromomethyl)pyridine hydrobromide (174.34 mg, 689.27 pmol, 1.2 eq). The mixture was stirred at 60 °C for 4 h. The mixture (combined with 20 mg scale) was poured into H2O (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 2 / 1) to get 9-(tert-butyl)3 -ethyl 4-(methoxymethyl)-5-(3- pyridylmethoxy)pyrido[3,4-b]indole-3, 9-dicarboxylate (150 mg) as a yellow oil. 'H NMR (400 MHz, DMSO-t / 6) 6 = 9.41 (s, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.64 (dd, J = 1.6, 4.8 Hz, 1H), 8.09 - 8.03 (m, 2H), 7.72 (t, J = 8.3 Hz, 1H), 7.51 (dd, J = 4.8, 7.7 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 5.43 (s, 2H), 4.93 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 2.87 (s, 3H), 1.74 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H).

[0495] Step 2: Preparation of ethyl 4-(methoxymethyl)-5-(pyridin-3-ylmethoxy)-9H- pyrido[ 3, 4-b ] indole-3- carboxylate

[0496] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(3- pyridylmethoxy)pyrido [3, 4-b]indole-3, 9-dicarboxylate (0.15 g, 305.17 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into sat. NaHCCh (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether / ethyl acetate= 10 / 1 to 1 / 10) to get ethyl 4- (methoxymethyl)-5-(3-pyridylmethoxy)-9H-pyrido[3,4-b]indole- 3-carboxylate (0.1 g, 255.48 pmol, 83.72% yield) as a yellow oil.XH NMR (400 MHz, DMSO-t / 6) 8 = 12.10 (s, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.76 (s, 1H), 8.61 (d, J = 3.6 Hz, 1H), 8.05 (br d, J = 7.7 Hz, 1H), 7.58 - 7.46 (m, 2H), 7.25 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 5.41 (s, 2H), 5.10 (s, 2H), 4.25 (q, J = 7.0 Hz, 2H), 2.86 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0497] Step 3: Preparation of 4-(methoxymethyl)-N-methyl-5-(pyridin-3-ylmethoxy)- 9H-pyrido[ 3, 4-b ] indole-3- carboxamide

[0498] A mixture of ethyl 4-(methoxymethyl)-5-(3-pyridylmethoxy)-9H-pyrido[3,4- b]indole-3 -carboxylate (0.1 g, 255.48 pmol, 1 eq) in toluene (2 mL) was added MeNH2 in THF (2 M, 191.61 pL, 1.5 eq) and AlMes (2 M, 255.48 pL, 2 eq) in a sealed tube, the mixture was stirred at 100 °C for 2 h. The reaction mixture was added water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3 condition column: WePure Biotech XP tC18 150 pm x 40 pm x 7 pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 10%-50% B over 8.0 min) to get 4-(methoxymethyl)-N-methyl-5-(3- pyridylmethoxy)-9H-pyrido[3,4-b]indole-3-carboxamide (58.6 mg, 152.55 pmol, 59.71% yield, 97.99% purity) as a white solid. 'H NMR (400 MHz, DMSO-t / 6) 6 = 11.95 (br s, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.74 (s, 1H), 8.57 (dd, J = 1.6, 4.8 Hz, 1H), 8.30 (q, J = 4.2 Hz, 1H), 8.01 (td, J = 1.8, 7.8 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.45 (dd, J = 5.0, 7.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.32 (s, 2H), 2.90 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H). LC-MS (ES+, m / z): 377.1 [(M+H)+]; Rt= 1.346 min.

[0499] Example 103. Synthesis of 4-(methoxymethyl)-N-methyl-5-(pyridin-4-ylmethoxy)- 9H-pyrido[3,4-b]indole-3-carboxamide (Compound 110)

[0500] Step 1 : Preparation of 9 -(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(pyridin-4- ylmethoxy)-9H-pyrido [ 3, 4-b ] indole-3, 9-dicarboxylate

[0501] To a solution of 9-(tert-butyl) 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b]indole- 3, 9-dicarboxylate (0.23 g, 574.39 pmol, 1 eq) in DMF (4.6 mL) was added K2CO3 (261.98 mg, 1.90 mmol, 3.3 eq) and 4-(bromomethyl)pyridine hydrobromide (174.34 mg, 689.27 pmol, 1.2 eq). The mixture was stirred at 60 °C for 4 h. The mixture (combined with 20 mg scale) was poured into H2O (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 2 / 1) to get 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(4- pyridylmethoxy)pyrido[3,4-b]indole-3, 9-dicarboxylate (200 mg) as a yellow oil.JH NMR (400 MHz, DMSO-t / 6) 8 = 9.43 (s, 1H), 8.66 - 8.61 (m, 2H), 8.06 (d, J = 8.3 Hz, 1H), 7.67 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 6.0 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 5.48 (s, 2H), 5.05 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 2.97 (s, 3H), 1.73 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).

