Tryptamine and methods of treating mood disorders

Abstract

Novel tryptamine compounds according to formulae (1), (2), (3), (4), (5) and (6) and their sub-formulae, pharmaceutical salts thereof, and pharmaceutical compositions thereof, and methods of treating mood disorders, including depressive disorders and bipolar mood disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of formulae (1), (2), (3), (4), (5) and (6), or a pharmaceutical composition thereof.

Description

[0001] Background

[0002] Depression is a common psychological problem and refers to a mental state of low mood and aversion to activity. The various symptoms associated with depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, and / or worthlessness, lethargy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleep, overeating, loss of appetite, insomnia, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of these symptoms vary according to the specific circumstances.

[0003] Approximately one-third of patients with major depressive disorder (MDD) fail to achieve remission of their symptoms even after multiple rounds of treatment with several known classes of antidepressants, including selective serotonin reuptake inhibitors (SSRI) (Rush et al., 2006). This high prevalence of treatment-resistant depression (TRD) creates a need for new and more effective pharmaceutical therapies for depression that target new mechanisms and / or patient populations.

[0004] Tryptamines are monoamine alkaloids that contain an indole ring and are structurally similar to the amino acid tryptophan, from which they derive their name. There are a large number of tryptamine compounds, including naturally occurring compounds and chemical derivatives with similar structures, which can be either unsubstituted or substituted on the ring. Many tryptamines are 5-HT2A receptor agonists and / or modulators of other serotonin receptors and are known to have psychoactive properties and, in many cases, cause long-lasting hallucinations. The most well-known tryptamines are psychedelic compounds, including compounds derived from hallucinogenic fungi (psilocybin and psilocin), N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), bufotenin, and ibogaine. These compounds are known to have a significant impact on thought, perception, and behavior. However, these compounds are currently classified as Schedule I drugs under the Controlled Substances Act because they have a high potential for abuse, no accepted medical use, and a lack of established safety. In addition, tryptamines are metabolized by multiple pathways, including monoamine oxidase in some cases, which limits the oral bioavailability of some compounds and results in a very short duration of action. In contrast, the duration of action of other tryptamines is very long, which makes their use challenging in a therapeutic setting where a supervised process lasting many hours is costly and inconvenient for both patients and healthcare providers. Therefore, there is still a need for safe and effective tryptamine compounds that can be reliably used to treat mood disorders. SUMMARY OF THE INVENTION

[0005] In a first aspect, the present disclosure relates to compounds of the following structure:

[0006]

[0007] and its pharmaceutically acceptable salts.

[0008] In formula (1), R 1 , R 2 , R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group having 1 to 5 carbon atoms (R); (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 4 is selected from H and an esterifying group that causes OR 4 to be an ester group; R 5 is selected from H and a hydrocarbon group having 1 to 5 carbon atoms (R); R 7 , R 7’ , R 8 and R 8’ are independently selected from H and F atoms; and R a , R b , R c and R d are independently selected from H and D atoms. The present disclosure also includes pharmaceutical compositions of the compounds of formula (1) and methods of using the same.

[0009] In a second aspect, the present disclosure relates to compounds having the following structure:

[0010]

[0011] and its pharmaceutically acceptable salts.

[0012] In formula (2), R 9 , R 10 and R 13 are independently selected from: (i) H; (ii) a hydrocarbon group having 1 to 5 carbon atoms (R); (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 11 is selected from H and an esterifying group that causes OR 11 to be an ester group; R 12 is isopropyl or cyclopropyl, optionally substituted with one or more fluorine atoms; R 14 and R 15 are independently selected from H and a hydrocarbon group having 1 to 5 carbon atoms (R), optionally substituted with one or more fluorine atoms; and R a , R b , R c and Rd independently selected from H and D atoms; provided that when R 9 , R 10 , R 11 , R 13 , R a , R b , R c and R d is H and R 12 is isopropyl, then R 14 and R 15 are not both methyl. The present disclosure also includes pharmaceutical compositions of the compounds of formula (2) and methods of using the same.

[0013] In a third aspect, the present disclosure relates to compounds having the following structure:

[0014]

[0015] and pharmaceutically acceptable salts thereof.

[0016] In formula (3), R 1 , R 2 , R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group containing 1 - 5 carbon atoms (R); (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 4 is selected from H and an esterifying group that causes OR 4 to be an ester group; R 5 is selected from H and a hydrocarbon group containing 1 - 5 carbon atoms (R); R a , R b , R c and R d are independently selected from H and D atoms; and R 16 is an allyl or propargyl group. The present disclosure also includes pharmaceutical compositions of the compounds of formula (3) and methods of using the same.

[0017] In a fourth aspect, the present disclosure relates to compounds having the following structure:

[0018]

[0019] In formula (4), R 1 is selected from: F, Cl, and methyl; R 2 , R 3 and R 6R is independently selected from: i) H; (ii) a hydrocarbon group (R) containing 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; 4 Select H and result in OR 4 is an esterification group of an ester group; R 5 is selected from H and a hydrocarbon group (R) containing 1 to 5 carbon atoms; R a , R b , R c and R d are independently selected from H and D atoms; and R 19 is selected from H and a hydrocarbon group (R) containing 1 to 5 carbon atoms, which is optionally substituted by one or more fluorine atoms. In an embodiment, the following first premise applies: when R 1 is F or methyl and R 2 , R 3 , R 4 , R 6 , R 19 , R a , R b , R c and R d When both are H, then R 5 is not H or methyl. In an embodiment, the following second premise applies: when R 1 Cl and R 2 , R 3 , R 4 , R 6 , R 19 , R a , R b , R c and R d When both are H, then R 5 is not H, methyl or ethyl. In an embodiment, the following third premise applies: when R 1 is F and R 2 , R 3 , R 4 , R 6 , R a , R b , R c and R d When both are H, then R 5 and R 19 Not all are methyl. Any one, two or all three of the first, second and third premises can be combined. The present disclosure also includes pharmaceutical compositions of compounds of formula (4) and methods of using the same.

[0020] In a fifth aspect, the present disclosure relates to compounds of the following structure:

[0021]

[0022] In formula (5), R 1 , R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 - 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 2 is selected from: F, Cl, and methyl; R a , R b , R c and R d are independently selected from H and D atoms; and R 20 is selected from H and a hydrocarbon group (R) having 1 - 5 carbon atoms, optionally substituted by one or more fluorine atoms. In an embodiment, the following precondition applies: when R 2 is F, R 3 is not methyl or OH. The present disclosure also includes a pharmaceutical composition of the compound of formula (5) and methods of using the same.

[0023] In a sixth aspect, the present disclosure relates to a compound having the following structure:

[0024]

[0025] In formula (6), R 1 , R 2 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 - 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 3 is selected from: F, Cl, and methyl; R a , R b , R c and R d are independently selected from H and D atoms; and R 21 is selected from H and a hydrocarbon group (R) having 1 - 5 carbon atoms, optionally substituted by one or more fluorine atoms. In an embodiment, the following first precondition applies: when R 3 is methyl, R 2 is not F and R 6 is not methyl. In an embodiment, the following second precondition applies: when R 3 is methyl and R 1 , R 2 , R 6, R a , R b , R c and R d When all of R 21 is not H, methyl or ethyl. In an embodiment, the following third premise applies: When R 3 is F or Cl and R 1 , R 2 , R 6 , R a , R b , R c and R d are all H, then R 21 is not H. Any one, two or all three of the foregoing first, second and third premises can be combined. The present disclosure also includes pharmaceutical compositions of the compounds of formula (6) and methods of using the same.

[0026] In a seventh aspect, the present disclosure includes a method of treating an emotional disorder in a patient in need thereof, which includes administering a therapeutically effective amount of any compound of formula (1), (2), (3), (4), (5) or (6) or a pharmaceutical composition thereof. In an embodiment, the method and composition can treat emotional disorders including depressive disorders, bipolar disorders and related disorders, substance-related disorders and / or anxiety disorders. In an embodiment, the depressive disorder is treatment-resistant depressive disorder. In an embodiment, the method and composition can treat emotional disorders including obsessive-compulsive disorder and related disorders. In an embodiment, the method and composition can treat emotional disorders including trauma- and stressor-related disorders. In an embodiment, the method and composition can treat emotional disorders including feeding and eating disorders. In an embodiment, the method and composition can treat emotional disorders including neurocognitive disorders. In an embodiment, the method and composition can treat emotional disorders including neurodevelopmental disorders. In an embodiment, the method and composition can treat emotional disorders including personality disorders. In an embodiment, the method and composition can treat emotional disorders including sexual dysfunction. In an embodiment, the method and composition can treat emotional disorders including gender identity disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] This patent or application document contains at least one color drawing. After requesting and paying the necessary fees, the Patent and Trademark Office will provide a copy of this patent or application publication with color drawings.

[0028] Figure 1 Illustrates the plasma pharmacokinetics of the test compound in male C57BL / 6 mice after subcutaneous (SC) administration (10 mg / kg). DETAILED DESCRIPTION

[0029] As used herein, the term "hydrocarbon group" (also represented by the group R) is defined as a chemical group consisting solely of carbon and hydrogen, but the hydrocarbon group may (i.e., optionally) be substituted by one or more fluorine atoms to result in partial or complete fluorination of the hydrocarbon group. In some embodiments, the hydrocarbon group consists solely of carbon and hydrogen atoms, i.e., does not include fluorine atoms. In other embodiments, the hydrocarbon group is a partially or completely fluorinated hydrocarbon group, such as a fluorinated straight-chain, branched-chain, or cyclic alkyl group, as described in further detail below. The hydrocarbon group typically contains one, two, three, four, or five carbon atoms or a number of carbon atoms within a range defined by any two of the foregoing values (e.g., 1-5, 1-4, 1-3, or 1-2 carbon atoms). The hydrocarbon groups in the different compounds described herein or at different positions in a compound may have the same or different numbers (or preferred ranges thereof) of carbon atoms in order to independently adjust or optimize the physical properties or therapeutic efficacy of the compound.

[0030] In one embodiment, the hydrocarbon group (R) is a straight-chain, branched-chain, or cyclic alkyl group. Some examples of straight-chain alkyl groups having 1-5 carbon atoms include methyl, ethyl, n-propyl, n-butyl, and n-pentyl, as well as their partially or fully fluorinated forms. Some specific examples of fluorinated straight-chain alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2-difluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl (perfluoroethyl), 3-fluoro-n-propyl, 3,3-difluoro-n-propyl, 3,3,3-trifluoro-n-propyl, 1,1,-difluoro-n-propyl, heptafluoro-n-propyl, 4-fluoro-n-butyl, 4,4-difluoro-n-butyl, 4,4,4-trifluoro-n-butyl, 1,1-difluoro-n-butyl, perfluoro-n-propyl, 5-fluoro-n-pentyl, 5,5-difluoro-n-pentyl, 5,5,5-trifluoro-n-pentyl, 1,1-difluoro-n-pentyl, 1,1,2,2-tetrafluoro-n-pentyl, and perfluoro-n-pentyl). Some examples of branched-chain alkyl groups having 1-5 carbon atoms include isopropyl (2-propyl), isobutyl (2-methylprop-1-yl), sec-butyl (2-butyl), tert-butyl (1,1-dimethyleth-1-yl), 2-pentyl, 3-pentyl, isopentyl (3-methylbut-1-yl), 1,2-dimethylprop-1-yl, 1,1-dimethylprop-1-yl, and neopentyl (2,2-dimethylprop-1-yl), as well as their partially or fully fluorinated forms. Some specific examples of fluorinated branched-chain alkyl groups include 2-fluoroisopropyl, 1-fluoroisopropyl, 1,2-difluoroisopropyl, 1,1’-difluoroisopropyl, 1,1,1-trifluoroisopropyl, 1,1,1,1’,1’,1’-hexafluoroisopropyl, perfluoroisopropyl, 3-fluoroisobutyl, 3,3-difluoroisobutyl, 3,3,3-trifluoroisobutyl, and 3,3,3,3’,3’,3’-hexafluoroisobutyl. Some examples of cyclic alkyl groups having 3-5 carbon atoms include cyclopropyl, cyclobutyl, and cyclopentyl, as well as their partially or fully fluorinated forms. Some specific examples of fluorinated cyclic alkyl groups include 2-fluorocycloprop-1-yl, 1-fluorocycloprop-1-yl, 2,2-difluorocycloprop-1-yl, 2,3-difluorocycloprop-1-yl, 2,2,3-difluorocycloprop-1-yl, 2,2,3,3-tetrafluorocycloprop-1-yl, 2-fluorocyclobut-1-yl, 3-fluorocyclobut-1-yl, 2,3-difluorocyclobut-1-yl, 2,2-difluorocyclobut-1-yl, 3,3-difluorocyclobut-1-yl, 2,4-difluorocyclobut-1-yl, 2,3,4-trifluorocyclobut-1-yl, 2,2,4,4-tetrafluorocyclobut-1-yl, 2,2,3,3,4,4-hexafluorocyclobut-1-yl, 2-fluorocyclopent-1-yl, 2,5-difluorocyclopent-1-yl, 2,2-difluorocyclopent-1-yl, 3,4-difluorocyclopent-1-yl, 3,3-difluorocyclopent-1-yl, and 3,3,4,4-tetrafluorocyclobut-1-yl.In some embodiments, any one or more of the foregoing alkyl groups or fluoroalkyl groups are excluded from one or more of the groups in any of the formulas disclosed in this application.

[0031] In another embodiment, the hydrocarbon group (R) is a straight-chain, branched-chain or cyclic alkenyl or alkynyl group. Some examples of straight-chain alkenyl groups containing 2-5 carbon atoms include vinyl, prop-1-en-1-yl (allyl), 3-buten-1-yl (CH2=CH-CH2-CH2-), 2-buten-1-yl (CH2-CH=CH-CH2-), butadienyl, 4-penten-1-yl, 3-penten-1-yl, 2-penten-1-yl and 2,4-pentadien-1-yl. Some examples of branched-chain alkenyl groups include prop-2-en-1-yl (CH2=C.-CH3), 1-buten-2-yl (CH2=C.-CH2-CH3), 1-buten-3-yl (CH2=CH-CH.-CH3), 1-prop-2-methyl-3-yl (CH2=C(CH3)-CH2-), 1-penten-4-yl, 1-penten-3-yl, 1-penten-2-yl, 2-penten-2-yl, 2-penten-3-yl, 2-penten-4-yl and 1,4-pentadien-3-yl and their partially or fully fluorinated forms (e.g., 2-fluoro vinyl, 2,2-difluoro vinyl, 1,2-difluoro vinyl and 1,2,2-trifluoro vinyl), where the dot in any of the foregoing groups indicates the point of attachment. Some examples of cyclic alkenyl groups containing 3-5 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclopentadienyl. Some examples of alkynyl groups containing 2-5 carbon atoms include ethynyl, propargyl (2-propynyl) and 3-butynyl and their partially or fully fluorinated forms. The hydrocarbon group may also contain a cyclic moiety attached to the acyclic moiety, for example, a methylene group attached to a cyclopropyl or cyclobutyl group.

[0032] In a first aspect, the present disclosure relates to compounds of the following structure:

[0033]

[0034] In formula (1), R 1 , R 2 , R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) containing 1-5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom. Their pharmaceutically acceptable salts are also within the scope of formula (1) and all sub-formulas disclosed in this application. In a first group of embodiments, R 1 、R 2 、R3 and R 6 any one, two, three (or all) of which are hydrogen atoms. In a second set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are independently selected from any hydrocarbon group (R) described anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a third set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are independently selected from alkoxy groups (OR), wherein R is selected from any hydrocarbon group (R) described anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a fourth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are independently selected from thioalkoxy groups (SR), wherein R is selected from any hydrocarbon group (R) described anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a fifth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are nitrile (CN) groups. In a sixth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are amino (NH2) groups. In a seventh set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are hydroxyl (OH) groups. In an eighth set of embodiments, R 1 , R 2 , R 3 and R 6Any one or more of them are halogen atoms (e.g., F, Cl, Br, or I atoms). Any two or three of the aforementioned first to eighth embodiments can also be combined, so that R 1 、R 2 、R 3 and R 6 are selected from two or three different groups described above. In other embodiments, for R 1 、R 2 、R 3 and / or R 6 , any one or more of the groups (i)-(viii) provided above can be independently excluded.

[0035] In a first particular embodiment, R 1 in formula (1) is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a second particular embodiment, R 2 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a third particular embodiment, R 3 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a fourth particular embodiment, R 6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. Any one of the first to fourth particular embodiments provided above can also be combined.

[0036] The group R 4 in formula (1) is selected from H and an esterifying group that causes OR 4 to be an ester group. When R 4 is H, OR 4 is a hydroxyl (OH) group. When R 4 is an esterifying group, OR 4 is an ester group. The esterifying group (R 4 ) can cause OR 4 to be any type of ester group, including, for example, a carboxylate, phosphate, or sulfonate ester. For example, R 4 can be -C(O)R to cause OR 4 to be -OC(O)R (carboxylate); or R 4 can be -P(O)(OR’)2, where R’ is independently selected from H and R, to cause OR 4 to be -OP(O)(OR’)2 (phosphate); or R 4 can be -SO2R to cause OR 4is -OSO2R (sulfonate). In addition, R 4 any one of the foregoing embodiments of may be combined with any one or more of the embodiments provided above earlier for R 1 、R 2 、R 3 and R 6 .

[0037] The group R in formula (1) 5 is selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms. In one group of embodiments, R 5 is H. In another group of embodiments, R 5 is a hydrocarbon group (R) having 1 to 5 carbon atoms, such as any R group described in detail anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) described above. In some embodiments, R 5 is selected from one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl. In some embodiments, for R 5 , any one or more of the foregoing R groups are excluded. In addition, any one of the foregoing embodiments of R 5 may be combined with any one or more of the embodiments provided above earlier for R 1 、R 2 、R 3 、R 4 and R 6 .

[0038] The groups R 7 、R 7’ 、R 8 and R 8’ in formula (1) are independently selected from H and F atoms. In one embodiment, R 7 、R 7’ 、R 8 and R 8’ are H atoms. In other embodiments, R 7 or R 8 is an F atom, while R 7’ and R 8’ are H atoms. In another embodiment, R 7 and R 8 are F atoms, while R 7’ and R 8’ are H atoms. In other embodiments, R 7 and R 7’ are F atoms, while R 8and R 8’ is an H atom (or R 8 and R 8’ is an F atom, while R 7 and R 7’ is an H atom). In another embodiment, R 7 、R 7’ 、R 8 and R 8’ are F atoms. In addition, any of the foregoing embodiments of R 7 、R 7’ 、R 8 and R 8’ can be combined with any of the embodiments provided for R 1 、R 2 、R 3 and R 6 、any of the embodiments provided for R 4 and any of the embodiments provided for R 5 .

[0039] The groups R a 、R b 、R c and R d in formula (1) are independently selected from H and D atoms. In one embodiment, R a 、R b 、R c and R d are all H atoms. In another embodiment, exactly one or two of R a 、R b 、R c and R d are D atoms, and the rest (if any) are H atoms. In another embodiment, R a 、R b 、R c and R d are all D atoms.

[0040] In some embodiments, the compound of formula (1) has the following structure:

[0041]

[0042] where R 1 、R 2 、R 3 、R 5 、R 6 、R 7 、R 8 、R 7’ 、R 8’ 、R a 、R b, R c and R d are each independently defined as in formula (1) and any of its sub - embodiments and combinations thereof, as provided above.

[0043] In some embodiments, the compound of formula (1) has the following structure:

[0044]

[0045] wherein R 5 , R 7 , R 8 , R 7’ , R 8’ , R a , R b , R c and R d are each independently defined as in formula (1) and any of its sub - embodiments and combinations thereof, as provided above.

[0046] In some embodiments, the compound of formula (1) has the following structure:

[0047]

[0048] wherein R 7 , R 8 , R 7’ , R 8’ , R a , R b , R c and R d are each independently defined as in formula (1) and any of its sub - embodiments and combinations thereof, as provided above.

[0049] In some embodiments, the compound of formula (1) has the following structure:

[0050]

[0051] wherein R 7 , R 8 , R 7’ and R 8’ are each independently defined as in formula (1) and any of its sub - embodiments and combinations thereof, as provided above.

[0052] In some embodiments, the compound of formula (1) has the following structure:

[0053]

[0054] wherein R a , R b , R c and Rd Independently as defined under formula (1) and any of its sub - embodiments and combinations thereof, as provided above.

[0055] In some embodiments, the compound of formula (1e) has the following specific structure:

[0056]

[0057] In other embodiments, the compound of formula (1e) has the following specific structure:

[0058]

[0059] It can be racemic or enantiomer - (or diastereomer -) enriched or pure.