[0502] Step 2: Preparation of ethyl 4-(methoxymethyl)-5-(pyridin-4-ylmethoxy)-9H- pyrido[ 3, 4-b ] indole-3- carboxylate

[0503] To a solution of 9-(tert-butyl) 3-ethyl 4-(methoxymethyl)-5-(4- pyridylmethoxy)pyrido[3,4-b] indole-3, 9-dicarboxylate (0.2 g, 406.89 pmol, 1 eq) in DCM (3 mL) was added TFA (1 mL).The mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into sat. NaHCCh (20 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate= 10 / 1 to 0 / 1) to get ethyl 4- (methoxymethyl)-5-(4-pyridylmethoxy)-9H-pyrido[3,4-b]indole-3- carboxylate (0.15 g, 383.22 pmol, 94.18% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-t / 6) 6 = 12.13 (s, 1H), 8.78 (s, 1H), 8.62 (d, J = 5.8 Hz, 2H), 7.57 (d, J = 5.7 Hz, 2H), 7.50 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.47 (s, 2H), 5.22 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 2.98 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0504] Step 3: Preparation of 4-(methoxymethyl)-N-methyl-5-(pyridin-4-ylmethoxy)- 9H-pyrido[ 3, 4-b ] indole-3- carboxamide

[0505] To a mixture of ethyl 4-(methoxymethyl)-5-(4-pyridylmethoxy)-9H- pyrido[3,4-b]indole-3 -carboxylate (150 mg, 383.22 pmol, 1 eq) in toluene (3 mL) was added MeNH2in THF (2 M, 287.42 pL, 1.5 eq) and AlMe3(2 M, 383.22 pL, 2 eq) in a sealed tube, the mixture was stirred at 100 °C for 2 h. The reaction mixture was added water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3 condition column: WePure Biotech XP tC18 150 pm x 40 pm x 7 pm; mobile phase: [H2O (10 mM NH4HCO3)- ACN];gradient: 10%-50% B over 8.0 min) to get 4-(methoxymethyl)-N-methyl-5-(4- pyridylmethoxy)-9H-pyrido[3,4-b]indole-3-carboxamide (85.4 mg, 226.70 pmol, 59.16% yield, 99.92% purity) as a white solid. 'H NMR (400 MHz, DMSO-t / 6) 8 = 12.04 (br s, 1H), 8.78 (s, 1H), 8.62 - 8.56 (m, 2H), 8.39 - 8.32 (m, 1H), 7.56 (d, J = 6.0 Hz, 2H), 7.46 (t, J = 8.1 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 5.51 (s, 2H), 5.44 (s, 2H), 3.03 (s, 3H), 2.81 (d, J = 4.8 Hz, 3H) LC-MS (ES+, m / z): 377.1 [(M+H)+]; Rt= 1.296 min.

[0506] Example 104. Synthesis of 5-(2-hydroxyethoxy)-4-(methoxymethyl)-N-methyl-9H- pyrido[3,4-b]indole-3 -carboxamide (Compound 112)

[0507] Step 1 : Preparation of 9-(tert-butyl) 3-ethyl 5-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-4-(methoxymethyl)- 9H-pyrido[3,4-b]indole-3,9- dicarboxylate

[0508] A mixture of 9-(tert-butyl) 3-ethyl 5-hydroxy-4-(methoxymethyl)pyrido[3,4- b]indole-3,9- dicarboxylate (0.2 g, 499.47 pmol, 1 eq), 2-bromoethoxy-tert-butyl- dimethyl-silane (143.38 mg, 599.36 pmol, 1.2 eq), K2CO3(151.87 mg, 1.10 mmol, 2.2 eq) in DMF (4 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 3 h under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mLx3). The combined organic was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:EtOAc=0:l) to get 9- (tert-butyl) 3-ethyl 5-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]- 4- (methoxymethyl)pyrido[3,4-b]indole-3,9-dicarboxylate (0.16 g, 286.36 pmol, 57.33% yield) as a brown solid. LC-MS (ES+, m / z): 459.0 [(M+H)+]; Rt= 0.674 min.

[0509] Step 2: Preparation of ethyl 5-(2-hydroxyethoxy)-4-(methoxymethyl)-9H- pyrido[ 3, 4-b ]indole-3-carboxylate

[0510] To a solution of 9-(tert-butyl) 3-ethyl 5-[2-[tert- butyl(dimethyl)silyl]oxyethoxy]-4- (methoxymethyl)pyrido[3,4-b]indole-3,9- dicarboxylate (0.16 g, 286.36 pmol, 1 eq) in DCM (2 mL) was added TFA (1.46 g, 12.82 mmol, 952.38 pL, 44.77 eq). The mixture was stirred at 20 °C for 2 h. The mixture was quenched by addition of saturated NaHCCh solution to pH=7-8 and diluted with H2O (20 mL), then extracted with EtOAc (15 mLx3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (petroleum ether:EtOAc=0: l) to get ethyl 5-(2- hydroxy ethoxy)-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate (0.1 g, 290.39 pmol, 96.58% yield) as a yellow oil. LC-MS (ES+, m / z): 344.9 [(M+H)+]; Rt= 0.375 min.