[0060] In some embodiments, the compound of formula (1e - 2) can be any of the following specific diastereomers or include any of the following specific diastereomers:

[0061]

[0062] Notably, although specific trans - and cis - diastereomers are shown above, the present disclosure also contemplates the following corresponding enantiomers of each diastereomer:

[0063]

[0064] Any enantiomer - enriched or resolved form of compound 8a, 8b, 9a or 9b is contemplated herein, as well as any mixture of these, e.g., a racemic mixture of compound 8a and 8b or a racemic mixture of compound 9a and 9b.

[0065] In a second aspect, the present disclosure relates to compounds having the following structure:

[0066]

[0067] In formula (2), R 9 、R 10 and R 13 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 - 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom. Pharmaceutically acceptable salts thereof are also within the scope of formula (2) and all sub - formulas disclosed in this application. In a first group of embodiments, any one, two, three (or all) of R 9 、R 10 and R 13 are hydrogen atoms. In a second group of embodiments, R 9, R 10 and R 13 Any one or more of which are independently selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a third set of embodiments, R 9 , R 10 and R 13 Any one or more of which are independently selected from alkoxy groups (OR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a fourth set of embodiments, R 9 , R 10 and R 13 Any one or more of which are independently selected from thioalkoxy groups (SR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a fifth set of embodiments, R 9 , R 10 and R 13 Any one or more of which are a nitrile (CN) group. In a sixth set of embodiments, R 9 , R 10 and R 13 Any one or more of which are an amino (NH2) group. In a seventh set of embodiments, R 9 , R 10 and R 13 Any one or more of which are a hydroxyl (OH) group. In an eighth set of embodiments, R 9 , R 10 and R 13 Any one or more of which are a halogen atom (e.g., F, Cl, Br or I atom). Any two or three of the foregoing first to eighth embodiments may also be combined, such that R 9 , R 10 and R 13 are selected from two or three different groups described above. In other embodiments, for R 9 , R 10 and R 13, can independently exclude any one or more of the groups (i)-(viii) provided above.

[0068] In a first particular embodiment of formula (2), R 9 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a second particular embodiment, R 10 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a third particular embodiment, R 13 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. Any one of the first to third particular embodiments provided above can also be combined.

[0069] The group R in formula (2) 11 is selected from H and an esterifying group that results in OR 11 being an ester group. When R 11 is H, OR 11 is a hydroxyl (OH) group. When R 11 is an esterifying group, OR 11 is an ester group. The esterifying group (R 11 ) can result in OR 11 being any type of ester group, including, for example, a carboxylate, phosphate, or sulfonate ester. For example, R 11 can be -C(O)R to result in OR 11 being -OC(O)R (carboxylate); or R 11 can be -P(O)(OR’)2, where R’ is independently selected from H and R, to result in OR 11 being -OP(O)(OR’)2 (phosphate); or R 11 can be -SO2R to result in OR 11 being -OSO2R (sulfonate). In addition, any one of the foregoing embodiments of R 11 can be combined with any one or more of the embodiments provided earlier for R 9 , R 10 , and R 13 .

[0070] The group R in formula (2) 12 is isopropyl or cyclopropyl, with optional substitution by one or more fluorine atoms. In one group of embodiments, R 12 is not substituted by fluorine atoms. In another group of embodiments, R 12 is substituted by one, two, or more fluorine atoms, in which case R 12may be partially or fully fluorinated. In addition, any one of the foregoing embodiments of R 12 may be combined with any one or more of the embodiments provided earlier hereinabove for R 9 、R 10 、R 11 and R 13 .

[0071] The groups R 14 and R 15 in formula (2) are independently selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted with one or more fluorine atoms. In one group of embodiments, both R 14 and R 15 are H. In another group of embodiments, one of R 14 and R 15 is selected from any hydrocarbon group (R) described anywhere hereinabove and hereinbelow, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5 or 3 to 4 carbon atoms) described above. In another group of embodiments, both R 14 and R 15 are independently selected from any hydrocarbon group (R) described anywhere hereinabove and hereinbelow, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5 or 3 to 4 carbon atoms) described above. In a first particular embodiment, either R 14 or R 15 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F and OH, or a subgroup thereof. In a second particular embodiment, both R 14 and R 15 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F and OH, or a subgroup thereof. In addition, any one of the foregoing embodiments of R 14 and R 15 may be combined with any one or more of the embodiments provided earlier hereinabove for R 9 、R 10 、R 11 、R 12 and R 13 .

[0072] The groups R a 、R b 、R c and R d in formula (2) are independently selected from H and D atoms. In one embodiment, Ra and R b and R c and R d are all H atoms. In another embodiment, R a and R b and R c and R d are precisely or at least one or two of them are D atoms, and the rest (if any) are H atoms. In another embodiment, R a and R b and R c and R d are all D atoms.

[0073] In some embodiments, when R 9 and R 10 and R 11 and R 13 and R a and R b and R c and R d are H and R 12 is isopropyl, then R 14 and R 15 are not both methyl. In other embodiments, only when R 9 and R 10 and R 11 and R 13 and R a and R b and R c and R d are not all H and / or when R 12 is not isopropyl (or when R 12 is cyclopropyl), R 14 and R 15 can both be methyl.

[0074] In some embodiments, the following compounds are excluded from the scope of formula (2):

[0075]

[0076] In some embodiments, the compounds of formula (2) have the following structure:

[0077]

[0078] where R 9 and R 10 and R 12 and R 13 and R 14 and R 15 and R a and R b and Rc and R d are each independently defined as in formula (2) and any of its sub - embodiments and combinations thereof, as provided above.

[0079] In some embodiments, the compound of formula (2) has the following structure:

[0080]

[0081] wherein R 9 、R 10 、R 11 、R 13 、R 14 、R 15 、R a 、R b 、R c and R d are each independently defined as in formula (2) and any of its sub - embodiments and combinations thereof, as provided above.

[0082] In some embodiments, the compound of formula (2b) has the following structure:

[0083]

[0084] wherein R 9 、R 10 、R 13 、R 14 、R 15 、R a 、R b 、R c and R d are each independently defined as in formula (2) and any of its sub - embodiments and combinations thereof, as provided above.

[0085] In some embodiments, the compound of formula (2) has the following structure:

[0086]

[0087] wherein R 9 、R 10 、R 11 、R 13 、R 14 、R 15 、R a 、R b 、R c and R d are each independently defined as in formula (2) and any of its sub - embodiments and combinations thereof, as provided above.

[0088] In some embodiments, the compound of formula (2c) has the following structure:

[0089]

[0090] wherein R 9 、R 10 、R 13 、R 14 、R 15 、R a 、R b 、R c and R d are independently defined as under formula (2) and any of its sub - embodiments and combinations thereof, as provided above.

[0091] In some embodiments, the compounds of formula (2) are selected from any of the following specific compounds:

[0092]

[0093] Any enantiomerically or diastereomerically enriched or resolved form of any of the above - mentioned compounds (such as compound 20a, 20b, 21a or 21b) is contemplated herein, as well as any mixtures of any of these, for example, a racemic mixture of compound 20a and 20b or a racemic mixture of compound 21a and 21b.

[0094] In a third aspect, the present disclosure relates to compounds of the following structure:

[0095]

[0096] In formula (3), R 1 、R 2 、R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) containing 1 - 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom. Pharmaceutically acceptable salts thereof are also within the scope of formula (3) and all sub - formulas disclosed in this application. In a first group of embodiments, any one, two, three (or all) of R 1 、R 2 、R 3 and R 6 are hydrogen atoms. In a second group of embodiments, R 1 、R 2 、R 3 and R 6any one or more of which are independently selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a third set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are independently selected from alkoxy groups (OR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a fourth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are independently selected from thioalkoxy groups (SR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) as described above. In a fifth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are a nitrile (CN) group. In a sixth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are an amino (NH2) group. In a seventh set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are a hydroxyl (OH) group. In an eighth set of embodiments, R 1 , R 2 , R 3 and R 6 any one or more of which are a halogen atom (e.g., F, Cl, Br or I atom). Any two or three of the foregoing first to eighth embodiments may also be combined, such that R 1 , R 2 , R 3 and R 6Selected from two or three different groups described above. In other embodiments, for R 1 , R 2 , R 3 and / or R 6 , any one or more of the groups (i)-(viii) provided above can be independently excluded.

[0097] In a first particular embodiment of formula (3), R 1 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a second particular embodiment, R 2 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a third particular embodiment, R 3 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a fourth particular embodiment, R 6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. Any one of the first to fourth particular embodiments provided above can also be combined.

[0098] The group R 4 in formula (3) is selected from H and an esterifying group that results in OR 4 being an ester group. When R 4 is H, OR 11 is a hydroxyl (OH) group. When R 4 is an esterifying group, OR 4 is an ester group. The esterifying group (R 4 ) can result in OR 4 being any type of ester group, including, for example, a carboxylate, phosphate, or sulfonate ester. For example, R 4 can be -C(O)R to result in OR 4 being -OC(O)R (carboxylate); or R 4 can be -P(O)(OR’)2, where R’ is independently selected from H and R, to result in OR 4 being -OP(O)(OR’)2 (phosphate); or R 4 can be -SO2R to result in OR 4 being -OSO2R (sulfonate). In addition, any one of the foregoing embodiments of R 4 can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 and R 6 .

[0099] The group R in formula (3) 5 is selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms. In one set of embodiments, R 5 is H. In another set of embodiments, R 5 is a hydrocarbon group (R) having 1 to 5 carbon atoms, such as any R group described in detail anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) described above. In some embodiments, R 5 is selected from one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl. In some embodiments, for R 5 , any one or more of the foregoing R groups are excluded. Additionally, any one of the foregoing embodiments for R 5 can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 4 and R 6 .

[0100] The group R in formula (3) 16 is an allyl or propargyl group. The allyl group has the structure -CH2-CH=CH2. The propargyl group has the structure -CH2-C≡CH. Additionally, any one of the foregoing embodiments for R 16 can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 4 , R 5 and R 6 .

[0101] The group R in formula (3) a , R b , R c and R d are independently selected from H and D atoms. In one embodiment, R a , R b , R c and R d are all H atoms. In another embodiment, R a , R b , R c and R dPrecisely or at least one or two of them are D atoms, and the rest (if any) are H atoms. In another embodiment, R a 、R b 、R c and R d are all D atoms.

[0102] In some embodiments, the compound of formula (3) has the following structure:

[0103]

[0104] wherein R 1 、R 2 、R 3 、R 5 、R 6 、R 16 、R a 、R b 、R c and R d are independently defined as under formula (3) and any of its sub - embodiments and their combinations, as provided above.

[0105] In some embodiments, the compound of formula (3) has the following structure:

[0106]

[0107] wherein R 5 、R 16 、R a 、R b 、R c and R d are independently defined as under formula (3) and any of its sub - embodiments and their combinations, as provided above.

[0108] In some embodiments, the compound of formula (3) has the following structure:

[0109]

[0110] wherein R 16 、R a 、R b 、R c and R d are independently defined as under formula (3) and any of its sub - embodiments and their combinations, as provided above.

[0111] In some embodiments, the compound of formula (3) has the following structure:

[0112]

[0113] wherein R 16As defined in Formula (3) and any of its sub - embodiments and combinations thereof, as provided above.

[0114] In some embodiments, the compound of Formula (3) has the following structure:

[0115]

[0116] wherein R 5’ is selected from hydrocarbon groups (R) containing 1, 2, 3, 4 or 5 carbon atoms.

[0117] In some embodiments, the compound of Formula (3d) has the following specific structure:

[0118]

[0119] In some embodiments, Formula (3) does not include the above - mentioned compound 23.

[0120] In other embodiments, the compound of Formula (3d) has the following specific structure:

[0121]

[0122] In some embodiments of Formula (3), when R 4 is OH and R 1 , R 2 , R 3 , R 5 , R 6 , R a , R b , R c and R d are all H, then R 16 is not allyl.

[0123] In a fourth aspect, the present disclosure relates to a compound having the following structure:

[0124]

[0125] In Formula (4), R 1 is selected from: F, Cl and methyl; R 2 , R 3 and R 6 are independently selected from: i) H; (ii) hydrocarbon groups (R) containing 1 - 5 carbon atoms; (iii) alkoxy groups (OR); (iv) thioalkoxy groups (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) halogen atoms; R 4 is selected from H and an esterifying group that results in OR 4 being an ester group; R 5Selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms; R a 、R b 、R c and R d are independently selected from H and D atoms; and R 19 is selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms. Its pharmaceutically acceptable salts are also within the scope of formula (4) and all sub-formulas disclosed in this application.

[0126] In a first group of embodiments, any one, two, or all of R 2 、R 3 and R 6 are hydrogen atoms. In a second group of embodiments, any one or more of R 2 、R 3 and R 6 are independently selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 - 4, 1 - 3, 1 - 2, 2 - 5, 2 - 4, 2 - 3, 3 - 5, or 3 - 4 carbon atoms) described above. In a third group of embodiments, any one or more of R 2 、R 3 and R 6 are independently selected from alkoxy groups (OR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 - 4, 1 - 3, 1 - 2, 2 - 5, 2 - 4, 2 - 3, 3 - 5, or 3 - 4 carbon atoms) described above. In a fourth group of embodiments, any one or more of R 2 、R 3 and R 6 are independently selected from thioalkoxy groups (SR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 - 4, 1 - 3, 1 - 2, 2 - 5, 2 - 4, 2 - 3, 3 - 5, or 3 - 4 carbon atoms) described above. In a fifth group of embodiments, any one or more of R 2 、R 3 and R 6 are nitrile (CN) groups. In a sixth group of embodiments, any one or more of R 2 、R 3 and R 6 are amino (NH2) groups. In a seventh group of embodiments, any one or more of R 2 、R 3and R 6 Any one or more of which is a hydroxyl (OH) group. In an eighth group of embodiments, R 2 , R 3 and R 6 Any one or more of which is a halogen atom (e.g., F, Cl, Br, or I atom). Any two or three of the foregoing first to eighth embodiments may also be combined, such that R 2 , R 3 and R 6 are selected from two or three different groups described above. In other embodiments, for R 2 , R 3 and / or R 6 , any one or more of the groups (i)-(viii) provided above may be independently excluded.

[0127] In some embodiments, for any of the foregoing first to eighth embodiments or combinations thereof described above, R 1 is F. In other embodiments, for any of the foregoing first to eighth embodiments or combinations thereof described above, R 1 is Cl. In other embodiments, for any of the foregoing first to eighth embodiments or combinations thereof described above, R 1 is methyl.

[0128] In a first particular embodiment of formula (4), R 2 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a second particular embodiment, R 3 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a third particular embodiment, R 6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. Any one of the foregoing first to third particular embodiments provided above may also be combined with each other and with the embodiments of R 1 described above.

[0129] The group R 4 in formula (4) is selected from H and an esterifying group that results in OR 4 being an ester group. When R 4 is H, OR 4 is a hydroxyl (OH) group. When R 4 is an esterifying group, OR 4 is an ester group. The esterifying group (R 4 ) may result in OR 4is any type of ester group, including, for example, carboxylic acid esters, phosphate esters, or sulfonate esters. For example, R 4 may be -C(O)R to result in OR 4 being -OC(O)R (carboxylic acid ester); or R 4 may be -P(O)(OR’)2, where R’ is independently selected from H and R, to result in OR 4 being -OP(O)(OR’)2 (phosphate ester); or R 4 may be -SO2R to result in OR 4 being -OSO2R (sulfonate ester). In some embodiments, for R 4 , any one or more of the foregoing groups are excluded. Additionally, any one of the foregoing embodiments of R 4 may be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 and R 6 .

[0130] The group R 5 in formula (4) is selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms. In one set of embodiments, R 5 is H. In another set of embodiments, R 5 is a hydrocarbon group (R) having 1 to 5 carbon atoms, such as any R group described in detail anywhere above and below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, or 3 to 4 carbon atoms) as described above. In some embodiments, R 5 is selected from one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, and cyclobutyl. In some embodiments, for R 5 , any one or more of the foregoing groups are excluded. Additionally, any one of the foregoing embodiments of R 5 may be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 4 and R 6 .

[0131] The group R 19 in formula (4) is selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted with one or more fluorine atoms. In one set of embodiments, R 19 is H. In another set of embodiments, R 19Any hydrocarbon group (R) selected from anywhere in the foregoing and following descriptions, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1-5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5, or 3-4 carbon atoms) described above. In some embodiments, R 19 is selected from one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, and cyclobutyl. In some embodiments, for R 19 , any one or more of the foregoing groups are excluded. Additionally, any one of the foregoing embodiments of R 19 can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 4 , R 5 and R 6 .

[0132] The groups R a , R b , R c and R d in formula (4) are independently selected from H and D atoms. In one embodiment, R a , R b , R c and R d are all H atoms. In another embodiment, exactly one or two of R a , R b , R c and R d are D atoms, and the remainder (if any) are H atoms. In another embodiment, R a , R b , R c and R d are all D atoms. Additionally, any one of the foregoing embodiments of R a , R b , R c and R d can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 19 .

[0133] In an embodiment of formula (4), the following first premise applies: When R 1 is F or methyl and R 2 , R3 , R 4 , R 6 , R 19 , R a , R b , R c and R d are all H, then R 5 is not H or methyl. In an embodiment of formula (4), the following second premise applies: When R 1 is Cl and R 2 , R 3 , R 4 , R 6 , R 19 , R a , R b , R c and R d are all H, then R 5 is not H, methyl or ethyl. In an embodiment of formula (4), the following third premise applies: When R 1 is F and R 2 , R 3 , R 4 , R 6 , R a , R b , R c and R d are all H, then R 5 and R 19 are not both methyl. Any one, two or all three of the foregoing first, second and third premises can be combined.

[0134] In some embodiments, the compound of formula (4) has the following structure:

[0135]

[0136] wherein R 1 , R 4 , R 5 , R 19 , R a , R b , R c and R d are independently defined as in formula (4) and any of its sub - embodiments and combinations thereof, as provided above. Formula (4a) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (4a), R 1 is F. In other embodiments of formula (4a), R 1 is Cl. In other embodiments of formula (4a), R 1 is methyl.

[0137] In some embodiments, the compound of formula (4) has the following structure:

[0138]

[0139] wherein R 1 、R 4 、R 19 、R a 、R b 、R c and R d are independently as defined under formula (4) and any of its sub - embodiments and combinations thereof, as provided above. Formula (4b) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (4b), R 1 is F. In other embodiments of formula (4b), R 1 is Cl. In other embodiments of formula (4b), R 1 is methyl.

[0140] In some embodiments, the compound of formula (4) has the following structure:

[0141]

[0142] wherein R 1 、R 4 and R 19 are independently as defined under formula (4) and any of its sub - embodiments and combinations thereof, as provided above. Formula (4c) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (4c), R 1 is F. In other embodiments of formula (4c), R 1 is Cl. In other embodiments of formula (4c), R 1 is methyl.

[0143] In some embodiments, the compound of formula (4) has any of the following specific structures:

[0144] and its pharmaceutically acceptable salts.

[0145] In more specific embodiments, any one or more of the following compounds are expressly excluded from formula (4):

[0146]

[0147] In a fifth aspect, the present disclosure relates to compounds having the following structure:

[0148]

[0149] In formula (5), R 1 、R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 - 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 2 is selected from: F, Cl, and methyl; R a 、R b 、R c and R d are independently selected from H and D atoms; and R 20 is selected from H and a hydrocarbon group (R) having 1 - 5 carbon atoms, which is optionally substituted by one or more fluorine atoms. Its pharmaceutically acceptable salts are also within the scope of formula (5) and all sub - formulas disclosed in this application.

[0150] In a first group of embodiments, any one, two, or all of R 1 、R 3 and R 6 are hydrogen atoms. In a second group of embodiments, any one or more of R 1 、R 3 and R 6 are independently selected from any hydrocarbon group (R) described anywhere above or below, including any straight - chain, branched - chain, or cyclic alkyl or alkenyl group having 1 - 5 carbon atoms or a sub - range thereof (e.g., 1 - 4, 1 - 3, 1 - 2, 2 - 5, 2 - 4, 2 - 3, 3 - 5, or 3 - 4 carbon atoms) as described above. In a third group of embodiments, any one or more of R 1 、R 3 and R 6 are independently selected from alkoxy groups (OR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight - chain, branched - chain, or cyclic alkyl or alkenyl group having 1 - 5 carbon atoms or a sub - range thereof (e.g., 1 - 4, 1 - 3, 1 - 2, 2 - 5, 2 - 4, 2 - 3, 3 - 5, or 3 - 4 carbon atoms) as described above. In a fourth group of embodiments, any one or more of R 1 、R 3 and R 6 are independently selected from thioalkoxy groups (SR), where R is selected from any hydrocarbon group (R) described anywhere above or below, including any straight - chain, branched - chain, or cyclic alkyl or alkenyl group having 1 - 5 carbon atoms or a sub - range thereof (e.g., 1 - 4, 1 - 3, 1 - 2, 2 - 5, 2 - 4, 2 - 3, 3 - 5, or 3 - 4 carbon atoms) as described above. In a fifth group of embodiments, R 1 、R3 and R 6 any one or more of which is a nitrile (CN) group. In a sixth set of embodiments, R 1 , R 3 and R 6 any one or more of which is an amino (NH2) group. In a seventh set of embodiments, R 1 , R 3 and R 6 any one or more of which is a hydroxyl (OH) group. In an eighth set of embodiments, R 1 , R 3 and R 6 any one or more of which is a halogen atom (e.g., an F, Cl, Br, or I atom). Any two or three of the foregoing first through eighth embodiments may also be combined, such that R 1 , R 3 and R 6 are selected from two or three different groups described above. In other embodiments, for R 1 , R 3 and / or R 6 , any one or more of the groups (i)-(viii) provided above may be independently excluded.

[0151] The variable R 2 in formula (5) is selected from: F, Cl, and methyl. In some embodiments, for any of the first through eighth embodiments described above or combinations thereof, R 2 is F. In other embodiments, for any of the first through eighth embodiments described above or combinations thereof, R 2 is Cl. In other embodiments, for any of the first through eighth embodiments described above or combinations thereof, R 2 is methyl.

[0152] In a first particular embodiment of formula (5), R 1 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a second particular embodiment, R 3 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a third particular embodiment, R 6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. Any one of the first through third particular embodiments provided above may also be combined with each other and with the embodiments of R 2 described above.

[0153] The group R in formula (5) 20 is selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms. In one set of embodiments, R 20 is H. In another set of embodiments, R 20 is selected from any of the hydrocarbon groups (R) described anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1-4, 1-3, 1-2, 2-5, 2-4, 2-3, 3-5 or 3-4 carbon atoms) described above. In some embodiments, R 20 is selected from one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl. In some embodiments, for R 20 , any one or more of the foregoing groups are excluded. Additionally, any one of the foregoing embodiments for R 20 can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 and R 6 .

[0154] The group R in formula (5) a , R b , R c and R d are independently selected from H and D atoms. In one embodiment, R a , R b , R c and R d are all H atoms. In another embodiment, exactly one or two of R a , R b , R c and R d are D atoms, and the remainder (if any) are H atoms. In another embodiment, R a , R b , R c and R d are all D atoms. Additionally, any one of the foregoing embodiments for R a , R b , R c and R d can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 6 and R 20 .

[0155] In any of the above embodiments of formula (5), the following premise may apply: When R 2 is F, R 3 is not methyl or OH.

[0156] In some embodiments, the compound of formula (5) has the following structure:

[0157]

[0158] wherein R 2 , R 20 , R a , R b , R c and R d are independently as defined under formula (5) and any of its sub - embodiments and combinations thereof, as provided above. Formula (5a) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (5a), R 2 is F. In other embodiments of formula (5a), R 2 is Cl. In other embodiments of formula (5a), R 2 is methyl.

[0159] In some embodiments, the compound of formula (5) has the following structure:

[0160]

[0161] wherein R 2 and R 20 are independently as defined under formula (5) and any of its sub - embodiments and combinations thereof, as provided above. Formula (5b) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (5b), R 2 is F. In other embodiments of formula (5b), R 2 is Cl. In other embodiments of formula (5b), R 2 is methyl.

[0162] In some embodiments, the compound of formula (5) has any of the following specific structures: and its pharmaceutically acceptable salts.

[0163] In a sixth aspect, the present disclosure relates to a compound having the following structure:

[0164]

[0165] In formula (6), R 1 , R 2 and R 6Independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 3 Selected from: F, Cl, and methyl; R a , R b , R c and R d Independently selected from H and D atoms; and R 21 Selected from H and a hydrocarbon group (R) having 1 to 5 carbon atoms, which is optionally substituted by one or more fluorine atoms. Its pharmaceutically acceptable salts are also within the scope of formula (6) and all sub-formulas disclosed in this application.

[0166] In a first group of embodiments, any one, two, or all of R 1 , R 2 and R 6 are hydrogen atoms. In a second group of embodiments, any one or more of R 1 , R 2 and R 6 are independently selected from any hydrocarbon group (R) described anywhere above and below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, or 3 to 4 carbon atoms) described above. In a third group of embodiments, any one or more of R 1 , R 2 and R 6 are independently selected from alkoxy groups (OR), where R is selected from any hydrocarbon group (R) described anywhere above and below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, or 3 to 4 carbon atoms) described above. In a fourth group of embodiments, any one or more of R 1 , R 2 and R 6 are independently selected from thioalkoxy groups (SR), where R is selected from any hydrocarbon group (R) described anywhere above and below, including any straight-chain, branched-chain, or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, or 3 to 4 carbon atoms) described above. In a fifth group of embodiments, any one or more of R 1 , R 2 and R 6Any one or more of them are nitrile (CN) groups. In a sixth group of embodiments, R 1 , R 2 and R 6 Any one or more of them are amino (NH2) groups. In a seventh group of embodiments, R 1 , R 2 and R 6 Any one or more of them are hydroxyl (OH) groups. In an eighth group of embodiments, R 1 , R 2 and R 6 Any one or more of them are halogen atoms (e.g., F, Cl, Br, or I atoms). Any two or three of the foregoing first to eighth embodiments may also be combined, such that R 1 , R 2 and R 6 are selected from two or three different groups described above. In other embodiments, for R 1 , R 2 and / or R 6 , any one or more of the groups (i)-(viii) provided above may be independently excluded.

[0167] The variable R 3 in formula (6) is selected from: F, Cl, and methyl. In some embodiments, for any of the first to eighth embodiments described above or combinations thereof, R 3 is F. In other embodiments, for any of the first to eighth embodiments described above or combinations thereof, R 3 is Cl. In other embodiments, for any of the first to eighth embodiments described above or combinations thereof, R 3 is methyl.

[0168] In a first particular embodiment of formula (6), R 1 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a second particular embodiment, R 2 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. In a third particular embodiment, R 6 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, F, and OH, or a subgroup thereof. Any one of the first to third particular embodiments provided above may also be combined with each other and with the embodiments of R 3 described above.

[0169] The group R 21Selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms. In one set of embodiments, R 21 is H. In another set of embodiments, R 21 is selected from any of the hydrocarbon groups (R) described anywhere above and below, including any straight-chain, branched-chain or cyclic alkyl or alkenyl group having 1 to 5 carbon atoms or a sub-range thereof (e.g., 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5 or 3 to 4 carbon atoms) as described above. In some embodiments, R 21 is selected from one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl and cyclobutyl. In some embodiments, for R 21 , any one or more of the foregoing groups are excluded. In addition, any one of the foregoing embodiments of R 21 can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 and R 6 .

[0170] The groups R a , R b , R c and R d in formula (6) are independently selected from H and D atoms. In one embodiment, R a , R b , R c and R d are all H atoms. In another embodiment, exactly one or two of R a , R b , R c and R d are D atoms, and the rest (if any) are H atoms. In another embodiment, R a , R b , R c and R d are all D atoms. In addition, any one of the foregoing embodiments of R a , R b , R c and R d can be combined with any one or more of the embodiments provided earlier for R 1 , R 2 , R 3 , R 6 and R 21 .

[0171] In an embodiment of formula (6), the following first premise applies: When R3 When R is methyl 2 is not F and R 6 is not methyl. In an embodiment of formula (6), the following second premise applies: When R 3 is methyl and R 1 , R 2 , R 6 , R a , R b , R c and R d are all H, then R 21 is not H, methyl or ethyl. In an embodiment of formula (6), the following third premise applies: When R 3 is F or Cl and R 1 , R 2 , R 6 , R a , R b , R c and R d are all H, then R 21 is not H. Any one, two, or all three of the aforementioned first, second, and third premises can be combined.

[0172] In some embodiments, the compound of formula (6) has the following structure:

[0173]

[0174] wherein R 3 , R 21 , R a , R b , R c and R d are independently defined as under formula (6) and any of its sub - embodiments and combinations thereof, as provided above. Formula (6a) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (6a), R 3 is F. In other embodiments of formula (6a), R 3 is Cl. In other embodiments of formula (6a), R 3 is methyl.

[0175] In some embodiments, the compound of formula (6) has the following structure:

[0176]

[0177] wherein R 3 and R 21 are independently defined as under formula (6) and any of its sub - embodiments and combinations thereof, as provided above. Formula (6b) also includes all of its pharmaceutically acceptable salts. In some embodiments of formula (6b), R3 is F. In other embodiments of formula (6b), R 3 is Cl. In other embodiments of formula (6b), R 3 is methyl.

[0178] In some embodiments, the compounds of formula (6b) have the following specific structures: and pharmaceutically acceptable salts thereof.

[0179] In a seventh aspect, the present disclosure relates to a compound having the following specific structure:

[0180]

[0181] In an eighth aspect, the present disclosure relates to any of the following specific compounds:

[0182]

[0183] The present disclosure also relates to pharmaceutical compositions of any of the compounds disclosed in the present application, including dosage forms. The pharmaceutical compositions generally comprise a pharmaceutically acceptable carrier, which contains (e.g., dissolved, suspended or admixed with) one or more active compounds. It is well known that pharmaceutically acceptable carriers consist of one or more substances that are considered safe and effective. The carrier includes all components of a pharmaceutical formulation other than the active ingredient. The term "carrier" includes, but is not limited to, diluents, binders, lubricants, glidants, disintegrants, fillers and coating compositions.

[0184] Suitable dosage forms of the compounds disclosed herein include, but are not limited to, oral forms such as tablets, hard or soft gelatin capsules, powders, granules and oral solutions, syrups or suspensions, lozenges, and sublingual, buccal, intratracheal, intraocular or intranasal forms, forms suitable for inhalation, topical forms, transdermal forms or parenteral forms, e.g., forms suitable for intravenous, intraarterial, intraperitoneal, intrathecal, intracardiac, intramuscular or subcutaneous administration. In an embodiment, for such parenteral administration, it may be in the form of a sterile aqueous solution, which may contain other substances, such as sufficient salts or glucose to render the solution isotonic with blood. If desired, the aqueous solution should be buffered appropriately (preferably buffered to a pH of 3 to 9). Preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0185] The pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant. The compositions can be prepared by any method well known in the pharmaceutical art. In commercial form, the pharmaceutical compositions may be supplied together with a package material, including instructions for use of the compositions as described herein.

[0186] The pharmaceutical compositions of the present invention may also have an immediate release, delayed release, extended release, or modified release profile. In embodiments, pharmaceutical compositions having different drug release profiles may be combined to produce a two-phase or three-phase release profile. For example, the pharmaceutical composition may have an immediate release and an extended release profile. In embodiments, the pharmaceutical composition may have an extended release and a delayed release profile. Such compositions may be provided as pulsatile formulations, multilayer tablets, or capsules containing tablets, beads, granules, etc.

[0187] The pharmaceutical composition may also contain one or more adjuvants. Adjuvants may also be referred to as auxiliary components and include any other conventional substances in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorants, antioxidants, and wetting agents. Such adjuvants are appropriately selected according to the intended form and route of administration and in accordance with conventional pharmaceutical practice.

[0188] A pharmaceutical composition suitable for oral administration may be formulated into discrete dosage units, such as pills, tablets, dragees, or capsules, or formulated into powders or granules, or formulated into solutions or suspensions. The active ingredient may also be present as a bolus or paste. The composition may also be processed into suppositories or enemas for rectal administration.

[0189] Tablets may contain the active ingredient compound and suitable binders, lubricants, disintegrants, colorants, flavorants, flow-inducing agents, and melting agents. Gelatin capsules may contain the active ingredient compound and a powdery carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents may be used to manufacture compressed tablets. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablets from atmospheric effects, or enteric-coated to cause selective disintegration in the gastrointestinal tract. For example, for oral administration in the form of dosage units of tablets or capsules, the active pharmaceutical ingredient may be combined with an orally non-toxic pharmaceutically acceptable inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0190] For oral administration in liquid dosage forms, the oral pharmaceutical components are combined with any non-toxic pharmaceutically acceptable inert carriers for oral use such as ethanol, glycerol, water and the like. Examples of suitable liquid dosage forms include, but are not limited to, solutions or suspensions, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents (including esters). Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, thickening agents and solubilizing agents. Liquid dosage forms for oral administration may contain coloring agents and flavoring agents to increase patient acceptance.

[0191] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile solutions. Generally, water, suitable oils, saline, aqueous dextrose (glucose) and related sugar solutions and diols (such as propylene glycol or polyethylene glycol) are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain water-soluble salts of the active ingredient, suitable stabilizers and, if necessary, buffering substances. Antioxidants (such as sodium bisulfite, sodium sulfite or ascorbic acid), alone or in combination, are suitable stabilizers. Citric acid and its salts as well as sodium EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methylparaben or propylparaben and chlorobutanol. The compositions may be present in unit-dose or multi-dose containers, such as sealed vials and ampoules, and may be stored under lyophilized (freeze-dried) conditions and require only the addition of a sterile liquid carrier, usually water or an aqueous solution, before use. For transdermal administration, gels, patches or sprays may be used. Compositions or preparations suitable for pulmonary administration (such as by nasal inhalation) include fine dusts or mists, which may be generated by metered-dose pressurized aerosols, nebulizers or insufflators. Parenteral and intravenous forms may also contain minerals and other materials to render them compatible with the selected type of injection or delivery system.

[0192] The compounds used in the methods of the present disclosure may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids such as cholesterol, stearylamine or phosphatidylcholine. These compounds may be administered as components of tissue-targeted emulsions.

[0193] The compounds used in the methods of the present disclosure may also be conjugated to soluble polymers to serve as targetable drug carriers or as prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparagine-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Additionally, the compounds may be conjugated to a class of biodegradable polymers that can be used to effect controlled release of a drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly(ε-caprolactone), polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic hydrogel block copolymers.

[0194] Abuse deterrent features can be provided to the pharmaceutical compositions herein by techniques known in the art, such as by making tablets that are difficult to crush or difficult to dissolve in water.

[0195] In another aspect, the present disclosure relates to methods of treating mood disorders. In such methods, one or more of the compounds described herein (typically in the form of a pharmaceutical composition) are administered to a subject in need thereof in a therapeutically effective amount. A therapeutically effective amount is an amount that provides an improvement (usually, a reduction or shortening in duration) of one or more symptoms of a mood disorder or prevents recurrence of one or more symptoms of a mood disorder.

[0196] In embodiments, the mood disorder is a depressive disorder. Some examples of depressive disorders include major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood dysregulation disorder, substance / drug-induced depressive disorder, and depressive disorder due to another medical condition. The depressive disorder may also be a treatment-resistant depressive disorder. Any one or more of the compounds described in the present disclosure may be administered to treat a depressive disorder, including those specifically identified above.

[0197] In some embodiments, depressive conditions include major depressive disorder and dysthymic disorder. In some embodiments, depressive conditions occur in unique circumstances, including but not limited to psychotic depression, postpartum depression, seasonal affective disorder (SAD), mood disorders, depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, post-traumatic stress disorder, and bipolar disorder (or manic-depressive disorder). In some embodiments, depressive conditions contemplated for treatment according to this aspect of the disclosure include but are not limited to major depressive disorder, dysthymic disorder, psychotic depression, postpartum depression, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder (SAD), anxiety disorders, mood disorders, depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress, post-traumatic stress disorder, and bipolar disorder (or manic-depressive disorder). Any one or more of the compounds described in the disclosure can be administered to treat any of the depressive disorders specifically identified above.

[0198] Also provided herein are methods of treating treatment-resistant depression, such as in patients suffering from a depressive disorder who have not responded and / or are not responding to a full course of treatment with at least one or at least two other antidepressant compounds or therapies. For example, provided herein is a method of treating depression in treatment-resistant patients, which includes a) optionally identifying the patient as treatment-resistant and b) administering an effective dose of a disclosed compound. As used herein, the term "depressive disorder" includes treatment-resistant depression. In some embodiments, treatment-resistant depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, dual and triple reuptake inhibitors, and / or anti-anxiety medications) as well as non-pharmacological treatments (such as psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation). In some embodiments, treatment-resistant patients can be identified as patients who have not experienced remission of one or more depressive symptoms (e.g., persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism) despite undergoing one or more standard pharmacological or non-pharmacological treatments. In certain embodiments, treatment-resistant patients are patients who have not experienced remission of one or more depressive symptoms despite undergoing treatment with two different antidepressant medications. In other embodiments, treatment-resistant patients are patients who have not experienced remission of one or more depressive symptoms despite undergoing treatment with four different antidepressant medications. In some embodiments, treatment-resistant patients can also be identified as patients who are unwilling or unable to tolerate the side effects of one or more standard pharmacological or non-pharmacological treatments. Any one or more of the compounds described in the disclosure can be administered to treat treatment-resistant or treatment-resistant depressive disorders, including those specifically identified above.

[0199] In some embodiments, symptoms associated with depression include, but are not limited to, persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, and / or worthlessness, low energy, restlessness, irritability, fatigue, loss of interest in pleasurable activities or hobbies, excessive sleep, overeating, loss of appetite, insomnia, suicidal thoughts or suicide attempts. In some embodiments, the various symptoms associated with anxiety disorders include fear, panic, palpitations, shortness of breath, fatigue, nausea, and headache, among others. Additionally, patients suffering from any form of depression often experience anxiety. It is contemplated that the methods of the present invention can be used to treat anxiety disorders or any of their symptoms. In some embodiments, the presence, severity, frequency, and duration of depressive symptoms vary on a case-by-case basis.

[0200] In other embodiments, the mood disorder is bipolar disorder or a related disorder. Some examples of bipolar disorder and related disorders include bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance / medication-induced bipolar disorder and related disorders, and bipolar disorder and related disorders due to another medical condition. Any one or more of the compounds described in the present disclosure can be administered to treat bipolar disorder or a related disorder, including those specifically identified above.

[0201] In other embodiments, the mood disorder is a substance-related disorder. Substance use disorders typically involve the abuse of psychoactive compounds such as alcohol, caffeine, cannabis, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. As used herein, "substance" or "substances" are psychoactive compounds that may be addictive, such as alcohol, caffeine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, nicotine, and tobacco. The methods described herein can be used to treat or prevent substance use cravings, reduce substance use cravings, and / or facilitate substance use cessation or withdrawal. In some embodiments, the methods can be used to facilitate smoking cessation or opioid use cessation. Any one or more of the compounds described in the present disclosure can be administered to treat substance-related disorders, including those specifically identified above.

[0202] In other embodiments, the mood disorder is an anxiety disorder. Some examples of anxiety disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance / medication-induced anxiety disorder, and anxiety disorder due to another medical condition. Any one or more of the compounds described in the present disclosure can be administered to treat anxiety disorders, including those specifically identified above.

[0203] In other embodiments, the mood disorder is an obsessive-compulsive disorder or related disorder, such as obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, substance / medication-induced obsessive-compulsive and related disorder, and obsessive-compulsive and related disorder due to another medical condition. Any one or more of the compounds described in the present disclosure can be administered to treat obsessive-compulsive disorder or related disorder, including those specifically indicated above.

[0204] In other embodiments, the mood disorder is a trauma- or stressor-related disorder. Some examples of such mood disorders include reactive attachment disorder, disinhibited social engagement disorder, posttraumatic stress disorder, acute stress disorder, and adjustment disorder. Any one or more of the compounds described in the present disclosure can be administered to treat trauma- or stressor-related disorder, including those specifically indicated above.

[0205] In other embodiments, the mood disorder is a feeding and eating disorder. Some examples of such mood disorders include anorexia nervosa, bulimia nervosa, binge-eating disorder, pica, rumination disorder, and avoidant / restrictive food intake disorder. Any one or more of the compounds described in the present disclosure can be administered to treat feeding or eating disorder, including those specifically indicated above.