[0511] Step 3: Preparation of 5-(2-hydroxyethoxy)-4-(methoxymethyl)-N-methyl-9H- pyrido[ 3, 4-b ]indole-3-carbox amide

[0512] To a mixture of ethyl 5-(2 -hydroxy ethoxy)-4-(methoxymethyl)-9H-pyrido[3, 4- b]indole-3- carboxylate (90 mg, 261.35 pmol, 1 eq) in toluene (2 mL) was added MeNEE (2 M, 196.02 pL, 1.5 eq) and AlMes (2 M, 261.35 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mLx3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral condition). Column: WePure Biotech XP tC18 150 pm x 40 pm x 7 pm; mobile phase: [H2O (10 mM NELElCOs^ACN]; gradient: 5%-35% B over 8.0 min Compound 5 -(2-hydroxy ethoxy)- 4- (methoxymethyl)-N-methyl-9H-pyrido [3, 4-b]indole-3 -carboxamide (32 mg, 97.16 pmol, 37.18% yield, 100% purity) was obtained as a white solid. ' H NMR (400 MHz, CD3OD) 5 = 8.73 (s, 1H), 7.53 (t, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.73 (s, 2H), 4.38 - 4.33 (m, 2H), 4.12 - 4.06 (m, 2H), 3.29 (s, 3H), 2.99 (s, 3H). LC-MS (ES+, m / z): 330.1 [(M+H)+]; Rt=1.945 min.

[0513] Example 105. Synthesis of ethyl 4-ethyl-5-(3-methoxypropyl)-9H-pyrido[3,4- b]indole-3 -carboxylate and 5-(2 -methoxy ethoxy)-4-(methoxymethyl)-N-methyl-9H- pyrido[3,4-b]indole-3- carboxamide (Compound 111)

[0514] Step 1 : Preparation of ethyl 5-hydroxy-4-(methoxymethyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0515] To a solution of ethyl 5-benzyloxy-4-(methoxymethyl)-9H-pyrido[3,4- b]indole-3 -carboxylate (0.9 g, 2.31 mmol, 1 eq) in EtOH (9 mL) was added Pd / C (0.3 g, 10% load) under Ar atmosphere. The mixture was stirred under H2 (15 Psi) at 25 °C for 6 h. The mixture was filtered by celite and the filtrate was concentrated under reduced pressure to get ethyl 5-hydroxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole- 3-carboxylate (0.6 g, 2.00 mmol, 86.67% yield) as a brown solid. 'HNMR (400 MHz, CDCI3) 8 = 10.63 (s, 1H), 8.88 (s, 1H), 8.79 (br s, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.43 (s, 2H), 4.53 (q, J = 7.1 Hz, 2H), 3.57 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H)

[0516] Step 2: Preparation of ethyl 4-ethyl-5-(3-methoxypropyl)-9H-pyrido[3,4- b ]indole-3-carboxylate

[0517] A mixture of ethyl 5-hydroxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylate (150 mg, 499.49 pmol, 1 eq), 1 -bromo-2-methoxy-ethane (83.31 mg, 599.38 pmol, 56.33 pL, 1.2 eq), K2CO3 (151.87 mg, 1.10 mmol, 2.2 eq) in DMF (3 mL), then the mixture was stirred at 100 °C for 3 h under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, petroleum ether / ethyl acetate=10 / l to 3 / 1) to get ethyl 5-(2-methoxyethoxy)-4-(methoxymethyl)- 9H-pyrido[3,4-b]indole-3-carboxylate (100 mg, 279.03 pmol, 55.86% yield) was obtained as a yellow solid. 'H NMR (400 MHz, CDCI3) 5 = 9.19 (br s, 1H), 8.77 (s, 1H), 7.47 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 5.67 (s, 2H), 4.49 (q, J = 7.2 Hz, 2H), 4.40 - 4.35 (m, 2H), 3.97 - 3.93 (m, 2H), 3.52 (s, 3H), 3.36 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS (ES+, m / z): 359.1 [(M+H)+]; Rt= 1.893 min.

[0518] Step 3: Preparation of 5-(2-methoxyethoxy)-4-(methoxymethyl)-N-methyl-9H- pyrido[ 3, 4-b ] indole-3- carboxamide

[0519] To a mixture of ethyl 5-(2 -methoxy ethoxy)-4-(methoxymethyl)-9H-pyrido[3, 4- b]indole-3- carboxylate (0.08 g, 223.22 pmol, 1 eq) in toluene (1.6 mL) was added MeNH2in THF (2 M, 167.42 pL, 1.5 eq) and AlMe3(2 M, 223.22 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. The reaction mixture (combined with another batch at 70 mg scale) was added water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: WePure Biotech XP tC18 150 pm x 40 pm x 10 pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 10%-40% B over 8.0 min) to get 5-(2- methoxyethoxy)-4-(methoxymethyl)-N-methyl-9H-pyrido[3,4-b]indole-3- carboxamide (58 mg, 99.37% purity) as a white solid.1H NMR (400 MHz, CD3OD) 5 = 8.68 (s, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 5.69 (s, 2H), 4.39 (dd, J = 3.6, 5.3 Hz, 2H), 3.95 (dd, J = 3.7, 5.4 Hz, 2H), 3.49 (s, 3H), 3.34 (s, 3H), 2.99 (s, 3H). LC-MS (ES+, m / z): 344.1 [(M+H)+]; Rt= 1.607 min. Example 106. Synthesis of ethyl 4-(methoxymethyl)-5-(oxetan-3-ylmethoxy)-9H- pyrido[3,4-b]indole-3- carboxylate and 4-(methoxymethyl)-N-methyl-5-(oxetan-3- ylmethoxy)-9H-pyrido[3,4-b]indole-3- carboxamide (Compound 113)

[0520] Step 1 : Preparation of ethyl 4-(methoxymethyl)-5-(oxetan-3-ylmethoxy)-9H- pyrido[ 3, 4-b ] indole-3- carboxylate