[0206] In other embodiments, the mood disorder is a neurocognitive disorder. Some examples of neurocognitive disorders include delirium, major neurocognitive disorder, mild neurocognitive disorder, major or mild neurocognitive disorder due to Alzheimer's disease, major or mild frontotemporal neurocognitive disorder, major or mild neurocognitive disorder with Lewy bodies, major or mild vascular neurocognitive disorder, major or mild neurocognitive disorder due to traumatic brain injury, major or mild substance / medication-induced neurocognitive disorder, major or mild neurocognitive disorder due to HIV infection, major or mild neurocognitive disorder due to prion disease, major or mild neurocognitive disorder due to Parkinson's disease, major or mild neurocognitive disorder due to Huntington's disease, major or mild neurocognitive disorder due to another medical condition, and major or mild neurocognitive disorder due to multiple etiologies. Any one or more of the compounds described in the present disclosure can be administered to treat neurocognitive disorder, including those specifically indicated above.

[0207] In other embodiments, the mood disorder is a neurodevelopmental disorder. Some examples of neurodevelopmental disorders include autism spectrum disorder, attention deficit / hyperactivity disorder, stereotyped movement disorder, tic disorder, Tourette disorder, persistent (chronic) motor or vocal tic disorder, and provisional tic disorder. In some embodiments, the methods according to the present disclosure can be used to treat various other neurological conditions. In some embodiments, the neurological conditions include but are not limited to learning disorders, autistic disorders (such as autism spectrum disorder), attention deficit hyperactivity disorder, Tourette syndrome, phobias, post-traumatic stress disorder, dementia, AIDS dementia, Alzheimer's disease, Parkinson's disease, spasticity, myoclonus, muscle spasms, bipolar disorder, substance use disorders, urinary incontinence, and schizophrenia. Any one or more of the compounds described in the present disclosure can be administered to treat neurodevelopmental disorders, including those specifically identified above.

[0208] In other embodiments, the mood disorder is a personality disorder. Personality disorders can belong to any known class, such as class A, class B, or class C. Some examples of personality disorders include paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, borderline personality disorder, antisocial personality disorder, narcissistic personality disorder, histrionic personality disorder, avoidant personality disorder, obsessive-compulsive personality disorder, and dependent personality disorder. Any one or more of the compounds described in the present disclosure can be administered to treat personality disorders, including those specifically identified above.

[0209] In other embodiments, the mood disorder may be related to sexual dysfunction. Some examples of such mood disorders include delayed ejaculation, erectile disorder, female orgasm disorder, female sexual interest / arousal disorder, genito-pelvic pain / penetration disorder, male hypoactive sexual desire disorder, premature (early) ejaculation, and substance / drug-induced sexual dysfunction. Any one or more of the compounds described in the present disclosure can be administered to treat sexual dysfunction, including those specifically identified above.

[0210] In other embodiments, the mood disorder is gender identity disorder. Any one or more of the compounds described in the present disclosure can be administered to treat gender identity disorder.

[0211] In another aspect, the present disclosure relates to methods for treating migraine, cluster headache, or other headache disorders. In the method, one or more of the compounds described herein (usually in the form of a pharmaceutical composition) are administered to a subject in need thereof in a therapeutically effective amount. A therapeutically effective amount is an amount that provides an improvement (usually, a reduction or shortening of the duration) of one or more symptoms of the headache disorder or prevents the recurrence of one or more symptoms of the headache disorder. Any one or more of the compounds described in the present disclosure can be administered to treat migraine, cluster headache, or other headache disorders.

[0212] In another aspect, the present disclosure relates to methods of treating inflammation or an inflammation-related condition (e.g., arthritis). In such methods, one or more of the compounds described herein (usually in the form of a pharmaceutical composition) are administered to a subject in need thereof in a therapeutically effective amount. A therapeutically effective amount is an amount that provides an improvement (usually, a reduction or shortening in duration) of one or more symptoms of inflammation or prevents recurrence of one or more symptoms of inflammation. Any one or more of the compounds described in the present disclosure can be administered to treat inflammation or an inflammation-related condition.

[0213] In an embodiment, the method includes treating a mood disorder, such as a depressive disorder, by administering to a patient in need thereof from about 0.01 mg to about 400 mg of a compound disclosed herein. The exact dosage and administration regimen of the composition will necessarily depend on the type and degree of therapeutic or nutritional effect to be achieved and may vary depending on factors such as the particular compound, formulation, route of administration, or the age and condition of the individual subject to whom the composition is to be administered.

[0214] In an embodiment, the administered dose can be, for example, in the range of about 0.01 to 400 mg, 0.01 to 300 mg, 0.01 to 250 mg, 0.01 to 200 mg, 0.01 to 150 mg, 0.01 to 100 mg, 0.01 to 75 mg, 0.01 to 50 mg, 0.01 to 25 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0.01 to 10 mg, 0.01 to 5 mg, 0.01 to 1 mg, 0.01 to 0.5 mg, 0.01 to 0.1 mg, 0.1 to 400 mg, 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 150 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1 mg, 0.5 to 400 mg, 0.5 to 300 mg, 0.5 to 250 mg, 0.5 to 200 mg, 0.5 to 150 mg, 0.5 to 100 mg, 0.5 to 75 mg, 0.5 to 50 mg, 0.5 to 25 mg, 0.5 to 20 mg, 0.5 to 15 mg, 0.5 to 10 mg, 0.5 to 5 mg, 0.5 to 1 mg, 1 to 400 mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to 150 mg, 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1 to 25 mg, 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 400 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 150 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 400 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 150 mg, 10 to 100 mg, 10 to 50 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 20 to 400 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 150 mg, 20 to 100 mg, 20 to 50 mg, 20 to 40 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg.In some embodiments, the dose is precisely or approximately 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 80 mg, 100 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg or 400 mg or an amount within the range between any two of these values (e.g., 2 - 5 mg, 40 - 80 mg, 80 - 100 mg, 80 - 120 mg, 100 - 120 mg or 120 - 150 mg). In some embodiments, any of the above doses is a dose per 50, 60 or 70 kg body weight. Any of the above doses can be administered once, twice or three times daily, or every two days, or every three days, or weekly or every two weeks. Any one or more of the compounds described in the present disclosure can be administered in any amount provided above or within the range between any two of these values to treat any of the mood disorders described above.

[0215] In certain embodiments, the dose can include, for example, an amount of the compounds disclosed herein within the range of about 1 mg to 200 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 15 mg, 0.01 mg to 10 mg, 0.1 mg to 15 mg, 0.15 mg to 12.5 mg or 0.2 mg to 10 mg, wherein doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 2.75 mg, 3 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg and 200 mg are specific examples of the dose. Any of the above doses can be administered once, twice or three times daily, or every two days, or every three days, or weekly or every two weeks.

[0216] Typically, the compounds disclosed herein are administered to a patient in need thereof once, twice, three times, or four times a day, every other day, every three days, once a week, twice a month, once a month, or 3 - 4 times a year. In some embodiments, the dose is, for example, about 1 - 400 mg / day, or 1 - 300 mg / day, or 1 - 250 mg / day, or 1 - 200 mg / day, such as 300 mg / day, 250 mg / day, 200 mg / day, 150 mg / day, 100 mg / day, 75 mg / day, 50 mg / day, 40 mg / day, 30 mg / day, 25 mg / day, 20 mg / day, 15 mg / day, 10 mg / day, 5 mg / day, or 1 mg / day.

[0217] In some embodiments, a pharmaceutical composition for parenteral administration or inhalation (e.g., a spray or aerosol) of the compounds disclosed herein comprises a concentration of from about 0.005 mg / ml to about 500 mg / mL. In an embodiment, the composition comprises the compounds disclosed herein at a concentration of, for example, from about 0.05 mg / mL to about 50 mg / mL, from about 0.05 mg / mL to about 100 mg / mL, from about 0.005 mg / mL to about 500 mg / mL, from about 0.1 mg / mL to about 50 mg / mL, from about 0.1 mg / mL to about 10 mg / mL, from about 0.05 mg / mL to about 25 mg / mL, from about 0.05 mg / mL to about 10 mg / mL, from about 0.05 mg / mL to about 5 mg / mL, or from about 0.05 mg / mL to about 1 mg / mL.

[0218] In an embodiment, the composition comprises the compounds disclosed herein at a concentration of, for example, from about 0.05 mg / mL to about 15 mg / mL, from about 0.5 mg / mL to about 10 mg / mL, from about 0.25 mg / mL to about 5 mg / mL, from about 0.5 mg / mL to about 7 mg / mL, from about 1 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 15 mg / mL, from about 5 mg / mL to 25 mg / mL, from about 5 mg / mL to 50 mg / mL, or from about 10 mg / mL to 100 mg / mL. In an embodiment, the pharmaceutical composition is formulated to have a total volume of, for example, about 10 mL, 20 mL, 25 mL, 50 mL, 100 mL, 200 mL, 250 mL, or 500 mL.

[0219] Typically, the dose can be administered to a subject once, twice, three times, or four times a day, every other day, every three days, once a week, twice a month, once a month, or 3 - 4 times a year. In an embodiment, the compounds disclosed herein are administered to a subject once in the morning or once in the evening. In an embodiment, the compounds disclosed herein are administered to a subject once in the morning and once in the evening. In an embodiment, the compounds disclosed herein are administered to a subject three times a day (e.g., at breakfast, lunch, and dinner) at a dose of, for example, 50 mg / dose (e.g., 150 mg / day).

[0220] In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 12.5 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 25 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 35 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 50 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 75 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 100 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 150 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 200 mg / day in one or more doses. In an embodiment, the compounds disclosed herein are administered to a subject at a dose of 250 mg / day in one or more doses.

[0221] In an embodiment, the dosage of the compounds disclosed herein is 0.0005 - 5 mg / kg, 0.001 - 1 mg / kg, 0.01 - 1 mg / kg, or 0.1 - 5 mg / kg, once, twice, three times, or four times a day. For example, in an embodiment, the dosage is 0.0005 mg / kg, 0.001 mg / kg, 0.005 mg / kg, 0.01 mg / kg, 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 2.5 mg / kg, or 5 mg / kg, once, twice, three times, or four times a day. In an embodiment, the total daily dosage of the compounds disclosed herein of 0.01 mg to 500 mg is administered to a subject once, twice, three times, or four times a day. In an embodiment, the total amount administered to a subject over a 24 - hour period is, for example, 0.01 mg, 0.025 mg, 0.05 mg, 0.075 mg, 0.1 mg, 0.125 mg, 0.15 mg, 0.175 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In an embodiment, a subject may start with a low dose and gradually increase the dose. In an embodiment, a subject may start with a high dose and decrease the dose.

[0222] In an embodiment, the compounds disclosed herein may be administered, for example, via inhalation or orally at specified time intervals. For example, during treatment, the compounds disclosed herein may be administered to a patient at time intervals of, for example, every 1 year, 6 months, 90 days, 60 days, 30 days, 14 days, 7 days, 3 days, 24 hours, 12 hours, 8 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1 hour, 0.75 hours, 0.5 hours, or 0.25 hours.

[0223] In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a healthcare provider. In embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are administered to a patient under the supervision of a healthcare provider at a clinic that specializes in providing psychoactive treatment.

[0224] In embodiments, the compounds of the present disclosure are administered to a patient under the supervision of a healthcare provider at a high dose intended to induce a psychedelic experience in the subject, such as 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, or 150 mg. In some embodiments, the high dose is administered to the patient under the supervision of a healthcare provider on a regular basis to maintain a therapeutic effect in the patient, such as every three days, twice a week, once a week, twice a month, once a month, three times a year, twice a year, or once a year.

[0225] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are self-administered by the patient at home or at other locations away from the supervision of a healthcare provider. In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are self-administered by the patient at home or at other locations away from the supervision of a healthcare provider at a low dose intended to have sub-perceptual or threshold psychoactive effects, such as 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, or 10 mg. In some embodiments, the low dose is self-administered by the patient on a regular basis to maintain a therapeutic effect in the patient, such as daily, every other day, every three days, twice a week, once a week, twice a month, or once a month.

[0226] In some embodiments, any compound (or its pharmaceutical composition) disclosed in the present application can be administered once, twice, three times, or four times a day, wherein the administrations can be the same or different and are independently selected from any of the doses provided in the present application. In some embodiments, any compound (or its pharmaceutical composition) disclosed in the present application can be administered once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times a week (possibly at equal or alternating time intervals), wherein the administrations can be the same or different and are independently selected from any of the doses provided in the present application. In some embodiments, any compound (or its pharmaceutical composition) disclosed in the present application can be administered once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, or fifteen times a month (possibly at equal or alternating time intervals, such as every two days, every three days, every four days, or every five days, or alternating between any of these), wherein the administrations can be the same or different and are independently selected from any of the doses provided in the present application. In some embodiments, any compound (or its pharmaceutical composition) disclosed in the present application can be administered once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, twenty times, twenty-one times, twenty-two times, twenty-three times, twenty-four times, or twenty-five times a year (possibly at equal or alternating time intervals, such as every two weeks, three weeks, or four weeks, or once or twice a month, or alternating between any of these), wherein the administrations can be the same or different and are independently selected from any of the doses provided in the present application.

[0227] In some embodiments, treatment with the compound can be part of a combination therapy or an adjuvant therapy. For example, treating or administering another drug for the disease to a subject or patient in need of a drug in combination with one or more of the compounds currently described. The combination therapy can be a sequential therapy, where the patient is first treated with one drug and then with another drug. Alternatively, the combination therapy can involve the simultaneous administration of two drugs. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.

[0228] In some embodiments, the compounds disclosed herein can be administered in combination with one or more other antidepressant drugs, such as for manufacturing drugs for treating depression, anxiety, and / or other related diseases, including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or anxiolytic drugs for relieving depression or anxiety and preventing recurrence of depression or anxiety. In some embodiments, the therapeutic agents that can be used in combination with the compounds of the present disclosure include, but are not limited to, Anafranil, Adapin, Aventyl, Elavil, Norpramin, Pamelor, Pertofrane, Sinequan, Surmontil, Tofranil, Vivactil, Parnate, Nardil, Marplan, Celexa, Lexapro, Luvox, Paxil, Prozac, Zoloft, Wellbutrin, Effexor, Remeron, Cymbalta, Desyrel (trazodone), and Ludiomill.

[0229] In the context of the present disclosure, the term "5-HT2A receptor agonist" is intended to mean any compound or substance that activates the 5-HT2A receptor. The agonist can be a partial or full agonist.

[0230] As used herein, the term "pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe", e.g., that are physiologically tolerable when administered to a human and generally do not produce allergic or similar undesirable reactions. In embodiments, the term refers to molecular entities and compositions approved by a regulatory agency of the federal or state government, such as the GRAS list of Sections 204 and 409 of the Federal Food, Drug, and Cosmetic Act, which have been premarket reviewed and approved by the FDA or a similar list, the United States Pharmacopeia, or other generally recognized pharmacopeias for use in animals, and more particularly in humans.

[0231] As used herein, the term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts, wherein the compound is modified by forming its acid or base salt. Any compound disclosed in the present application may be in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, e.g., formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, and oxalic acid. Pharmaceutically acceptable salts of the compounds disclosed herein can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods.

[0232] As used herein, the term "about" or "approximately" refers to an acceptable error range of a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, "about" can mean within 3 or more standard deviations in the practice of the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly for biological systems or processes, the term can mean within an order of magnitude of the value, e.g., within 5-fold or within 2-fold. "About" and "approximately" are used interchangeably herein.

[0233] In an embodiment, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound, material, composition, medicament, or other material that effectively achieves a specific pharmacological and / or physiological effect or effectively provides a desired pharmacological and / or physiological effect, the specific pharmacological and / or physiological effect including but not limited to reducing sadness or drowsiness, depressive mood, feelings of anxiety or sadness, reduced interest in all or almost all activities, significantly increased or decreased appetite leading to weight gain or weight loss, insomnia, irritability, fatigue, feelings of worthlessness, helplessness, inability to concentrate, and frequency or severity of recurrent thoughts of death or suicide, the desired pharmacological and / or physiological effect being, for example, alleviating, inhibiting, or reversing one or more underlying pathophysiological mechanisms of neurological dysfunction, modulating dopamine levels or signaling, modulating serotonin levels or signaling, modulating norepinephrine levels or signaling, modulating glutamate or GABA levels or signaling, modulating synaptic connectivity or neurogenesis in certain brain regions, or combinations thereof. The exact dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, clinical symptoms, etc.), the disease or disorder being treated, and the route of administration and pharmacokinetics of the administered agent.

[0234] The present disclosure also intends to include all isotopes of atoms present in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C.

[0235] It should be noted that throughout this application, any symbol for carbon in a structure, when used without further symbol, is intended to represent all isotopes of carbon, such as 12 C, 13 C, or 14 C. In addition, any compound containing 13 C or 14 C can specifically have the structure of any compound disclosed herein.

[0236] It should also be noted that throughout this application, any symbol for hydrogen in a structure, when used without further symbol, is intended to represent all isotopes of hydrogen, such as 1 H, 2 H, or 3 H. In addition, any compound containing 2 H or 3 H can specifically have the structure of any compound disclosed herein.

[0237] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the unlabeled reagents employed.

[0238] In embodiments, deuterium-rich variants of the compounds disclosed herein and their uses are contemplated and are within the scope of the methods and compositions described herein. Deuterium can be incorporated synthetically selectively or non-selectively at any position to replace hydrogen (protium) according to synthetic procedures known in the art. For example, deuterium can be incorporated via proton-deuterium equilibration exchange into various positions having exchangeable protons such as amine N-H. Alternatively, deuterium can be introduced during the synthesis of the compound by using deuterium-rich reagents. For example, in formula (1), deuterium can be incorporated into one or more groups attached to the 2-, 4-, 5-, 6-, and / or 7-positions of the indole ring system, into the methylene linking group attached at the 3-position, or into the cyclopropyl ring. As yet another example, in formula (2), deuterium can be incorporated into one or more groups attached to the 2-, 4-, 5-, and / or 7-positions of the indole ring system, into the methylene linking group attached at the 3-position, or into R 14 and / or R 15 groups. As yet another example, in formula (3), deuterium can be incorporated into one or more groups attached to the 2-, 4-, 5-, and / or 7-positions of the indole ring system, into the methylene linking group attached at the 3-position, or into R 16 groups. As yet another example, in formula (4), deuterium can be incorporated into one or more groups attached to the 2-, 4-, 5-, and / or 7-positions of the indole ring system, into the methylene linking group attached at the 3-position, or into R 17 and / or R 18 groups. As yet another example, in formula (5), deuterium can be incorporated into one or more groups attached to the 2-, 4-, 6-, and / or 7-positions of the indole ring system, into the methylene linking group attached at the 3-position, or into R 19 groups. In some embodiments, the deuterium level at each deuterium-rich H site of the compound is from 0.02% to 100%. In some embodiments, the deuterium level at each deuterium-rich H site of the compound is 50%-100%, 70%-100%, 90%-100%, 95%-100%, 96%-100%, 97%-100%, 98%-100% or 99%-100%.

[0239] The compounds disclosed herein may be in their racemic and / or optically active isomers. In this regard, some compounds may have asymmetric carbon atoms and may thus exist as a racemic mixture or as individual optical isomers (enantiomers). The compounds described herein that contain chiral centers include all possible stereoisomers of the compounds, including compositions that are racemic mixtures containing both enantiomers, and compositions that contain individual enantiomers that are substantially free of the other enantiomer. Thus, for example, a composition is contemplated herein that contains the S enantiomer of a compound that is substantially free of the R enantiomer, or the R enantiomer that is substantially free of the S enantiomer. If the specified compound contains more than one chiral center, the scope of the present disclosure also includes compositions that are mixtures containing different proportions of diastereomers, and compositions that contain one or more diastereomers and are substantially free of one or more other diastereomers. "Substantially free of" means that the composition contains less than 25%, 15%, 10%, 8%, 5%, 3% or less than 1% of the minor enantiomer or diastereomer.

[0240] Examples

[0241] Methods for synthesizing, separating, preparing, and administering various stereoisomers are known in the art. Separation of diastereomers or cis- and trans-isomers can be achieved by conventional techniques such as, for example, fractional crystallization, chromatography, or high performance liquid chromatography (HPLC) of a stereoisomeric mixture of the agent or a suitable salt or derivative thereof. The individual enantiomers of the compounds disclosed herein can also be prepared from the corresponding optically pure intermediates, or by resolution, such as by HPLC of the corresponding racemate using a suitable chiral support, or by fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

[0242] The compounds of the present disclosure can be prepared by techniques known in organic synthesis and familiar to those of ordinary skill in the art. For example, the compounds can be prepared by the synthetic transformations shown in the following general procedure schemes 1-5 and further described in the subsequent specific examples.