[0521] A mixture of ethyl 5-hydroxy-4-(methoxymethyl)-9H-pyrido[3,4-b]indole-3- carboxylate (150 mg, 499.49 pmol, 1 eq), 3-(bromomethyl)oxetane (90.51 mg, 599.38 pmol, 1.2 eq), K2CO3(151.87 mg, 1.10 mmol, 2.2 eq) in DMF (3 mL), then the mixture was stirred at 100 °C for 3 h under N2atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / l to 3 / 1) to get ethyl 4-(methoxymethyl)-5-(oxetan-3-ylmethoxy)-9H- pyrido[3,4-b]indole-3 -carboxylate (100 mg, 269.98 pmol, 54.05% yield) as a yellow solid.1H NMR (400 MHz, CDC13) 8 = 9.31 (br s, 1H), 8.79 (s, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 8.1 Hz, 1H), 5.50 (s, 2H), 5.03 (t, J = 7.0 Hz, 2H), 4.63 (t, J = 6.0 Hz, 2H), 4.54 (d, J = 7.5 Hz, 2H), 4.49 (q, J = 7.2 Hz, 2H), 3.75 - 3.66 (m, 1H), 3.30 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). LC-MS (ES+, m / z): 371.1 [(M+H)+]; Rt= 1.820 min.

[0522] Step 2: Preparation of 4-(methoxymethyl)-N-methyl-5-(oxetan-3-ylmethoxy)~ 9H-pyrido[ 3, 4-b ]indole-3-carboxamide

[0523] To a solution of ethyl 4-(methoxymethyl)-5-(oxetan-3-ylmethoxy)-9H- pyrido[3,4-b]indole-3- carboxylate (0.08 g, 215.98 pmol, 1 eq) in toluene (1.6 mL) was added MeNH2in THF (2 M, 161.99 pL, 1.5 eq) and AlMe3(2 M, 215.98 pL, 2 eq) in a sealed tube. The mixture was stirred at 100 °C for 2 h. The reaction mixture (combined with another batch at 70 mg scale) was added water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: WePure Biotech XP tC 18 150 m x 40 um x 10 uum; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 10%-40% B over 8.0 min) to get 4-(methoxymethyl)- N-methyl-5-(oxetan-3-ylmethoxy)-9H-pyrido[3,4-b]indole-3-carboxamide (33 mg, 97.11% purity) as a gray solid. 1H NMR (400 MHz, MeOD-d4) 6 = 8.70 (s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 5.55 (s, 2H), 5.00 (dd, J = 6.4, 7.7 Hz, 2H), 4.65 (t, J = 6.1 Hz, 2H), 4.57 (d, J = 7.3 Hz, 2H), 3.78 - 3.69 (m, 1H), 3.26 (s, 3H), 2.98 (s, 3H). LC-MS (ES+, m / z): 356.1 [(M+H)+]; Rt= 1.546 min.

[0524] Example 107. Additional exemplary compounds

[0525] The compounds in Table 1 were prepared analogous to the examples listed in the column “Preparation method”

[0526] Table 1. Structure, analytical data for additional exemplary analogs

[0527] Example 108. GABA-A receptor affinity

[0528] The apparent affinity of test compounds to GABA-A receptors was determined using the GABA-A (Non-Selective) Rat Ion Channel [3H]-Flunitrazepam Binding Agonist Radioligand LeadHunter Assay, commercially available at Eurofins (“GAB AA-Non-Selective-Rat-Ion-Channel-3H-Flunitrazepam -Binding- Agonist- Radioligand-LeadHunter-Assay-FR” n.d.). In general, concentration response curves including up to 5 different concentrations were obtained. Available information about the radioligand binding assay used to establish the GAB A-A affinity for test compounds is presented in Table 2.

[0529] Table 2. Radioligand binding assay information

[0530] Assay 2:

[0531] For some test compounds, the apparent affinity to GABA-A receptors was also determined using the GABA-A (Non- Selective) Rat Ion Channel [3H]-Rol51788 Assay, commercially available at Reaction Biology

[0532] Materials / Solutions:

[0533] Reaction Buffer: 50 mM Tris-HCl (pH8.0); 3 mM MgCh; 0.5 mM CaCh

[0534] Wash Buffer: 50 mM Tris-HCl (pH8.0)

[0535] Rat Brain Membrane: 8.70 g in 43.5 mL homogenizing buffer (BioIVT S05244) [3H]-Rol51788 (Revvity NET757250UC)

[0536] Protocol:

[0537] (1) Flumazenil (unlabeled reference compound) and test compounds are added to a 96-well Reaction Plate using Tecan D300e Digital Dispenser.

[0538] (2) Rat brain membrane is diluted to 50% in Reaction Buffer. (3) [3H]-Rol51788 is diluted to 30 nM concentration in Reaction Buffer.

[0539] (4) Diluted membrane (100 pL) is added to all wells of Reaction Plate.

[0540] (5) Diluted [3H]-Rol51788 (50 pL) is added to all wells of Reaction Plate (final concentration 10 nM).

[0541] (6) Incubate Reaction Plate at room temperature for 90-120 min with gentle rocking.

[0542] (7) After incubation, the reactions are transferred to PEI-treated 96-well Filter Plate using vacuum filtration.