[0243] Abbreviations

[0244] DCM: Dichloromethane

[0245] DMAc: Dimethylacetamide

[0246] DMF: N,N-Dimethylformamide

[0247] DMSO: Dimethyl sulfoxide

[0248] HLM: Human liver microsomes

[0249] HPLC: High performance liquid chromatography

[0250] HRMS: High Resolution Mass Spectrometry

[0251] LC-MS: Liquid Chromatography-Mass Spectrometry

[0252] MAO: Monoamine Oxidase

[0253] MTBE: Methyl Tert-Butyl Ether

[0254] NADPH: Nicotinamide Adenine Dinucleotide Phosphate Hydride

[0255] NMR: Nuclear Magnetic Resonance

[0256] PBS: Phosphate Buffered Saline

[0257] Pd / C: Palladium on Carbon

[0258] R.T.: Room Temperature / Ambient Temperature

[0259] TEA: Triethylamine

[0260] THF: Tetrahydrofuran

[0261] General Procedure

[0262] Scheme 1. General procedure for synthesizing the compounds of the present disclosure.

[0263]

[0264] Some compounds can be prepared by alternative methods, such as those generally described in Schemes 2-5.

[0265] Scheme 2. Alternative synthetic method.

[0266]

[0267] Scheme 3. Alternative synthetic method.

[0268]

[0269] Scheme 4. Alternative synthetic method.

[0270]

[0271] Scheme 5. Alternative synthetic method.

[0272]

[0273] However, these may not be the only methods to synthesize or obtain the desired compounds.

[0274] It should be understood that the embodiments and implementations provided herein are exemplary. Those skilled in the art will envision various modifications to the embodiments and implementations that are consistent with the scope disclosed herein. Such modifications are intended to be covered by the claims. Specific Embodiments

[0276] Example 1. Preparation of Compound 1

[0277]

[0278] Step 1: Preparation of 1H-indol-4-yl acetate.

[0279] Under a nitrogen atmosphere, a stirred solution of 1H-indol-4-ol (100 g, 751.03 mmol, 1.0 eq.) in dry DCM (1000 mL) was added to a reaction vessel. The reaction was then cooled to 0 °C and pyridine (72.60 mL, 901.24 mmol, 1.2 eq.) was added dropwise. Then acetic anhydride (102.57 mL, 826.14 mmol, 1.10 eq.) was added dropwise at 0 °C, and the mixture was stirred at 0 °C for 10 minutes. The reaction was then warmed to room temperature and stirred for 4 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (1,000 mL) and extracted with DCM (2 x 500 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C to obtain the crude compound. The crude compound was stirred in 200 mL of ether for 10 minutes, then the solid was filtered and dried in vacuo to obtain 1H-indol-4-yl acetate as an off-white solid (yield: 100 g, 76%). 1 1H NMR (400 MHz, DMSO-d6): δ = 11.28 (s, 1H), 7.34 - 7.28 (m, 2H), 7.08 - 7.04 (t, 1H), 6.73 - 6.71 (d, J = 8.0 Hz, 1H), 6.33 - 6.32 (t, 1H), 2.34 (s, 3H); HRMS m / z 176.25 [M+1] + 。

[0280] Step 2: Preparation of 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate.

[0281] Oxalyl chloride (8.81 mL, 102.75 mmol, 1.2 eq.) was added dropwise to a stirred solution of 1H-indole-4-yl acetate (15.0 g, 85.62 mmol, 1 eq.) in MTBE (300 mL) at 0 °C. The reaction mixture was then stirred at 0 °C for 30 minutes and at room temperature for 3 hours (during which a yellow precipitate formed). After completion of the reaction (confirmed by TLC monitoring), the mixture was diluted with heptane (100 mL), filtered under a nitrogen atmosphere, the solid was washed with heptane (150 mL), and dried in vacuo to give 3-(2-chloro-2-oxoacetyl)-1H-indole-4-yl acetate as a pale yellow solid (yield: 19 g, 83.53% crude). This crude material was used directly in the next step without further purification or characterization.

[0282] Step 3: Preparation of 3-(2-amino-2-oxoacetyl)-1H-indole-4-yl acetate.

[0283] Ammonia gas was bubbled through a stirred solution of the crude 3-(2-chloro-2-oxoacetyl)-1H-indole-4-yl acetate (6.5 g, 1 eq.) in DCM (130 mL) at -20 °C for 10 minutes (the color of the solution changed from yellow to light brown), and then the stirring was continued at 0 °C for an additional 1 hour. After completion of the reaction (monitored by TLC), the reaction mass was concentrated under reduced pressure on a rotary evaporator at 45 °C to give the crude compound. The crude material was diluted with 50 mL of DCM, stirred for 5 minutes, filtered, the solid was washed with 50 mL of DCM and dried in vacuo to give 3-(2-amino-2-oxoacetyl)-1H-indole-4-yl acetate as a pale yellow solid (yield: 3.5 g, 60%). HRMS m / z 247.10 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 8.56 (s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.44 - 7.42 (d, J = 8.0, 1H), 7.28 - 7.24 (t, 1H), 6.88 - 6.86 (d, J = 8 Hz, 1H), 2.36 (s, 3H).

[0284] Step 4: Preparation of 3-(2-aminoethyl)-1H-indol-4-ol (1).

[0285] At 0 °C, a solution of LAH (2.0 M in THF; 24.36 mL, 48.74 mmol, 8 eq.) was added dropwise to a stirred solution of 3-(2-amino-2-oxoacetyl)-1H-indol-4-yl acetate (1.5 g, 6.09 mmol, 1 eq.) in dry THF (60 mL). The mixture was stirred at 0 °C for 30 minutes, then at room temperature for 10 minutes, and then heated at 60 °C for 5 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to 0 °C and quenched dropwise with a THF / water mixture (1:1) until effervescence ceased, then diluted with additional THF (100 mL) and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was then filtered through celite, washed with THF (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure on a rotary evaporator at 45 °C in an inert atmosphere to give a light brown viscous solid. The crude compound was purified by preparative HPLC to give 3-(2-aminoethyl)-1H-indol-4-ol (1) as an off-white solid (yield: 13 mg, 1.21%). HRMS m / z 177.10 [M+1] + ; 1 H NMR (400 MHz, CD3OD): δ = 6.91 (s, 1H), 6.89 - 6.81 (m, 2H), 6.35 - 6.33 (dd, J = 8.0, 0.8 Hz, 1H), 3.12 - 3.09 (m, 4H).

[0286] Example 2. Preparation of Compound 2

[0287]

[0288] Step 1: Preparation of 3-(2-(methylamino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0289] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (6.5 g, 24.47 mmol, 1 eq.) in DCM (140 mL) at 0 °C was added methylamine (2 M in THF, 18.35 mL, 36.70 mmol, 1.5 eq.). Triethylamine (5.12 mL, 36.70 mmol, 1.5 eq.) was then added dropwise at 0 °C. Stirring was continued at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C. The crude material was suspended in 50 mL of DCM, stirred for 5 min, filtered, the solid was washed with 50 mL of DCM, and dried under reduced pressure to afford 3-(2-(methylamino)-2-oxoacetyl)-1H-indol-4-yl acetate as a pale yellow solid (Yield: 4.50 g, 70.67%). HRMS m / z 261.05 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.42 (s, 1H), 8.71 - 8.66 (d, J = 4.4 Hz, 1H), 8.59 - 8.58 (d, J = 4 Hz, 1H), 7.46 - 7.44 (d, J = 8.0 Hz, 1H), 7.29 - 7.25 (t, 1H), 6.88 (d, J = 8 Hz, 1H), 2.74 (d, J = 4.8 Hz 3H), 2.35 (s, 3H).

[0290] Step 2: Preparation of 3-(2-(methylamino)ethyl)-1H-indol-4-ol (2).

[0291] At 0 °C, a solution of LAH (2.0 M in THF) (23.05 mL, 46.10 mmol, 8 eq.) was added dropwise to a stirred solution of crude 3-(2-(methylamino)-2-oxoacetyl)-1H-indol-4-yl acetate (1.5 g, 5.76 mmol, 1 eq.) in dry THF (60 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then at room temperature for 10 minutes, and then heated to 60 °C and maintained for 5 hours. After the reaction was completed (monitored by TLC), the mixture was cooled to 0 °C and quenched dropwise with a THF / water mixture (1:1) until the evolution of gas ceased. Then the reaction mixture was diluted with THF (100 mL) and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The mixture was filtered through Celite, washed with THF (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure at 45 °C using a rotary evaporator in an inert atmosphere to give a light brown solid. The crude material was purified by trituration. First, the crude material was dissolved in 5% methanol / DCM, then ether was added to afford a solid, which was filtered and dried to give 3-(2-(methylamino)ethyl)-1H-indol-4-ol (2) as an off-white solid (yield: 180.0 mg, 16.42%). HRMS m / z 191.11 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 6.897 - 6.892 (d, J = 2.0 Hz, 1H), 6.81 - 6.77 (t, 1H), 6.73 - 6.71 (d, J = 8 Hz, 1H), 6.23 - 6.21 (d, J = 8 Hz, 1H), 2.86 - 2.83 (t, 2H), 2.73 (t, 2H), 2.27 (s, 3H).

[0292] Example 3. Preparation of Compounds 3 and 4

[0293]

[0294] Step 1: Preparation of 3-(2-(cyclopropylamino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0295] To a stirred solution of crude 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (6.0 g, 22.59 mmol, 1 eq.) in DCM (140 mL) at 0 °C was added cyclopropylamine (1.55 g, 1.2 eq.). Then, triethylamine (4.72 mL, 33.88 mmol, 1.5 eq.) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the mixture was diluted with water (300 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C to give the crude material. It was diluted with 30 mL of DCM, stirred for 5 min, filtered, the solid was washed with 30 mL of DCM and dried in vacuo to give 3-(2-(cyclopropylamino)-2-oxoacetyl)-1H-indol-4-yl acetate as a pale yellow solid (Yield: 6.0 g, 85%). 1 H NMR (400 MHz, DMSO-d6): δ 12.42 (s, 1H), 8.66 (d, J = 4.8, 0 Hz, 1H), 8.57 (s, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 2.85 - 2.79 (m, 1H), 2.35 (s, 3H), 0.71 - 0.66 (m, 2H), 0.65 - 0.62 (m, 2H).

[0296] Step 2: Preparation of 3-(2-(propylamino)ethyl)-1H-indol-4-ol (3) and 3-(2-(cyclopropylamino)ethyl)-1H-indol-4-ol (4).

[0297] To a stirred solution of crude 3-(2-(cyclopropylamino)-2-oxoacetyl)-1H-indole-4-yl acetate (1.5 g, 5.24 mmol, 1 eq.) in dry THF (60 mL) at 0 °C was added dropwise LAH solution (2.0 M in THF; 20.9 mL, 41.91 mmol, 8 eq.). The mixture was stirred at 0 °C for 30 minutes. Then the reaction mixture was stirred at room temperature for 10 minutes and then heated to 60 °C for 5 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to 0 °C and quenched with THF / water mixture (1:1) until the evolution of gas ceased. The mixture was diluted with THF (100 mL) and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The resulting mixture was filtered through celite, washed with THF (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C in an inert atmosphere to give a pale brown viscous solid. The material was purified by column chromatography using silica gel (100 - 200 mesh size) and eluting the compounds with a gradient of 7 - 9% MeOH in DCM. The desired fractions were concentrated under reduced pressure to give 3-(2-(propylamino)ethyl)-1H-indole-4-ol (3) as an off-white solid (yield: 200 mg, 17.49%) and 3-(2-(cyclopropylamino)ethyl)-1H-indole-4-ol (4) as an off-white solid (yield: 105 mg, 9%).

[0298] Compound 3: HRMS m / z 219.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.22 (d, J = 7.2 Hz, 1H), 2.85 (t, J = 5.2 Hz, 2H), 2.76 (t, J = 5.6 Hz, 2H), 2.50 - 2.45 (m, 2H), 1.48 - 1.39 (m, 2H), 0.85 (t, J = 7.6 Hz, 3H) ppm.

[0299] Compound 4: HRMS m / z 217.15 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 2H), 6.89 - 6.89 (d, J = 2 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.25 - 6.23 (d, J = 8 Hz, 1H), 2.86 (s, 4H), 2.13 - 2.08 (m, 1H), 0.38 - 0.33 (m, 2H), 0.31 - 0.24 (m, 2H).

[0300] Example 4. Preparation of Compound 5

[0301]

[0302] Step 1: Preparation of 3-(2-(ethylamino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0303] Ethylamine hydrochloride (1.15 g, 14.12 mmol, 1.5 eq.) was added to a stirred solution of crude 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (2.5 g, 9.41 mmol, 1 eq.) in DCM (40 mL) at 0 °C, and then triethylamine (3.97 mL, 28.23 mmol, 3 eq.) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The organic layers were combined, pooled, dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C. The crude material was suspended in 15 mL of DCM, stirred for 5 min, filtered, the solid was washed with 10 mL of DCM, and dried under reduced pressure to give 3-(2-(ethylamino)-2-oxoacetyl)-1H-indol-4-yl acetate as a pale yellow solid (yield: 1.5 g, 58.11%). HRMS m / z 273.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.4 (s, 1H), 8.63 (s, 2H), 7.43 (d, J = 8 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.31 - 3.16 (m, 2H), 2.36 (s, 3H), 1.10 (t, J = 8.0 Hz, 3H).

[0304] Step 2: Preparation of 3-(2-(ethylamino)ethyl)-1H-indol-4-ol (5).

[0305] At 0 °C, a solution of LAH (2.0 M in THF, 21.9 mL, 43.8 mmol, 8 eq.) was added dropwise to a stirred solution of 3-(2-(ethylamino)-2-oxoacetyl)-1H-indol-4-yl acetate (1.5 g, 5.47 mmol, 1 eq.) in dry THF (25 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then at room temperature for 10 minutes, and then heated at 60 °C for 6 hours. After completion of the reaction, it was cooled to 0 °C and quenched with a THF / water mixture (1:1) until the evolution of gas ceased, then diluted with additional THF (100 mL) and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The resulting mixture was filtered through celite, washed with THF (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C in an inert atmosphere to give a light brown solid. The crude material was purified by trituration. First, the crude material was dissolved in 5% methanol / DCM, then ether was added to produce a solid, which was filtered and dried to give 3-(2-(ethylamino)ethyl)-1H-indol-4-ol (5) as an off-white solid (yield: 114.0 mg, 10.20%). HRMS m / z 205.15 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.56 (s, 1H), 6.897 (d, J = 2.4 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 8 Hz, 1H), 6.23 (d, J = 7.2 Hz, 1H), 2.85 (t, J = 5.8 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H).

[0306] Example 5. Preparation of Compound 6

[0307]

[0308] Step 1: Preparation of 3-(2-(isopropylamino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0309] To a stirred solution of crude 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (2.5 g, 9.41 mmol, 1 eq.) in DCM (40 mL) at 0 °C was added propan-2-amine (1.21 mL, 14.1 mmol, 1.5 eq.), followed by dropwise addition of triethylamine (2.65 mL, 18.8 mmol, 2 eq.) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The organic layers were combined, pooled, dried over anhydrous Na2SO4 and concentrated under reduced pressure using a rotary evaporator at 45 °C. The crude compound was obtained, which was suspended in 15 mL of DCM, stirred for 5 min, filtered, the solid was washed with 10 mL of DCM and dried under reduced pressure to give 3-(2-(isopropylamino)-2-oxoacetyl)-1H-indol-4-yl acetate as a pale yellow solid (yield: 2 g, 73.79%). HRMS m / z 289.10 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.25 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 12.0 Hz, 1H), 7.25 (t, J = 6.6 Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 4.05 - 3.97 (m, 1H), 2.53 - 2.50 (m, 2H), 2.50 - 2.42 (m, 3H), 1.22 - 1.13 (m, 6H), 0.95 - 0.92 (m, 3H).

[0310] Step 2: Preparation of 3-(2-(isopropylamino)ethyl)-1H-indol-4-ol (6).

[0311] At 0 °C, a solution of LAH (2 M in THF, 27.7 mL, 55.5 mmol, 8.0 eq.) was added dropwise to a stirred solution of 3-(2-(isopropylamino)-2-oxoacetyl)-1H-indole-4-yl acetate (2 g, 6.94 mmol, 1 eq.) in dry THF (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, then at room temperature for 10 minutes, and then heated at 60 °C for 6 hours. After completion of the reaction, it was cooled to 0 °C and quenched with a THF / water mixture (1:1) until the evolution of gas ceased, then diluted with additional THF (100 mL) and stirred at room temperature for 30 minutes under a nitrogen atmosphere. The resulting mixture was filtered through celite, washed with THF (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure using a rotary evaporator at 45 °C in an inert atmosphere to give a light brown solid. The crude material was purified by trituration. First, the crude material was dissolved in 5% methanol / DCM, then ether was added to afford a solid, which was filtered and dried to give 3-(2-(isopropylamino)ethyl)-1H-indole-4-ol (6) as a light gray solid (yield: 183.0 mg, 12.09%). HRMS m / z 219.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.55 (s, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.79 (t, J = 7.8 Hz 1H), 6.72 (d, J = 4 Hz, 1H), 6.23 (d, J = 8 Hz, 1H), 2.84 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.72 - 2.66 (m, 1H), 0.997 - 0.982 (d, 6H).

[0312] Example 6. Preparation of Compound 26

[0313]

[0314] Step 1: Preparation of 1-(benzyloxy)-4-bromo-2-fluoro-5-nitrobenzene.

[0315] At 0 °C under a N2 atmosphere, NaH (1.02 g, 25.42 mmol) was added portionwise to a stirred solution of 4-bromo-2-fluoro-5-nitrophenol (5 g, 21.19 mmol) in anhydrous DMF (50 mL), and the mixture was stirred for 15 minutes. At 0 °C, benzyl bromide (3.7 mL, 31.78 mmol) was added dropwise to the reaction mixture via an addition funnel over 10 minutes, and the reaction mixture was stirred for an additional 45 minutes at the same temperature. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography, eluting with 0 - 5% EtOAc / hexane, to give 1-(benzyloxy)-4-bromo-2-fluoro-5-nitrobenzene as a white solid (yield: 5.5 g, 80%). 1 1H NMR (400 MHz, DMSO-d6): δ = 8.07 - 8.05 (d, J = 7.6 Hz 1H), 7.98 - 7.95 (d, J = 10.4 Hz 1H), 7.50 - 7.46 (d, J = 8.4 Hz 2H), 7.44 - 7.35 (m, 3H), 5.27 (s, 2H) ppm.

[0316] Step 2: Preparation of 4-(benzyloxy)-7-bromo-5-fluoro-1H-indole.

[0317] At -40 °C, vinylmagnesium bromide (2.0 M in THF; 25.30 mL, 50.59 mmol) was added to a stirred solution of 1-(benzyloxy)-4-bromo-2-fluoro-5-nitrobenzene (5.5 g, 16.86 mmol) in anhydrous THF (50 mL), and the resulting mixture was stirred for an additional 60 minutes at the same temperature. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the mixture was quenched by dropwise addition of saturated ammonium chloride solution (15 mL), then the reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography, eluting with 0 - 20% EtOAc / hexane, gave 4-(benzyloxy)-7-bromo-5-fluoro-1H-indole as an orange liquid (yield: 2.2 g, 40.74%). HRMS m / z 320.10 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 11.41 (s, 1H), 7.47 - 7.45 (d, J = 7.6 Hz, 2H), 7.40 - 7.28 (m, 5H), 6.67 (s, 1H), 5.27 (s, 2H) ppm.

[0318] Step 3: Preparation of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride.

[0319] To a stirred solution of 4-(benzyloxy)-7-bromo-5-fluoro-1H-indole (1.0 g, 3.12 mmol) in MTBE (20 mL) at 0 °C was added dropwise (COCl)2 (1.34 mL, 15.62 mmol) over 5 minutes. The reaction mixture was stirred at 0 °C for 30 minutes, then warmed to room temperature and stirred for 5 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated and placed under a N2 atmosphere to give 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride as a pale yellow liquid (Yield: 1.2 g, 93.56%). Note: The crude compound was used directly in the next step without further purification.

[0320] Step 4: Preparation of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide.