[0543] (8) The Filter Plate is then washed 6x with ice-cold Wash Buffer and transferred to a 30C oven for 1 h.

[0544] (9) The Filter plate is allowed to fully dry overnight at room temperature.

[0545] (10) A BackSeal is applied to the Filter plate and 100 pl Microscint-0 added to each well and incubated for 4 h with gentle rocking.

[0546] (11) The Filter Plate is then read on a Revvity MicroBeta Microplate Counter.

[0547] GABA-A electrophysiology profiling

[0548] Compounds were assessed at up to 3 concentrations against GABA-A aip2y2 in positive allosteric modulator (PAM) mode at GABA EC20 using the SyncroPatch automated platform at room temperature. Compounds were prepared as 10 mM DMSO stocks.

[0549] Concentrations and replicates: 3 concentrations of compounds were tested across the plate, with a single concentration of compound per well. A minimum of 2 wells are obtained per each concentration of compound. Concentrations were chosen as lOx, lOOx or lOOOx the binding affinity Ki.

[0550] Controls for GABA EC20: Up to 6 concentrations of diazepam and the negative control, DMSO (0.2%) at the concentrations described in Table 3, are assessed with a single concentration of compound per well.

[0551] Table 3. Reference controls final concentrations used Storage: Powder stocks are stored at room temperature and DMSO stocks are stored at -20°C post assessment.

[0552] Solutions: The standard extracellular solution (NE-1) contains: 140 mM NaCl, 4 mM KC1, 2 mM CaCh, 1 mM MgCh, 10 mM HEPES, 5 mM Glucose and 0.2% DMSO, pH 7.4 with NaOH. The standard intracellular solution (NI-12) contains: 50 mM KF, 90 mM KC1, 1.5 mM MgCh, 11.1 mM EGTA and 10 mM HEPES, pH 7.2 with KOH. 2 mM of NaATP is added fresh on the day of testing.

[0553] Voltage protocol: A steady-state voltage pulse at -80 mV is applied throughout the assay.

[0554] Application protocol: The SyncroPatch assay is performed at room temperature. A fast application protocol is used, in which the ligand is rapidly applied and then removed from the cell. To test for PAM activity, the agonist (GABA EC 20) is applied three times as a control and to show reproducibility, followed by a minimum 2-minute pre-incubation of client compound and then re-application of agonist (GABA EC20) in the presence of client compound. Finally, a saturating concentration of agonist (GABA EC100) is applied. An example of this is shown in FIG. 1.

[0555] Analysis: Automated patch clamp-recordings are performed using the SyncroPatch 384i. The voltage protocol generation and data collection are performed with Patch Controller 384 V2.2 and Data Controller V2.2.1.

[0556] Cells are removed under the following QC conditions:

[0557] • Identifiable solution exchange artefacts

[0558] • Identifiable unstable baseline

[0559] • Lack of Diazepam activity as a PAM compound at GABA EC20

[0560] • Lack of Bicuculline activity as a NAM compound at GABA ECso

[0561] To determine PAM activity, the fold increase is generated using the following equation,

[0562] ( comp I control - 1 , where Icomp is the current amplitude in the presence of the compound and I control is the current amplitude in the presence of GABA EC20 alone. This builds a concentration-response curve, where + represents PAM activity < 100%, ++ represents PAM activity between 100% and 200%, and +++ represents PAM activity >200%. The results are shown in Table 4.

[0563] Table 4. Results of GABA-A electrophysiology profiling

[0564]

[0565] N / A = not available

[0566] Example 109: In vivo inhibition of harmaline-induced tremor

[0567] The therapeutic effects of compounds of this disclosure were evaluated preclinically using a harmaline mouse model. Propranolol (2.5, 5 or 10 mg / kg, i.p.) was used as a reference control and harmaline (30 mg / kg, i.p.) was used to induced tremor activity measured with a piezoelectric plate in male CD-I mice.

[0568] The study design is shown in the FIG. 2. Harmaline was formulated in saline (10 mL / kg) and dosed at 30 mg / kg, 10 mL / kg, via i.p. injection, n=15. Propranolol was formulated in saline, and used at 2.5 to 10 mg / kg, 10 mL / kg, via i.p. injection, n=15. Test article was dosed at 0.1 to 10 mg / kg, 10 mL / kg, i.p. or p.o., n=15. All compounds were formulated on each day of dosing and all dosing or animal handling was carried out blinded by dedicated staff, respectively.

[0569] Experimental conditions

[0570] 1. Mouse were allowed to acclimate in standard laboratory animal facility conditions for at least 5-7 days prior to use.

[0571] 2. Mouse were placed in a Plexiglas chamber with a piezoelectric plate attached at the bottom to transduce tremor behavioral into electronic signal. Electric signal of tremor is amplified lOOx with A-M Systems (model 1700) and digitized with CED- micro 1401 at a sampling rate of 512 Hz and saved in “smr” format for offline analyses using Spike-2 software (version 7.07).

[0572] 3. One day prior to the first testing day, a naive mouse was put in the testing chamber to verify the spontaneous activity baseline is within the range of 3000-10000 uv, this sensitivity level generally allows the detection of all the tremor signal with the system.

[0573] 4. Test was done between 9:30 AM- 16:00 PM. A 5 groups experiment (5x15=75 mice) was done on 4 days with balanced group arrangement each day.

[0574] 5. The animals were randomly assigned into each treatment group and across the testing days.

[0575] 6. In each testing day, each mouse will be allowed for at least 30-min acclimation session in the test room. 7. Prior to testing, the mouse was placed into the testing chamber for a 5 min system offset to ensure the baseline activity is within the accepted range (3000-10000 uv), followed by a 10 min baseline recording (pre-dose) in the testing chamber.

[0576] 8. Each mouse was administered with test article, propranolol or vehicle control at 20 min prior to Harmaline injection.

[0577] 9. After that, the mouse was kept in the test chamber, and a 20 min baseline recording was conducted (-20 min to 0 min) before Harmaline (30 mg / kg) treatment (pre- harmaline). Testing of 8 mice was carried out simultaneously by using 8 testing chambers in a counterbalanced order.

[0578] 10. After 20 min baseline recording (-20 min to 0 min), each mouse was i.p. -dosed with Harmaline (30 mg / kg) or Saline.

[0579] 11. Post Harmaline effect was measured for 20 min (0 min to 20 min).

[0580] Power spectral density analysis

[0581] Electrical tremor signal was processed with fast Fourier transform (FFT) at resolution of 0.5 Hz bin. PZ power density was computed from 20 min before and 20 min after Harmaline injection (10 min to 30 min) in the frequency range between 1 to 40 Hz. Non-normalized power density after Harmaline administration was plotted in 0.5 Hz bins. Changes of power density after Harmaline administration were normalized to 1) the average of the 10 min baseline; 2) the average of the 20 min baseline of each mouse in 0.5 Hz bins. Average power density over the appropriate bandwidth (7-20 Hz band, 8-13 Hz band or 9-12 Hz band) was expressed in percent change relative to baseline value individually and plotted as a bar graph. Average maximum power density across the corresponding frequency band in 0.5 Hz bins was calculated and plotted as a bar graph.

[0582] Power-time analysis

[0583] Electrical tremor signal was processed with fast Fourier transform (FFT) in time bins of 1 min through the appropriate frequency bandwidth (7-20 Hz band, 8-13 Hz band or 9-12 Hz band). Non-normalized average power density over the chosen frequency range from 20 min pre-harmaline to 20 min post-harmaline administration in 1 minute bins was plotted as a line graph (See FIG. 6). Raw data of non-normalized power density was collected over the frequency band from 20 min pre-harmaline to 20 min post-harmaline administration from individual animals in each group. Changes of power density after Harmaline administration were normalized to 1) the average of the 10 min baseline; 2) the average of the 20 min baseline of each mouse in a time bin of 1 min. Area under the power change-time curve (AUC) over the 20 min time period after Harmaline administration was calculated for each mouse and average of AUC was plotted as a bar graph. Dominant EEG frequency over time period from pre-harmaline to 20-min post was also established and plotted.

[0584] Statistical analysis

[0585] Data was reviewed and a data point that met the criterion for an outlier (based on being outside the mean ± 2SD) was excluded from further analysis. Two-Way ANOVA followed by Bonferroni post-hoc test was applied in line graphs for absolute data and normalized data:

[0586] 1. Veh / Harmaline vs. Propranolol / Harmaline

[0587] 2. Veh / Harmaline vs. test article / Harmaline

[0588] Student t-test was applied in bar graphs for absolute data and normalized data to compare:

[0589] 1. Veh / Harmaline vs. Propranolol / Harmaline

[0590] 2. Veh / Harmaline vs. test article / Harmaline

[0591] One-way ANOVA was applied in bar graphs for absolute data and normalized data to compare:

[0592] 1. Veh / Harmaline vs. test article / Harmaline

[0593] Example 110: Pharmacokinetics and brain penetration

[0594] Pharmacokinetic profiles and brain distribution of test compounds (e.g., 6- (benzyloxy)-7V-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide) were investigated following the time course for the plasma concentrations after a single intravenous (i.v.) or oral (p.o.) administration to male C57BL / 6 mice.

[0595] The i.v. and p.o. dosing solutions were prepared in 5% DMSO + 5% solutol HS 15 + 90% saline at 0.2 and 1 mg / mL, respectively. The limit of quantification LoQ was 1.00 ng / mL for 6-(benzyloxy)-7V-ethyl-4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3- carboxamide in mouse plasma.

[0596] Analysis of pharmacokinetic parameters indicates that 6-(benzyloxy)-7V-ethyl- 4-(methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide dosed at 1 mg / kg i.v. or 10 mg / kg p.o. in male C57BL / 6 mice has moderate clearance (36.7 mL / min / kg), short half- life (0.3 h) and low to moderate volume of distribution (0.74 L / Kg). The oral leg showed a good Cmax (554 ng / mL), short Tmax (0.25h) and short half-life (Ti / 2=lh) and low oral bioavailability (F=9.2%). See FIG. 8.