[0321] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (1.2 g, 2.92 mmol) in anhydrous THF (20 mL) at 0 °C was added CH3NH2 (2 M in THF; 2.19 mL, 4.38 mmol). Triethylamine (1.22 mL, 8.76 mmol) was added dropwise to the reaction mixture at 0 °C. Then the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography, eluting with 0 - 5% MeOH / DCM, to give 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a yellow solid (Yield: 0.650 g, 54.89%). HRMS m / z 406.95 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 12.52 (s, 1H), 8.69 (br s, 1H), 8.60 (s, 1H), 7.59 - 7.56 (d, J = 10.8 Hz, 1H), 7.54 - 7.52 (d, J = 7.2 Hz, 1H), 7.39 - 7.30 (m, 3H), 5.05 (s, 2H), 2.73 - 2.72 (d, J = 4.8 Hz, 3H) ppm.

[0322] Step 5: Preparation of 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide.

[0323] At room temperature under a N2 atmosphere, 10% Pd / C (0.759 g, 0.642 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide (1.3 g, 3.21 mmol) in methanol (25 mL). The reaction mixture was degassed with N2 for 2 - 3 minutes and then stirred at room temperature under a H2 atmosphere (balloon) for 12 hours. After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the pad was washed with 10% MeOH / DCM (2 x 30 mL). The organic solvents were combined and concentrated under reduced pressure to give the crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to afford 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a brown viscous solid (yield: 0.700 g, 92.3%). HRMS m / z 237.10 [M+1] + 。

[0324] Step 6: Preparation of 5-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (26).

[0325] At 0 °C, H2SO4 (0.63 mL, 11.85 mmol) was added dropwise to a stirred solution of LiAlH4 (2.0 M in THF; 11.8 mL, 23.7 mmol) in anhydrous THF (25 mL). The reaction mixture was stirred at 0 °C for 30 minutes, and then 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide (0.70 g, 2.96 mmol) in THF (50 mL) was added at 0 °C over 10 minutes. The reaction mixture was then heated to 70 °C and maintained for 5 hours. The progress of the reaction was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and quenched with THF:water (1:1) at 0 °C until bubbling ceased. The mixture was then diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, and filtered through Celite. The Celite was washed with THF (200 mL), the organic solvents were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 5-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (26) as a grey solid (yield: 0.10 g, 16.2%). HRMS m / z 209.20 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.60 (s, 1H), 9.09 (br s, 2H), 6.96 (d, J = 2 Hz 1H), 6.81 - 6.76 (m, 1H), 6.61 - 6.58 (dd, J = 3.6 Hz, J = 8.4 Hz 1H), 2.85 - 2.81 (m, 2H), 2.77 - 2.74 (m, 2H), 2.29 (m, 3H) ppm.

[0326] Example 7. Preparation of Compound 7 Hemifumarate

[0327]

[0328] Step 1: Preparation of 3-(2-((2-fluoroethyl)amino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0329] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (0.50 g, 1.8 mmol) in anhydrous THF (10 mL) at 0 °C was added 2-fluoroethan-1-amine hydrochloride (0.281 mg, 2.82 mmol). Triethylamine (0.79 mL, 5.65 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography using 0 - 5% MeOH / DCM to afford 3-(2-((2-fluoroethyl)amino)-2-oxoacetyl)-1H-indol-4-yl acetate as a pale yellow solid (yield: 0.50 g, 90.89%). HRMS m / z 243.05 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.46 (s, 1H), 8.85 (t, J = 6 Hz, 1H), 8.63 (s, 1H), 7.44 (d, J = 8 Hz, 1H), 7.27 (t, J = 8 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.60 (t, J = 5.2 Hz, 1H), 4.48 (t, J = 5.2 Hz, 1H), 3.56 - 3.52 (m, 1H), 3.50 - 3.33 (m, 1H), 2.37 (s, 3H) ppm.

[0330] Step 2: Preparation of 3-(2-((2-fluoroethyl)amino)ethyl)-1H-indol-4-ol (7) formate.

[0331] To a stirred solution of 3-(2-((2-fluoroethyl)amino)-2-oxoacetyl)-1H-indol-4-yl acetate (0.300 g, 1.03 mmol) in anhydrous THF (15 mL) at 0 °C was added BH3-THF solution (2.0 M in THF; 7.70 mL, 15.40 mmol) over 10 min, followed by heating to 70 °C for 12 h. The progress of the reaction was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and then cooled to 0 °C. The reaction was quenched with MeOH (10 mL) until bubbling ceased. The reaction mixture was then diluted with THF (100 mL), stirred at room temperature for 30 min under a N2 atmosphere and then concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC (0.1% aqueous formic acid / acetonitrile; 2% to 98% gradient in 17 min. Flow rate: 18 ml / min. Column: Waters XBridge C8 Purified with 5μm, 19mm X 250mm to obtain 3-(2-((2-fluoroethyl)amino)ethyl)-1H-indol-4-ol (7) formate as a gray solid (yield: 0.065 g, 28.49%). HRMS m / z 223.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.62 (s, 1H), 8.22 (s, 1H), 6.92 (d, J = 2 Hz, 1H), 6.80 (t, J = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 4.59 (t, J = 5.2 Hz, 1H), 4.47 (t, J = 4.8 Hz, 1H), 4.67 (t, J = 4.4 Hz, 1H), 4.56 (t, J = 4 Hz, 2H), 2.98 - 2.89 (m, 6H) ppm.

[0332] Step 3: Preparation of 3-(2-((2-fluoroethyl)amino)ethyl)-1H-indol-4-ol (7) hemifumarate.

[0333] At 0 °C, fumaric acid (0.011 g, 0.094 mmol) was added to a stirred solution of 3-(2-((2-fluoroethyl)amino)ethyl)-1H-indol-4-ol (7) formate (0.042 g, 0.188 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude residue was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to obtain 3-(2-((2-fluoroethyl)amino)ethyl)-1H-indol-4-ol (7) hemifumarate as a gray solid (yield: 0.033 g). HRMS m / z 223.25 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.63 (s, 2H), 9.09 (s, 2H), 6.92 (d, J = 2.4 Hz, 2H), 6.82 - 6.74 (m, 4H), 6.49 (s, 2H), 6.29 - 6.27 (m, 2H), 4.60 (t, J = 4.8 Hz, 2H), 4.48 (t, J = 4.8 Hz, 2H) 3.01 - 2.92 (m, 12H) ppm.

[0334] Example 8. Preparation of Compound 27 Hemifumarate

[0335]

[0336] Step 1: Preparation of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride.

[0337] To a stirred solution of 4-(benzyloxy)-7-bromo-5-fluoro-1H-indole (1.5 g, 4.69 mmol) in MTBE (15 mL) at 0 °C was added dropwise (COCl)2 (0.6 mL, 7.03 mmol) over 5 minutes. The reaction mixture was stirred at 0 °C for 30 minutes and then allowed to stir at room temperature for 5 hours. The progress of the reaction was monitored by TLC. Once complete, the solvent was removed under reduced pressure (and backfilled with N2 atmosphere) to afford 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride as a pale yellow liquid (yield: 1.5 g, 77.97%). Note: The crude compound was used directly in the next step without further purification.

[0338] Step 2: Preparation of N-benzyl-2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-cyclopropyl-2-oxoacetamide.

[0339] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (1.5 g, 3.65 mmol) in anhydrous THF (20 mL) at 0 °C was added N-benzylcyclopropylamine (0.783 mL, 4.38 mmol). Then triethylamine (1.53 mL, 10.96 mmol) was added dropwise to the reaction mixture at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. Purification by silica gel chromatography using 0 - 5% MeOH / DCM afforded N-benzyl-2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-cyclopropyl-2-oxoacetamide as a yellow solid (yield: 0.900 g, 47.25%). HRMS m / z 522.85 [M+2] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.67 (s, 1H), 8.03 (s, 1H), 7.59 (d, J = 10.8 Hz, 1H), 7.51 (d, J = 7.2 Hz, 2H), 7.41 - 7.29 (m, 8H), 5.09 (s, 2H), 4.54 (s, 2H), 2.66 - 2.56 (m, 1H), 0.63 (d, J = 4 Hz, 2H), 0.56 (d, J = 6.8 Hz, 2H) ppm.

[0340] Step 3: Preparation of N-benzyl-N-(2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)ethyl)cyclopropanamine.

[0341] To a stirred solution of LiAlH4 (2.0 M in THF; 3.45 mL, 6.90 mmol) in anhydrous THF (4.5 mL) at 0 °C was added dropwise H2SO4 (0.18 mL, 3.45 mmol) and the reaction mixture was stirred at 0 °C for 30 minutes. Then at 0 °C, N-benzyl-2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-cyclopropyl-2-oxoacetamide (0.900 g, 1.73 mmol) in THF (9.0 mL) was added to the solution over 10 minutes and the resulting mixture was heated to 60 °C for 5 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was allowed to cool to room temperature and then quenched at 0 °C with THF / water (1:1) until the evolution of gas ceased. The quenched reaction mixture was then diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes and then filtered through Celite. The Celite pad was washed with THF (200 mL), the organic solvents were combined and dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (0.1% aqueous formic acid / acetonitrile; 2% to 99% gradient in 17 minutes. Flow rate: 18 ml / min. Column: Waters XSelect CSH C18 5 μm, 19 mm X 250 mm) to give N-benzyl-N-(2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)ethyl)cyclopropanamine as a colorless viscous solid (yield: 0.440 g, 51.66%). HRMS m / z 494.95 [M+2] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 11.08 (s, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.38 - 7.32 (m, 3H), 7.31 - 7.16 (m, 6H), 7.07 (s, 1H), 5.11 (s, 2H), 3.62 (s, 2H), 2.94 - 2.88 (m, 2H), 2.72 - 2.66 (m, 2H), 1.67 - 1.66 (m, 1H), 0.29 (d, J = 6.4 Hz, 2H), 0.18 (s, 2H) ppm.

[0342] Step 4: Preparation of 3-(2-(cyclopropylamino)ethyl)-5-fluoro-1H-indol-4-ol (27).

[0343] At room temperature under a N2 atmosphere, 10% Pd / C (0.144 g, 0.121 mmol) was added to a stirred solution of N-benzyl-N-(2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)ethyl)cyclopropanamine (0.300 g, 0.608 mmol) in methanol (25 mL). The reaction mixture was degassed with N2 for 2 - 3 minutes and then placed under a H2 atmosphere (balloon) and stirred at room temperature for 7 hours. After completion (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the pad was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic solvents were removed under reduced pressure to give the crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL). This gave 3-(2-(cyclopropylamino)ethyl)-5-fluoro-1H-indol-4-ol (27) as a colorless viscous solid (yield: 0.030 g, 21.06%). HRMS m / z 235.17 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.68 (s, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.8 Hz, 11.2 Hz, 1H), 6.67 (dd, J = 3.6 Hz, 8.8 Hz, 1H), 2.96 - 2.90 (m, 4H), 2.27 (s, 1H), 0.480 (d, J = 6 Hz, 2H), 0.42 (br s, 2H) ppm.

[0344] Step 5: Preparation of 3-(2-(cyclopropylamino)ethyl)-5-fluoro-1H-indol-4-ol (27) hemifumarate.

[0345] At 0 °C, fumaric acid (0.007 g, 0.064 mmol) was added to a stirred solution of 3-(2-(cyclopropylamino)ethyl)-5-fluoro-1H-indol-4-ol (27; 0.030 g, 0.128 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude material, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to give 3-(2-(cyclopropylamino)ethyl)-5-fluoro-1H-indol-4-ol (27) hemifumarate as a grey solid (yield: 0.020 g). HRMS m / z 235 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 10.70 (s, 2H), 10.00 (br. 2H), 7.01 (s, 2H), 6.85 - 6.80 (m, 2H), 6.68 (dd, J = 2.8 Hz, J = 8.4 Hz, 2H), 6.54 (s, 2H), 2.98 - 2.96 (m, 4H), 2.93 - 2.92 (m, 4H), 2.30 - 2.29 (m, 2H), 0.49 - 0.45 (m, 8H) ppm.

[0346] Example 9. Preparation of Compound 23

[0347]

[0348] Step 1: Preparation of 3-(2-(allylamino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0349] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (see Example 1; 1.2 g, 4.52 mmol) in anhydrous THF (20 mL) at 0 °C was added allyl amine (0.51 mL, 6.78 mmol). Triethylamine (0.63 mL, 4.52 mmol) was added dropwise to the reaction mixture at 0 °C, and then the mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue. Purification by silica gel chromatography using 0 - 5% MeOH / DCM gave 3-(2-(allylamino)-2-oxoacetyl)-1H-indol-4-yl acetate as a yellow solid (yield: 0.900 g, 69.59%). HRMS m / z 287.00 [M + 1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.43 (s, 1H), 8.83 (t, J = 5.6 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 8 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 5.90 - 5.83 (m, 1H) 5.19 - 5.08 (m, 2H), 3.82 (br, 2H), 2.36 (s, 3H) ppm.

[0350] Step 2: Preparation of 3-(2-(allylamino)ethyl)-1H-indol-4-ol (23).

[0351] To a stirred solution of LiAlH4 (2.0 M in THF; 12.57 mL, 25.15 mmol) in anhydrous THF (25 mL) at 0 °C was added 3-(2-(allylamino)-2-oxoacetyl)-1H-indol-4-yl acetate (0.90 g, 3.14 mmol) in THF (50 mL) over 10 minutes. The mixture was then heated to 70 °C for 6 hours. The reaction progress was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and then to 0 °C. The reaction was quenched with THF / H2O (1:1) until all bubbling ceased. The reaction mixture was then diluted with THF (100 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, and then filtered through Celite. The filter pad was washed with THF (200 mL), the organic filtrates were combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 3-(2-(allylamino)ethyl)-1H-indol-4-ol (23) as a grey solid (yield: 0.190 g, 27.94%). HRMS m / z 217.25 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.57 (s, 1H), 6.89 (d, J = 2 Hz, 1H), 6.81 - 6.77 (m, 1H), 6.73 (d, J = 7 Hz, 1H), 6.24 (d, J = 6.8 Hz, 1H), 5.87 - 5.77 (m, 1H), 5.16 (d, J = 4 Hz, 1H), 5.04 (d, J = 8 Hz, 1H), 3.15 (d, J = 6 Hz, 2H), 2.86 (t, J = 6 Hz, 2H), 2.76 (t, J = 6 Hz, 2H) ppm.

[0352] Example 10. Preparation of Compound 24

[0353]

[0354] Step 1: Preparation of 3-(2-oxo-2-(prop-2-yn-1-ylamino)acetyl)-1H-indol-4-yl acetate.

[0355] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-1H-indol-4-yl acetate (see Example 1; 2.3 g, 8.66 mmol) in anhydrous THF (20 mL) at 0 °C was added propargyl-1-amine (0.83 mL, 12.9 mmol). Then, triethylamine (3.62 mL, 25.97 mmol) was added dropwise to the reaction mixture at 0 °C and the resulting mixture was stirred at room temperature for 2 h. After completion (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material, which was purified by silica gel chromatography using 0 - 5% MeOH / DCM to afford 3-(2-oxo-2-(prop-2-yn-1-ylamino)acetyl)-1H-indol-4-yl acetate as a yellow solid (yield: 1.6 g, 65.01%). HRMS m / z 243.05 [M+1] + 。

[0356] Step 2: Preparation of 3-(2-(prop-2-yn-1-ylamino)ethyl)-1H-indol-4-ol (24).

[0357] To a stirred solution of LiAlH4 (2 M in THF; 22.5 mL, 45.03 mmol) in anhydrous THF (50 mL) at 0 °C was added dropwise a solution of 3-(2-oxo-2-(prop-2-yn-1-ylamino)acetyl)-1H-indol-4-yl acetate (1.6 g, 5.63 mmol) in THF (50 mL) over 10 min. Then the reaction mixture was heated to 70 °C for 6 h. The progress of the reaction was monitored by TLC and LC-MS. Once judged complete, the reaction mixture was allowed to reach room temperature and then quenched with THF / water (1:1) at 0 °C until the evolution of gas ceased. The reaction mixture was diluted with THF (100 mL), stirred at room temperature for 30 min under a N2 atmosphere, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to afford 3-(2-(prop-2-yn-1-ylamino)ethyl)-1H-indol-4-ol (24) as a grey solid (yield: 0.445 g, 36.90%). HRMS m / z 215.20 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 10.58 (s, 1H), 10.16 (br s, 1H), 6.89 (d, J = 2 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.25 (d, J = 7.2 Hz, 1H), 3.32 - 3.31 (m, 2H), 3.04 (t, J = 2.4 Hz, 1H), 2.89 - 2.87 (m, 2H), 2.84 - 2.83 (m, 2H) ppm.

[0358] Example 11. Preparation of Compound 28 Hemifumarate

[0359]

[0360] Step 1: Preparation of 2-(4-(Benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-ethyl-2-oxoacetamide.

[0361] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (see Example 6; 1.2 g, 2.92 mmol) in anhydrous THF (20 mL) at 0 °C was added ethylamine (2 M in THF; 2.19 mL, 4.38 mmol). Then, triethylamine (1.22 mL, 8.77 mmol) was added dropwise to this solution at 0 °C and the reaction mixture was stirred at room temperature for 1 hour. After completion (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography (0 - 5% MeOH / DCM) to afford 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-ethyl-2-oxoacetamide as a yellow liquid (yield: 0.500 g, 51.98%). HRMS m / z 418.8 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.53 (s, 1H), 8.75 (t, J = 5.6 Hz 1H), 8.57 (s, 1H), 7.58 (d, J = 10.4 Hz, 1H), 7.54 - 7.52 (m, 2H), 7.47 - 7.13 (m, 3H), 5.05 (s, 2H), 3.21 (t, J = 6.4 Hz, 2H), 3.26 - 3.19 (m 2H), 1.10 (t, J = 8 Hz, 3H) ppm.

[0362] Step 2: Preparation of N-Ethyl-2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxoacetamide.

[0363] At room temperature under a N2 atmosphere, 10% Pd / C (1.3 g, 1.09 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-ethyl-2-oxoacetamide (1.8 g, 5.47 mmol) in methanol (25 mL). The reaction mixture was purged with N2 for 2 - 3 minutes, then evacuated and stirred at room temperature under a H2 atmosphere (balloon) for 12 hours. After completion (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the filter was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give a crude residue, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to afford N-ethyl-2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxoacetamide as a brown viscous solid (yield: 0.550 g, 51.19%). HRMS m / z 251.05 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 12.62 (s, 1H), 11.32 (s, 1H), 8.95 - 8.82 (m, 2H), 7.16 - 7.11 (m, 1H), 6.94 - 6.91 (m, 1H) 3.28 - 3.12 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H) ppm.

[0364] Step 3: Preparation of 3-(2-(ethylamino)ethyl)-5-fluoro-1H-indol-4-ol (28).

[0365] To a stirred solution of LiAlH4 (2 M in THF; 8.79 mL, 17.58 mmol) in anhydrous THF (20 mL) at 0 °C was added dropwise H2SO4 (0.47 mL, 8.79 mmol). The reaction mixture was stirred at 0 °C for 30 minutes, then a solution of N-ethyl-2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxoacetamide (0.550 g, 2.20 mmol) in THF (20 mL) was added dropwise at 0 °C over 10 minutes. The reaction mixture was then heated to 70 °C for 5 hours. The progress of the reaction was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature, then cooled to 0 °C and quenched with THF / water (1:1) until bubbling ceased. The quenched reaction mixture was diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 3-(2-(ethylamino)ethyl)-5-fluoro-1H-indol-4-ol (28) as a grey solid (yield: 0.057 g, 11.67%). HRMS m / z 223.20 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.59 (s, 1H), 9.07 (br s, 2H), 6.96 (d, J = 2 Hz, 1H), 6.81 - 6.76 (m, 1H), 6.61 - 6.58 (dd, J = 3.6 Hz, J = 8.4 Hz 1H), 2.85 - 2.82 (m, 2H), 2.78 - 2.76 (m, 2H), 2.58 - 2.49 (m, 2H), 2.29 (t, J = 8 Hz, 3H) ppm.

[0366] Step 4: Preparation of 3-(2-(ethylamino)ethyl)-5-fluoro-1H-indol-4-ol (28) hemifumarate.

[0367] At 0 °C, fumaric acid (0.078 g, 0.674 mmol) was added to a stirred solution of 3-(2-(ethylamino)ethyl)-5-fluoro-1H-indol-4-ol (28; 0.300 g, 1.35 mmol) in 10% MeOH / DCM (5 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure to give a crude residue. The material was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to give 3-(2-(ethylamino)ethyl)-5-fluoro-1H-indol-4-ol (28) hemifumarate as a grey solid (yield: 0.222 g). HRMS m / z 223.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.74 (s, 2H), 9.33 (brss, 2H), 7.03 - 7.02 (s, 2H), 6.86 - 6.81 (m, 2H), 6.69 - 6.54 (m, 2H), 6.43 (s, 2H), 2.99 (s, 8H), 2.85 - 2.71 (m, 4H), 1.10 (t, J = 7.2 Hz, 6H) ppm.