[0597] Brain penetration was investigated in mice by dosing 6-(benzyloxy)-7V-ethyl-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide via single i.p. administration to male C57BL / 6 mice. The dosing solution was prepared in 20% hydroxypropyl-P- cyclodextrin (HP-P-CD) in water at 0.3 mg / mL. Brain tissue was homogenized with 3 volumes (v / w) of PBS and then analyzed with LC-MS / MS. The brain concentration was corrected with a dilution factor of 4 as following:

[0598] Brain concentration = Brain homogenate concentration x 4 assuming 1 g wet brain tissue equals to 1 mL. The limit of quantification was 1.00 ng / mL or ng / g for 6-(benzyloxy)-V-ethyl-4-(methoxymethyl)-97 / -pyrido[3,4- Z>]indole-3 -carboxamide in mouse plasma and brain homogenate, respectively. Values of brain / plasma concentration suggest free passage of 6-(benzyloxy)-7V-ethyl-4- (methoxymethyl)-9J / -pyrido[3,4-Z>]indole-3 -carboxamide across the blood-brain barrier in mouse. See FIG. 9.

[0599] Example 111. Inhibition of pentylenetetrazole-induced seizures

[0600] Adult male CD-I mice (25-35 g; n = 10 per group; Vital River, Beijing, China) were used. Mice were fed ad lib and kept at a 12: 12 light-dark cycle throughout the experiment (lights on at: 5 am - 5 pm)

[0601] Mice were administered compound 28 (10, 30, or 100 mg / kg; 30 min pretreat) or vehicle (5% DMAC + 5% Solutol HS 15 + 90% saline; 5 mL / kg, PO 30 min prior to subcutaneous administration of 120 mg / kg pentylenetetrazole (PTZ)

[0602] (PTZ; Sigma-Aldrich Co, St Louis, MO, USA) dissolved in 0.9% sterile saline. Immediately after PTZ injection, mice were placed into an observation chamber (25 cm x 15 cm x 15 cm) for 30 min. The latencies to clonic and tonic seizure onset were recorded by a person blinded to the treatment. Clonic seizures were defined as seizures that persisted for >3 seconds followed by an absence of righting reflex. Tonic seizures were defined as rigid extension of all four limbs exceeding a 90° angle with the body plane. Statistical significance was assessed with GraphPad Prism software using one-way ANOVA with Dunnett’s post- hoc test for multiple comparisons. Sedative side effect is observed at the time right before dosing PTZ of each mouse, and marked in a 4-grade scale below:

[0603] • None: normal behavior

[0604] • Mild sedation: mouse showed less locomotion or immobility when stayed alone, but showed normal locomotion activity if it was touched by hand.

[0605] • Moderate sedation: mouse showed immobility when stayed alone; and reduced capability of locomotion when it was pushed or touched by hand.

[0606] • Severe sedation: mouse completely lost the capability of movement.

[0607] Results:

[0608] Compound 28 dosed at 30 and 100 mg / kg (P.O.) significantly increased the latency to clonic / tonic compared to vehicle group (FIG. 10). Compound 28 also significantly increased latency to death at 10 and 100 mg / kg (P.O.) relative to vehicle (FIG. 11). Diazepam (3 mg / kg, P.O.) was used as a positive control.

[0609] OTHER EMBODIMENTS

[0610] It is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein:Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-C8alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-salkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, ORa, and O(CH2)mRa; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rlaand Rlbare each optionally substituted with 1-3 independently selected R4groups; each Rais independently selected from Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2- salkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups; m is 1, 2, 3, 4, or 5;R2is hydrogen or C(O)OR2y; n is 1, 2, 3, or 4;Rxland Rx2are each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-8alkenyl, C2-8alkynyl, 3-10 membered cycloalkyl, and 3-10 membered heterocyclyl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups; o is 1, 2, 3, 4, or 5;each Ryand R2yis independently selected from Ci-Cs alkyl, Ci-shaloalkyl, C2- salkenyl, C2-salkynyl, 3-8 membered cycloalkyl, and 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, C2-salkenyl, C2-salkynyl, 3-10 membered cycloalkyl, and 3-10 membered heterocyclyl of Rxare each optionally substituted with 1-3 independently selected R8groups; andR4, R5, R6, and R7are independently selected from halogen, CN, N(R8)2, OH, Ci-ealkoxyl, Ci-ealkyl, Ci-ehaloalkyl, C2-ealkenyl, C2-ealkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and each R8is independently selected from halogen, Ci-ealkyl and Ci-ehaloalkyl; wherein when R2is hydrogen, Rxlis methoxymethyl, Rx2is C(O)ORy, and Ryis Ci-Cs alkyl; then Rlais not unsubstituted benzyloxy or unsubstituted phenoxy, or Rlbis not hydrogen.

2. The compound of claim 1, wherein:Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, Ci-shaloalkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, ORa, and O(CH2)mRa; m is 1, 2, 3, 4, or 5;Rais selected from Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups; and the Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R1are each optionally substituted with 1-3 independently selected R4groups.

3. The compound of claim 1 or 2, wherein:Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, ORa, and O(CH2)mRa; m is 1, 2, 3, 4, or 5;Rais selected from Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups; and the Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R1are each optionally substituted with 1-3 independently selected R4groups.

4. The compound of any one of claims 1-3, wherein:Rlaand Rlbare each independently selected from hydrogen, halogen, OH, CN, Ci-Cs alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl, ORa, and O(CH2)mRa; m is 1;Rais selected from Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl; the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Raare each optionally substituted with 1 or 2 independently selected R5groups; and the Ci-Cs alkyl, Ci-shaloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of R1are each optionally substituted with 1 or 2 independently selected R4groups.

5. The compound of any one of claims 1-4, wherein Rlaand Rlbare each independently selected from hydrogen and CN.

6. The compound of any one of claims 1-4, wherein Rlaand Rlbare each independently selected from hydrogen and OH.

7. The compound of any one of claims 1-4, wherein Rlaand Rlbare each independently selected from hydrogen and Ci-Cs alkyl.