[0368] Example 12. Preparation of Compound 29

[0369]

[0370] Step 1: Preparation of 6-fluoro-1H-indol-4-yl acetate.

[0371] At 0 °C under a N2 atmosphere, pyridine (0.79 mL, 9.92 mmol) was added portionwise to a stirred solution of 6-fluoro-1H-indol-4-ol (1 g, 6.62 mmol) in anhydrous DCM (15 mL) and the resulting solution was stirred for 15 minutes. Then acetic anhydride (0.98 mL, 7.94 mmol) was added dropwise at 0 °C over 5 minutes and the reaction mixture was stirred at 0 °C for an additional 3 hours. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the mixture was quenched with ice-cold water (15 mL) and extracted with DCM (2 x 75 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue. The material was purified by silica gel chromatography, eluting with 0 - 5% EtOAc / hexane, to give 6-fluoro-1H-indol-4-yl acetate as a white solid (yield: 1.1 g, 86.06%). HRMS m / z 192.05 [M-1] - ; 1HNMR(400MHz, DMSO-d6): δ = 11.33(s, 1H), 7.34 - 33(m, 1H), 7.10(d, J = 9.6Hz, 1H), 6.72(dd, J = 2Hz, J = 10.4Hz, 1H), 6.34(s, 1H), 2.35(s, 3H) ppm.

[0372] Step 2: Preparation of 3-(2-chloro-2-oxoacetyl)-6-fluoro-1H-indol-4-yl acetate.

[0373] To a stirred solution of 6-fluoro-1H-indol-4-yl acetate (1.1 g, 5.69 mmol) in MTBE (15 mL) at 0 °C was added dropwise (COCl)2 (0.58 mL, 6.83 mmol) over 5 minutes, and the reaction mixture was stirred at 0 °C for 30 minutes. Then the reaction mixture was stirred at room temperature for 5 hours. The progress of the reaction was monitored by TLC. Once complete, the solvent was removed under reduced pressure (and backfilled with N2) to afford crude 3-(2-chloro-2-oxoacetyl)-6-fluoro-1H-indol-4-yl acetate as a pale yellow liquid (yield: 1.2 g, 74.30%). Note: The crude compound was used directly in the next step without further purification.

[0374] Step 3: Preparation of 3-(2-(ethylamino)-2-oxoacetyl)-6-fluoro-1H-indol-4-yl acetate.

[0375] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-6-fluoro-1H-indol-4-yl acetate (1.2 g, 4.23 mmol) in anhydrous THF (20 mL) at 0 °C was added ethylamine hydrochloride (0.51 g, 6.35 mmol). Then triethylamine (1.77 mL, 12.69 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 3-(2-(ethylamino)-2-oxoacetyl)-6-fluoro-1H-indol-4-yl acetate as a yellow solid (yield: 0.550 g, 44.48%). HRMS m / z 291.00 [M - 1] - . Note: The crude material was used directly in the next step without further purification.

[0376] Step 4: Preparation of 3-(2-(ethylamino)ethyl)-6-fluoro-1H-indol-4-ol (29).

[0377] To a stirred solution of LiAlH4 (2.0 M in THF; 7.53 mL, 15.05 mmol) in anhydrous THF (15 mL) at 0 °C was added dropwise a solution of 3-(2-(ethylamino)-2-oxoacetyl)-6-fluoro-1H-indole-4-yl acetate (0.550 g, 1.88 mmol) in THF (50 mL) over 10 minutes. The resulting solution was heated to 70 °C and maintained for 6 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was allowed to cool to room temperature and then further cooled to 0 °C. The mixture was quenched with THF / H2O (1:1) until effervescence ceased. The mixture was diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through celite, and the celite pad was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to afford 3-(2-(ethylamino)ethyl)-6-fluoro-1H-indol-4-ol (29) as a grey solid. (Yield: 0.238 g, 56.90%). HRMS m / z 223.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.62 (s, 1H), 8.51 (br, 1H), 6.88 (s, 1H), 6.43 (dd, J = 2 Hz, J = 9.6 Hz, 1H), 6.02 (dd, J = 2 Hz, J = 12 Hz, 1H), 2.81 - 2.79 (m, 2H), 2.76 - 2.75 (m, 2H), 2.61 - 2.55 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H) ppm.

[0378] Example 13. Preparation of Compound 30 Hemifumarate

[0379]

[0380] Step 1: Preparation of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetamide.

[0381] Bubbling for 10 minutes, ammonia gas (excess; the color of the solution changed from yellow to light brown) was added to a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (see Example 6; 1.2 g, 2.92 mmol) in THF (20 mL) at -20 °C, and then the mixture was stirred at room temperature for 1.5 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography using 0 - 5% MeOH / DCM to give 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetamide as a light brown solid (yield: 0.770 g, 67.35%). HRMS m / z 393.05 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.53 (s, 1H), 8.49 (s, 1H), 8.14 (s, 1H), 7.74 (s, 1H), 7.59 - 7.53 (m, 3H), 7.39 - 7.30 (m, 3H), 5.05 (s, 2H) ppm.

[0382] Step 2: Preparation of 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxoacetamide.

[0383] 10% Pd / C (0.466 g, 0.393 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetamide (0.770 g, 1.97 mmol) in methanol (25 mL) at room temperature under a N2 atmosphere. The reaction mixture was purged with N2 for 2 - 3 minutes, and then stirred at room temperature for 12 hours under a H2 atmosphere (balloon). After completion (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to obtain a crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to give 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxoacetamide as a brown viscous solid (yield: 0.400 g, 91.47%). HRMS m / z 221.00 [M-1] - 。

[0384] Step 3: Preparation of 3-(2-aminoethyl)-5-fluoro-1H-indol-4-ol (30).

[0385] To a stirred solution of LiAlH4 (2 M, in THF; 7.20 mL, 14.40 mmol) in anhydrous THF (15 mL) at 0 °C was added dropwise H2SO4 (0.38 mL, 7.20 mmol). The reaction mixture was stirred at 0 °C for 30 minutes, then a solution of 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxoacetamide (0.400 g, 1.80 mmol) in THF (50 mL) was added over 10 minutes, and the reaction mixture was heated to 70 °C for 5 hours. The reaction progress was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and then quenched with THF / H2O (1:1) at 0 °C until bubbling ceased. The quenched reaction mixture was diluted with THF (100 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to afford 3-(2-aminoethyl)-5-fluoro-1H-indol-4-ol (30) as a gray solid (yield: 0.050 g, 14.30%). HRMS m / z 195.09 [M+1] + 。

[0386] Step 4: Preparation of 3-(2-aminoethyl)-5-fluoro-1H-indol-4-ol (30) hemifumarate.

[0387] To a stirred solution of 3-(2-aminoethyl)-5-fluoro-1H-indol-4-ol (30; 0.050 g, 0.257 mmol) in 10% MeOH / DCM (2 mL) at 0 °C was added fumaric acid (0.015 g, 0.128 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to give a crude residue, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to afford 3-(2-aminoethyl)-5-fluoro-1H-indol-4-ol (30) hemifumarate as a gray solid (yield: 0.026 g). HRMS m / z 195.25 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.72 (s, 1H), 8.38 (br s, 4H), 7.00 (d, J = 2 Hz, 2H), 6.85 - 6.80 (m, 2H), 6.68 - 6.65 (dd, J = 3.2 Hz J = 8.4 Hz, 2H), 6.36 (s, 2H), 2.93 (s, 8H) ppm.

[0388] Example 14. Preparation of Compound 31 Hemifumarate

[0389]

[0390] Step 1: Preparation of 4-(benzyloxy)-6-fluoro-1H-indole-3-carbaldehyde.

[0391] Phosphorus oxychloride (2.5 mL, 27.36 mmol) was added dropwise to anhydrous dimethylformamide (20 mL) at 0 °C. The mixture was stirred for 30 minutes and then 4-(benzyloxy)-6-fluoro-1H-indole (2.2 g, 9.12 mmol) in dimethylformamide solution (10 mL per 1 g of indole) was added. The mixture was allowed to warm to room temperature and stirred for 7 hours. The reaction became a thick suspension and vigorous stirring was required. Aqueous potassium hydroxide solution (5.12 g, 91.19 mmol) at 3.8 M was added to the suspension via a dropping funnel and the mixture was heated to reflux for 7 hours. It was cooled to room temperature, then saturated aqueous NaHCO3 and ethyl acetate (50 mL) were added until the mixture became clear and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 x 50 mL), the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude 4-(benzyloxy)-6-fluoro-1H-indole-3-carbaldehyde as a yellow solid (yield: 0.900 g, 36.65%). HRMS m / z 270.00 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.26 (s, 1H), 10.25 (s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 6.92 (dd, J = 2 Hz, 9.2 Hz, 1H), 6.84 (dd, J = 1.6 Hz, 12 Hz, 1H), 5.29 (s, 2H) ppm.

[0392] Step 2: Preparation of (E)-4-(benzyloxy)-6-fluoro-3-(2-nitrovinyl)-1H-indole.

[0393] At room temperature under a N2 atmosphere, NH4OAc (0.630 g, 8.17 mmol) was added to a stirred solution of 4-(benzyloxy)-6-fluoro-1H-indole-3-carbaldehyde (0.800 g, 2.97 mmol) in nitromethane (10 mL). The reaction mixture was then stirred at 85 °C for 3 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude residue was triturated with n-pentane (10 mL) and diethyl ether (2 mL) to afford (E)-4-(benzyloxy)-6-fluoro-3-(2-nitrovinyl)-1H-indole as a yellow solid (yield: 0.750 g, 80.83%). HRMS m / z 313.00 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ 12.26 (s, 1H), 8.58 (d, J = 13.2 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J = 16 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.51 - 7.36 (m, 3H), 6.92 (dd, J = 2 Hz, 9.2 Hz, 1H), 6.83 (dd, J = 1.6 Hz, 11.6 Hz, 1H), 5.27 (s, 2H) ppm.

[0394] Step 3: Preparation of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)ethan-1-amine.

[0395] To a stirred solution of LiAlH4 (2.0 M in THF; 2.56 mL, 5.12 mmol) in anhydrous THF (10 mL) at 0 °C was added dropwise H2SO4 (0.14 mL, 2.56 mmol). The solution was stirred for 30 minutes and then a solution of (E)-4-(benzyloxy)-6-fluoro-3-(2-nitrovinyl)-1H-indole (0.400 g, 1.28 mmol) in THF (50 mL) was added over 10 minutes at 0 °C. The reaction mixture was then heated to 70 °C for 5 hours. The reaction progress was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and quenched at 0 °C with THF / water (1:1) until bubbling ceased. The quenched reaction mixture was diluted with THF (100 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, filtered through Celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)ethan-1-amine as a brown viscous solid (crude) (yield: 0.240 g, 65.90%). HRMS m / z 285.05 [M+1] + . Note: The crude compound was used directly in the next step without further purification.

[0396] Step 4: Preparation of 3-(2-aminoethyl)-6-fluoro-1H-indol-4-ol (31).

[0397] To a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)ethan-1-amine (0.070 g, 0.246 mmol) in methanol (25 mL) at room temperature under a N2 atmosphere was added 10% Pd / C (0.058 g, 0.058 mmol). The reaction mixture was degassed with N2 for 2 - 3 minutes and then placed under a H2 atmosphere (balloon) and stirred at room temperature for 12 hours. After completion of the reaction (monitored by TLC and LC-MS), the mixture was filtered through Celite to remove the catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to afford the crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to give 3-(2-aminoethyl)-6-fluoro-1H-indol-4-ol (31) as a brown solid (yield: 0.040 g, 83.66%). HRMS m / z 195.10 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 10.69 (s, 1H), 8.05 (br, 1H), 6.91 (s, 1H), 6.48 (dd, J = 2 Hz, 9.6 Hz, 1H), 6.07 (dd, J = 1.6 Hz, 12 Hz, 1H), 2.89 - 2.86 (m, 4H), 1.89 (s, 2H) ppm.

[0398] Step 5: Preparation of 3-(2-aminoethyl)-6-fluoro-1H-indol-4-ol (31) hemifumarate.

[0399] To a stirred solution of 3-(2-aminoethyl)-6-fluoro-1H-indol-4-ol (31; 0.040 g, 0.205 mmol) in 10% MeOH / DCM (2 mL) at 0 °C was added fumaric acid (0.012 g, 0.103 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure to give a crude residue, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to afford 3-(2-aminoethyl)-6-fluoro-1H-indol-4-ol (31) hemifumarate as a grey solid (yield: 0.030 g). HRMS m / z 195.20 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.82 (s, 1H), 9.02 (br, 3H), 6.96 (d, J = 1.6 Hz, 1H), 6.53 (dd, J = 2 Hz, 9.6 Hz, 1H), 6.43 (s, 1H), 6.21 (dd, J = 2 Hz, 11.6 Hz, 1H), 3.06 - 3.01 (m, 4H) ppm.

[0400] Example 15. Preparation of Compound 32 Hemifumarate

[0401]

[0402] Step 1: Preparation of 4-(benzyloxy)-1-fluoro-2-nitrobenzene.

[0403] Under a N2 atmosphere, NaH (3.06 g, 76.38 mmol) was added portionwise to a stirred solution of 4-fluoro-3-nitrophenol (10.00 g, 63.65 mmol) in anhydrous DMF (80 mL) at 0 °C, and the mixture was stirred for 15 minutes. Then, it was added dropwise via an addition funnel over 15 minutes at 0 °C, and the mixture was stirred for an additional 45 minutes at the same temperature. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This material was purified by silica gel chromatography, eluting with 0 - 5% EtOAc / hexane, to give 4-(benzyloxy)-1-fluoro-2-nitrobenzene as a white solid (yield: 10 g, 63.55%). 1 1H NMR (400 MHz, DMSO-d6): δ = 7.74 - 7.72 (m, 1H), 7.56 - 7.33 (m, 7H), 5.20 (s, 2H) ppm.

[0404] Step 2: Preparation of 4-(benzyloxy)-7-fluoro-1H-indole.

[0405] Vinylmagnesium bromide (1.0 M in THF; 48.54 mL, 48.54 mmol) was added to a stirred solution of 4-(benzyloxy)-1-fluoro-2-nitrobenzene (4.0 g, 16.18 mmol) in anhydrous THF (50 mL) at -40 °C, and the reaction mixture was stirred for an additional 15 minutes at the same temperature. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched by dropwise addition of saturated ammonium chloride solution (15 mL), diluted with water (25 mL), and extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. Purification was carried out by silica gel chromatography, eluting with 0 - 20% EtOAc / hexane, to give 4-(benzyloxy)-7-fluoro-1H-indole as an orange liquid (yield: 0.650 g, 16.65%). 1 1H NMR (400 MHz, DMSO-d6): δ = 11.55 (s, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 2.8 Hz, 1H), 6.76 (dd, J = 8.4 Hz, 11.2 Hz, 1H), 6.52 - 6.51 (m, 1H), 6.44 (dd, J = 3.2 Hz, 8.4 Hz, 1H), 5.16 (s, 2H) ppm.

[0406] Step 3: Preparation of 4-(benzyloxy)-7-fluoro-1H-indole-3-carbaldehyde.

[0407] Phosphorus oxychloride (0.968 mL, 10.36 mmol) was added dropwise to dry dimethylformamide (20 mL) at 0 °C. The mixture was stirred for 30 minutes and then 4-(benzyloxy)-7-fluoro-1H-indole (1.0 g, 4.14 mmol) in dimethylformamide solution (10 mL) was added. The mixture was allowed to warm to room temperature and stirred for 7 hours. The reaction became a thick suspension and vigorous stirring was required. At this point, 3.8 M aqueous potassium hydroxide (2.3 g, 41.45 mmol) was added via a dropping funnel and the mixture was heated to reflux for 7 hours. The reaction was cooled to room temperature, then a mixture of saturated aqueous NaHCO3 and ethyl acetate (30 mL) was added until the mixture became clear and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3 x 30 mL), the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude 4-(benzyloxy)-7-fluoro-1H-indole-3-carbaldehyde as a yellow solid (yield: 0.900 g, 80.64%). HRMS m / z 270.00 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.80 (s, 1H), 10.32 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.99 (dd, J = 8.4 Hz, 10.4 Hz, 1H), 6.77 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 5.26 (s, 2H) ppm.

[0408] Step 4: Preparation of (E)-4-(benzyloxy)-7-fluoro-3-(2-nitrovinyl)-1H-indole.

[0409] At room temperature under a N2 atmosphere, NH4OAc (0.472 g, 6.13 mmol) was added to a stirred solution of 4-(benzyloxy)-7-fluoro-1H-indole-3-carbaldehyde (0.600 g, 2.23 mmol) in nitromethane (10 mL). The reaction mixture was then heated and stirred at 85 °C for 3 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude residue was triturated with n-pentane (10 mL) and diethyl ether (2 mL) to give (E)-4-(benzyloxy)-7-fluoro-3-(2-nitrovinyl)-1H-indole as a yellow solid (yield: 0.550 g, 79.04%). HRMS m / z 312.90 [M+1] + . Note: The crude compound was used directly in the next step without further purification.

[0410] Step 5: Preparation of 2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethan-1-amine.

[0411] To a stirred solution of LiAlH4 (2.0 M in THF) (3.52 mL, 7.04 mmol) in anhydrous THF (15 mL) at 0 °C, H2SO4 (0.18 mL, 3.52 mmol) was added dropwise and the resulting mixture was stirred at 0 °C for 30 min. At this point, (E)-4-(benzyloxy)-7-fluoro-3-(2-nitrovinyl)-1H-indole (0.550 g, 1.76 mmol) in THF (50 mL) was added to this solution at 0 °C over 10 min and then the reaction was stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction mixture was cooled to 0 °C and then quenched with THF / H2O (1:1) until bubbling ceased. The reaction mixture was then diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 min, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethan-1-amine as a brown viscous solid (crude) (yield: 0.500 g, 99.85%). HRMS m / z 285.05 [M+1] + . Note: The crude compound was used directly in the next step without further purification.

[0412] Step 6: Preparation of tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)carbamate.

[0413] Under an inert atmosphere, Et3N (0.49 mL, 3.52 mmol) and di-tert-butyl dicarbonate (0.60 mL, 2.64 mmol) were added to a stirred solution of 2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethan-1-amine (0.500 g, 1.76 mmol) in THF (10 mL) at 0 °C, and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (50 mL) solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography using 0 - 5% EtOAc / hexane as eluent to give tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)carbamate as a pale yellow solid (yield: 0.400 g, 59.17%). HRMS m / z 383.10 [M-1] - ; 1 H NMR (400 MHz, DMSO-d6): δ = 11.26 (s, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33 - 7.29 (m, 1H), 7.03 (s, 1H), 6.76 - 6.69 (m, 2H), 6.40 (dd, J = 3.2 Hz, 8.4 Hz, 1H), 5.17 (s, 2H), 3.22 - 3.17 (m, 2H), 2.93 (t, J = 7.2 Hz, 2H), 1.35 (s, 9H) ppm.

[0414] Step 7: Preparation of tert-butyl (2-(7-fluoro-4-hydroxy-1H-indol-3-yl)ethyl)carbamate.

[0415] At room temperature under a N2 atmosphere, 10% Pd / C (0.246 g, 0.208 mmol) was added to a stirred solution of tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)carbamate (0.400 g, 1.04 mmol) in methanol (25 mL). The reaction mixture was degassed with N2 for 2 - 3 minutes and then placed under a H2 atmosphere (balloon) and stirred at room temperature for 12 hours. After completion (monitored by TLC and LC-MS), the reaction mixture was passed through celite to remove the catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give a crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to afford tert-butyl (2-(7-fluoro-4-hydroxy-1H-indol-3-yl)ethyl)carbamate as a white solid (yield: 0.250 g, 81.64%). HRMS m / z 293.05 [M - 1] - 。

[0416] Step 8: Preparation of 3-(2-aminoethyl)-7-fluoro-1H-indol-4-ol (32) formate.