8. The compound of any one of claims 1-4, wherein Rlaand Rlbare each independently selected from hydrogen, and 6-10 membered aryl.

9. The compound of any one of claims 1-4, wherein Rlaand Rlbare each independently selected from hydrogen and 0(CH2)mRa; m is 1; Rais selected from 6- 10 membered aryl and 5-10 membered heteroaryl; and the 6-10 membered aryl, 5-10 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups.

10. The compound of any one of claims 1-4, wherein Rlaand Rlbare each independently selected from hydrogen and O(CH2)mRa; m is 1; Rais selected from phenyl and 5-6 membered heteroaryl; and the phenyl and 5-6 membered heteroaryl of Raare each optionally substituted with 1-3 independently selected R5groups.

11. The compound of claim 14 or 15, wherein R5is halogen.

12. The compound of any one of claims 1-11, wherein:Rxland Rx2are each independently selected from hydrogen, CN, Ci-Cs alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups; o is 1, 2, 3, 4, or 5; andRyor R2yis independently Ci-Cs alkyl, Ci-shaloalkyl, or 3-8 membered cycloalkyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, and 3-10 membered cycloalkyl of Ryor R2yare each optionally substituted with 1-3 independently selected R8groups.

13. The compound of any one of claims 1-12, wherein:Rxland Rx2are each independently selected from CN, Ci-Cs alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rxland Rx2are each optionally substituted with 1-3 independently selected R7groups; o is 1, 2, 3, 4, or 5; andRyor R2yis independently Ci-Cs alkyl, Ci-shaloalkyl, or 3-8 membered cycloalkyl; wherein the Ci-Cs alkyl, Ci-shaloalkyl, and 3-10 membered cycloalkyl of Ryor R2yare each optionally substituted with 1-3 independently selected R8groups.

14. The compound of any one of claims 1-18, wherein:Rxland Rx2are each independently selected from CN, Ci-Cs alkyl, 6-10 membered aryl, 5-10 membered heteroaryl, C(O)Ry, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, ORy, and O(CH2)oRy; or Rxland Rx2together form a 3-8 membered cycloalkyl or a 3-8 membered heterocyclyl; wherein the Ci-Cs alkyl, 6-10 membered aryl, and 5-10 membered heteroaryl of Rxland Rx2are each optionally substituted with 1 or 2 independently selected R7groups; o is 1;Ryis Ci-Cs alkyl, Ci-shaloalkyl, or 3-8 membered cycloalkyl; wherein the Ci- Csalkyl, Ci-shaloalkyl, and 3-10 membered cycloalkyl of Ryare each optionally substituted with 1 or 2 independently selected R8groups; andR7and R8are independently selected from halogen, Ci-ealkyl, and Ci- ehaloalkyl.

15. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from CN, C(O)ORy, C(O)N(Ry)2, C(O)NHRy, (CH2)oORy, 5-10 membered heteroaryl optionally substituted with 1 or 2 independently selected R7groups.

16. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from CN and (CH2)oORy; wherein o is 1 and Ryis Ci-ealkyl.

17. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from C(O)ORyand (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl.

18. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from 5-10 membered heteroaryl optionally substituted with a R7group and (CH2)oORy; wherein o is 1, each Ryis independently selected from Ci-ealkyl, and the R7group is Ci-ehaloalkyl.

19. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from a 5-membered heteroaryl optionally substituted with a R7group and (CH2)oORy; wherein o is 1, Ryis Ci-ealkyl, and the R7group is Ci-ehaloalkyl.

20. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from a 6-membered heteroaryl and (CH2)oORy; wherein o is 1, and Ryis Ci-ealkyl.

21. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from C(O)N(Ry)2 and (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl.

22. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from C(O)NHRyand (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl.

23. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from C(O)NHRyand (CH2)oORy; wherein o is 1 and each Ryis independently selected from Ci-ealkyl and Ci-ehaloalkyl.

24. The compound of any one of claims 1-14, wherein Rxland Rx2are each independently selected from C(O)NHRyand (CH2)oORy; wherein o is 1, each Ryis independently selected from Ci-ealkyl and 3-8 membered cycloalkyl optionally substituted with 1 or 2 independently selected R8groups, and the 1 or 2 independently selected R8groups are halogen.

25. The compound of any one of claims 1-24, wherein Rxlis (CH2)oORy; wherein o is 1 and Ryis Ci-ealkyl.

26. The compound of any one of claims 1-25, wherein Rxlis (CH2)oORy; wherein o is 1 and Ryis methyl.

27. The compound of any one of claims 1-14, wherein Rxland Rx2together form a 5-membered heterocyclyl.

28. The compound of any one of claims 1-11, wherein Rxland Rx2are hydrogen.

29. The compound of any one of claims 1-11, wherein Rxland Rx2are hydrogen or C(O)ORy.

30. The compound of claim 29, wherein Ryis Ci-ealkyl.

31. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound of any one of claims 1- 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. A method of treating a neurological disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32.

34. The method of claim 33, wherein the neurological disorder is essential tremor.

35. The method of claim 33, wherein the neurological disorder is epilepsy.

36. The method of claim 33, wherein the neurological disorder is a seizure.

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