[0417] To a stirred solution of tert-butyl (2-(7-fluoro-4-hydroxy-1H-indol-3-yl)ethyl)carbamate (0.250 g, 0.849 mmol) in dichloromethane (2 mL) at 0 °C was added 4N hydrogen chloride in 1,4-dioxane (3 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by preparative HPLC (0.1% aqueous formic acid / acetonitrile; 2% to 99% gradient in 19 minutes. Flow rate: 18 ml / min. Column: Waters XSelect CSH C18 5 μm, 19 mm X 250 mm) to afford 3-(2-aminoethyl)-7-fluoro-1H-indol-4-ol (32) formate as an off-white solid (yield: 0.150 g, 73.51%). HRMS m / z 195.12 [M + 1] + 。 1 1H NMR (400 MHz, DMSO-d6): δ = 11.17 (s, 1H), 8.38 (s, 1H), 8.01 (br. 1H), 7.04 (d, J = 2 Hz, 1H), 6.64 (dd, J = 8.4 Hz, 10.8 Hz, 1H), 6.20 (dd, J = 3.2 Hz, 8.4 Hz, 1H), 3.04 - 2.98 (m, 4H) ppm.

[0418] Step 9: Preparation of 3-(2-aminoethyl)-7-fluoro-1H-indol-4-ol (32) hemifumarate.

[0419] To a stirred solution of 3-(2-aminoethyl)-7-fluoro-1H-indol-4-ol (32) formate (0.045 g, 0.231 mmol) in 10% MeOH / DCM (2 mL) at 0 °C was added fumaric acid (0.013 g, 0.116 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude compound, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to afford 3-(2-aminoethyl)-7-fluoro-1H-indol-4-ol (32) hemifumarate as a grey solid (yield: 0.035 g). HRMS m / z 195.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 11.17 (s, 1H), 8.50 (br. 3H), 7.04 (d, J = 1.6 Hz, 1H), 6.66 - 6.61 (m, 1H), 6.39 (s, 1H), 6.20 (dd, J = 3.2 Hz, 8 Hz, 1H), 3.06 - 3.00 (m, 4H) ppm.

[0420] Example 16. Preparation of Compound 33 Fumarate

[0421]

[0422] Step 1: Preparation of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride.

[0423] To a stirred solution of 4-(benzyloxy)-6-fluoro-1H-indole (2 g, 8.29 mmol) in MTBE (15 mL) at 0 °C was added (COCl)2 (1.07 mL, 12.43 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 0 °C for 30 minutes and then allowed to stir at room temperature for 5 hours. The progress of the reaction was monitored by TLC. Once complete, the solvent was removed under reduced pressure and then backfilled with N2 atmosphere to afford crude 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride as a pale yellow liquid (yield: 1.8 g, 65.46%). Note: The crude compound was used directly in the next step without further purification.

[0424] Step 2: Preparation of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide.

[0425] To a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (2 g, 6.03 mmol) in anhydrous THF (20 mL) at 0 °C was added methylamine (2.0 M in THF; 6.03 mL, 12.06 mmol). Then triethylamine (2.52 mL, 18.09 mmol) was added dropwise to the reaction mixture at 0 °C and the solution was stirred at room temperature for 2 h. After completion (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography using 0 - 5% MeOH / DCM to afford 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a yellow solid (yield: 0.650 g, 33.04%). HRMS m / z 327.05 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.17 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H) 6.89 (dd, J = 2&8.8 Hz, 1H), 6.70 (dd, J = 1.6&12.4 Hz, 1H), 5.25 (s, 2H), 2.67 (d, J = 7.6 Hz, 3H) ppm.

[0426] Step 3: Preparation of 2-(6-fluoro-4-hydroxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide.

[0427] At room temperature under a N2 atmosphere, 10% Pd / C (0.871 g, 0.735 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide (1.2 g, 3.68 mmol) in methanol (25 mL). The reaction mixture was purged with N2 for 2 - 3 minutes and then stirred at room temperature for 12 hours under a H2 atmosphere (balloon). After completion (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The organic filtrates were combined and concentrated under reduced pressure to give a crude residue, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to afford 2-(6-fluoro-4-hydroxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a brown viscous solid (yield: 0.800 g, 92.10%). HRMS m / z 237.05 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6); δ = 11.41 (s, 1H), 8.88 (d, J = 4.8 Hz, 1H), 8.81 (s, 1H), 6.78 (d, J = 4.4 Hz, 1H), 6.17 (d, J = 4.4 Hz, 1H), 2.75 (d, J = 4.8 Hz, 1H) ppm.

[0428] Step 4: Preparation of 6-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (33).

[0429] To a stirred solution of LiAlH4 (2.0 M in THF; 6.77 mL, 13.55 mmol) in anhydrous THF (15 mL) at 0 °C was added dropwise H2SO4 (0.36 mL, 6.77 mmol). The solution was stirred at 0 °C for 30 minutes and then 2-(6-fluoro-4-hydroxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide (0.400 g, 1.69 mmol) in THF (20 mL) was added at 0 °C over 10 minutes. The reaction mixture was then heated to 70 °C for 5 hours. The progress of the reaction was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and then quenched with THF / H2O (1:1) at 0 °C until bubbling ceased. The reaction mixture was then diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (0.1% aqueous formic acid / acetonitrile; 3% to 97% gradient over 17 minutes. Flow rate: 18 ml / min. Column: Waters SunFire C18 10 μm, 19 mm X 250 mm) to give 6-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (33) as a yellow viscous solid (yield: 0.028 g, 7.94%). HRMS m / z 209.15 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.63 (s, 1H), 6.88 (d, J = 2 Hz, 1H), 6.44 (dd, J = 2.4 & 10 Hz, 1H), 6.02 (dd, J = 2 & 12 Hz, 1H), 2.83 - 2.73 (m, 4H), 2.28 (s, 3H) ppm.

[0430] Step 5: Preparation of 6-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (33) fumarate.

[0431] At 0 °C, fumaric acid (0.015 g, 0.134 mmol) was added to a stirred solution of 6-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (33; 0.028 g, 0.134 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes. The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to afford 6-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (33) fumarate as a yellow solid. (Yield: 0.036 g). HRMS m / z 209.25 [M+1] + 。 1 H NMR (400 MHz, DMSO-d6): δ = 10.79 (s, 1H), 9.67 (br., 3H), 6.95 (d, J = 1.6 Hz, 1H), 6.51 (dd, J = 2&10 Hz, 1H), 6.42 (s, 2H), 6.16 (dd, J = 1.6&11.6 Hz, 1H), 3.04 - 3.00 (m, 4H), 2.47 (s, 3H) ppm.

[0432] Example 17. Preparation of Compound 34 Hemifumarate

[0433]

[0434] Step 1: Preparation of 2-(4-(Benzyloxy)-7-fluoro-1H-indol-3-yl)-N-methylethan-1-amine

[0435] At 0 °C, lithium aluminum hydride (2.0 M in THF) (1.17 mL, 2.34 mmol) was added to a stirred solution of tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)carbamate (see Example 15; 0.300 g, 0.780 mmol) in anhydrous THF (5 mL) over 5 minutes, and the resulting mixture was stirred at 70 °C for 5 hours. The progress of the reaction was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and then quenched with THF / water (1:1) at 0 °C until bubbling ceased. The quenched reaction mixture was diluted with THF (50 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, filtered through Celite, and the filter cake was washed with THF (100 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)-N-methylethan-1-amine as a brown viscous solid (crude) (Yield: 0.310 g). HRMS m / z 299.00 [M+1] +Note: The crude compound was used directly in the next step without further purification.

[0436] Step 2: Preparation of tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)(methyl)carbamate.

[0437] Under an inert atmosphere, Boc anhydride (0.35 mL, 1.56 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)-N-methylethan-1-amine (0.310 g, 1.04 mmol) in THF (10 mL) at 0 °C and the resulting mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography. Elution with 0 - 5% EtOAc / hexane gave tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)(methyl)carbamate as a pale yellow solid (yield: 0.160 g, 38.65%). HRMS m / z 397.05 [M-1] - ; 1 H NMR (400 MHz, DMSO-d6): δ = 11.25 (s, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.77 (dd, J = 8.4 Hz, 10.8 Hz, 1H), 6.45 (dd, J = 3.2 Hz, 8.8 Hz, 1H), 5.15 (s, 2H), 3.38 - 3.36 (m, 2H), 2.90 (t, J = 6.8 Hz, 2H), 2.55 - 2.45 (m, 3H), 1.36 - 1.04 (m, 9H) ppm.

[0438] Step 3: Preparation of tert-butyl (2-(7-fluoro-4-hydroxy-1H-indol-3-yl)ethyl)(methyl)carbamate.

[0439] At room temperature under a N2 atmosphere, 10% Pd / C (0.095 g, 0.08 mmol) was added to a stirred solution of tert-butyl (2-(4-(benzyloxy)-7-fluoro-1H-indol-3-yl)ethyl)(methyl)carbamate (0.160 g, 0.401 mmol) in methanol (15 mL). The reaction mixture was degassed with N2 for 2 - 3 minutes and then placed under a H2 atmosphere (balloon) and stirred at room temperature for 24 hours. After completion (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The organic filtrates were combined and concentrated under reduced pressure to give the crude product, and the crude product was triturated with n-pentane (10 mL) and diethyl ether (3 mL). Tert-butyl (2-(7-fluoro-4-hydroxy-1H-indol-3-yl)ethyl)(methyl)carbamate was obtained as a brown solid (yield: 0.100 g, 80.77%). HRMS m / z 307.05 [M-1] - ; 1 1H NMR (400 MHz, DMSO-d6): δ = 11.02 (s, 1H), 9.33 - 9.27 (m, 1H), 6.96 - 6.90 (m, 1H), 6.60 (dd, J = 8.4 Hz, 11.2 Hz, 1H), 6.17 (dd, J = 3.2 Hz, 8 Hz, 1H), 3.46 - 3.35 (m, 3H), 2.92 (t, J = 6.45 Hz, 2H), 2.74 (s, 2H), 1.38 - 1.12 (m, 9H) ppm.

[0440] Step 4: Preparation of 7-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (34) formate.

[0441] At 0 °C, 4N hydrogen chloride in 1,4-dioxane (3 mL) was added to a stirred solution of tert-butyl (2-(7-fluoro-4-hydroxy-1H-indol-3-yl)ethyl)(methyl)carbamate (0.100 g, 0.324 mmol) in dichloromethane (2 mL) over 5 minutes. The reaction mixture was stirred at room temperature for 3 hours. At this time, the reaction mixture was concentrated under reduced pressure and the resulting crude material was purified by preparative HPLC (0.1% aqueous formic acid / acetonitrile; 2% to 99% gradient in 17 minutes. Flow rate: 18 ml / min. Column: Waters XSelect C18 5 μm, 19 mm X 250 mm) to give 7-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (34) formate as a brown viscous solid (yield: 0.024 g, 35.54%). 11H NMR (400 MHz, DMSO-d6): δ = 11.15 (s, 1H), 8.56 (s, 1H), 7.03 (s, 1H), 6.63 (dd, J = 8.4 Hz, 10.8 Hz, 1H), 6.17 (dd, J = 3.2 Hz, 8 Hz, 1H), 2.99 (s, 4H), 2.43 (s, 4H) ppm.

[0442] Step 5: Preparation of 7-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (34) hemifumarate.

[0443] To a stirred solution of 7-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (34) formate (0.024 g, 0.115 mmol) in 10% MeOH / DCM (2 mL) at 0 °C was added fumaric acid (0.007 g, 0.057 mmol) over 5 minutes. The reaction mixture was stirred at room temperature for 4 h. At this time, the reaction mixture was concentrated under reduced pressure to give a crude material, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to give 7-fluoro-3-(2-(methylamino)ethyl)-1H-indol-4-ol (34) hemifumarate as a grey solid (yield: 0.023 g). HRMS m / z 209.15 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 11.17 (s, 2H), 9.37 (br, 4H), 7.04 (d, J = 1.6 Hz, 2H), 6.66 - 6.61 (m, 2H), 6.39 (s, 2H), 6.20 (dd, J = 3.2 Hz, 8 Hz, 2H), 3.00 (s, 8H), 2.44 (s, 6H) ppm.

[0444] Example 18. Preparation of Compound 35 Formate

[0445]

[0446] Step 1: Preparation of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide.

[0447] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (see Example 6; 1.2 g, 2.92 mmol) in anhydrous THF (20 mL) at 0 °C was added i-Pr-NH2 (0.37 mL, 4.38 mmol). Then, triethylamine (1.22 mL, 8.76 mmol) was added dropwise to the reaction mixture at 0 °C and the mixture was stirred at room temperature for 1 h. After completion (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography using 0 - 5% MeOH / DCM to give 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide as a yellow liquid (yield: 0.80 g, 63.18%). HRMS m / z 434.95 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.53 (s, 1H), 8.58 - 8.56 (d, J = 8 Hz, 1H), 8.49 (s, 1H), 7.58 (d, J = 10.5 Hz, 2H), 7.52 (d, J = 6.8 Hz, 2H), 7.39 - 7.30 (m, 3H), 5.06 (s, 2H), 4.06 - 3.97 (m, 1H), 1.22 - 1.00 (s, 6H) ppm.

[0448] Step 2: Preparation of 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide.

[0449] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide (0.800 g, 1.85 mmol) in methanol (25 mL) at room temperature under a N2 atmosphere was added 10% Pd / C (0.437 g, 0.369 mmol). The reaction mixture was purged with N2 for 2 - 3 min and then stirred at room temperature for 12 h under a H2 atmosphere (balloon). After completion (monitored by TLC and LC-MS), the reaction mixture was filtered through a Celite pad to remove the catalyst and the pad was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give a crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to give 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide as a brown sticky solid (yield: 0.400 g, 81.9%). HRMS m / z 265.10 [M+1] + 。

[0450] Step 3: Preparation of 5-fluoro-3-(2-(isopropylamino)ethyl)-1H-indol-4-ol (35) formate.

[0451] To a stirred solution of LiAlH4 (2 M, in THF; 6.05 mL, 12.11 mmol) in anhydrous THF (15 mL) at 0 °C was added dropwise H2SO4 (0.32 mL, 6.05 mmol). The reaction mixture was stirred at 0 °C for 30 minutes, then 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-N-isopropyl-2-oxoacetamide (0.400 g, 1.51 mmol) in THF (50 mL) was added at 0 °C over 10 minutes. Once addition was complete, the reaction mixture was heated to 70 °C for 5 hours. The reaction progress was monitored by TLC and LC-MS. Once complete, the reaction mixture was allowed to cool to room temperature and then quenched with THF / H2O (1:1) at 0 °C until bubbling ceased. The quenched reaction mixture was diluted with THF (100 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, filtered through Celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (0.1% aqueous formic acid / acetonitrile; 2% to 90% gradient over 18 minutes. Flow rate: 18 ml / min. Column: Phenomenex Kinetex Biphneyl, 5 μm, 19 mm X 250 mm) to give 5-fluoro-3-(2-(isopropylamino)ethyl)-1H-indol-4-ol (35) formate as a grey solid (yield: 0.016 g, 4%). HRMS m / z 237.25 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.69 (s, 1H), 8.29 (s, 1H), 7.01 - 7.00 (d, J = 2 Hz, 1H), 6.84 - 6.80 (m, 1H), 6.66 - 6.64 (dd, J = 3.2 Hz, J = 8.4 Hz, 1H), 2.92 (brs, 5H), 1.09 (d, J = 6.4 Hz, 6H) ppm.

[0452] Example 19. Preparation of Compound 36 hemifumarate

[0453]

[0454] Step 1: Preparation of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide.

[0455] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (see Example 6; 1.2 g, 2.92 mmol) in anhydrous THF (20 mL) at 0 °C was added n-Pr-NH2 (0.36 mL, 4.38 mmol). Triethylamine (1.22 mL, 8.77 mmol) was added dropwise to the reaction mixture at 0 °C, and then the reaction mixture was stirred at room temperature for 1 h. After completion (monitored by TLC), the mixture was diluted with water (20 mL) and the aqueous phase was extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound, which was purified by silica gel chromatography using 0 - 5% MeOH / DCM to afford 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide as a yellow solid (yield: 0.800 g, 63.18%). HRMS m / z 433.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.5 (s, 1H) 8.76 (t, J = 5.6 Hz, 1H) 8.55 (s, 1H) 7.60 - 7.54 (m, 3H) 7.40 - 7.33 (m, 3H) 5.07 (s, 2H) 3.19 - 3.17 (m, 2H) 1.55 - 1.53 (m, 2H) 0.77 (t, J = 7.6 Hz, 3H) ppm.

[0456] Step 2: Preparation of 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxo-N-propylacetamide.

[0457] To a stirred solution of 2-(4-(benzyloxy)-7-bromo-5-fluoro-1H-indol-3-yl)-2-oxo-N-propylacetamide (0.800 g, 2.33 mmol) in methanol (25 mL) at room temperature under N2 atmosphere was added 10% Pd / C (0.552 g, 0.466 mmol). The reaction mixture was purged with N2 for 2 - 3 min and then stirred at room temperature for 12 h under H2 atmosphere (balloon). After completion (monitored by TLC and LC-MS), the reaction mixture was filtered through a Celite pad to remove the catalyst and the pad was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give a crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to afford 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxo-N-propylacetamide as a brown viscous solid (yield: 0.450 g, 92.23%). HRMS m / z 265.10 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 12.59 (s, 1H), 11.29 (s, 1H), 8.90 (s, 1H), 8.80 (d, J = 3.6 Hz, 1H), 7.16 - 7.13 (m, 1H), 7.10 - 6.95 (m, 1H), 3.21 - 3.16 (m, 2H), 1.58 - 1.52 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H) ppm.

[0458] Step 3: Preparation of 5-fluoro-3-(2-(propylamino)ethyl)-1H-indol-4-ol (36).

[0459] To a stirred solution of LiAlH4 (2 M in THF; 6.81 mL, 13.62 mmol) in anhydrous THF (15 mL) at 0 °C was added dropwise H2SO4 (0.66 mL, 6.81 mmol) and the solution was stirred at 0 °C for 30 minutes. Then at 0 °C, 2-(5-fluoro-4-hydroxy-1H-indol-3-yl)-2-oxo-N-propylacetamide (0.450 g, 1.70 mmol) in THF (50 mL) was added to the mixture over 10 minutes. Then the reaction mixture was heated to 70 °C and maintained for 5 hours. The progress of the reaction was monitored by TLC and LC-MS. Once completed, the reaction mixture was allowed to cool to room temperature and then quenched at 0 °C with THF / H2O (1:1) until all bubbling ceased. The reaction mixture was diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 5-fluoro-3-(2-(propylamino)ethyl)-1H-indol-4-ol (36) as a grey solid (yield: 0.16 g, 39.76%). HRMS m / z 237.20 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.59 (s, 1H), 8.88 (br s, 1H), 6.96 (s, 1H), 6.95 - 6.76 (m, 1H), 6.62 - 6.59 (m, 1H), 2.85 - 2.83 (m, 2H), 2.78 - 2.76 (m, 2H), 2.47 - 2.33 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H) ppm.

[0460] Step 4: Preparation of 5-fluoro-3-(2-(propylamino)ethyl)-1H-indol-4-ol (36) hemifumarate.

[0461] At 0 °C, fumaric acid (0.024 g, 0.211 mmol) was added to a stirred solution of 5-fluoro-3-(2-(propylamino)ethyl)-1H-indol-4-ol (36; 0.100 g, 0.423 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes. The reaction mixture was then stirred at room temperature for 4 hours. At this point, the mixture was concentrated under reduced pressure to give a crude residue, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to give 5-fluoro-3-(2-(propylamino)ethyl)-1H-indol-4-ol (36) hemifumarate as a grey solid (yield: 0.096 g). HRMS m / z 237.25 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.73 (s, 1H), 9.53 (br s, 4H), 7.03 - 7.02 (s, 2H), 6.86 - 6.81 (m, 2H), 6.69 - 6.66 (m, 2H), 6.43 (s, 2H), 2.98 (s, 8H), 2.70 - 2.66 (m, 4H), 1.58 - 1.52 (m, 4H), 0.88 (t, J = 7.6 Hz, 6H) ppm.

[0462] Example 20. Preparation of compound 37 hemifumarate

[0463]

[0464] Step 1: Preparation of 5-methyl-1H-indol-4-yl acetate.

[0465] At 0 °C under a N2 atmosphere, pyridine (0.90 mL, 11.21 mmol) was added portionwise to a stirred solution of 5-methyl-1H-indol-4-ol (1.1 g, 7.47 mmol) in anhydrous DCM (15 mL) and the mixture was stirred for 15 minutes. Then, acetic anhydride (1.1 mL, 8.97 mmol) was added dropwise to the above reaction mixture via an addition funnel at 0 °C over 5 minutes and the resulting mixture was stirred at 0 °C for an additional 3 hours. The reaction progress was monitored by TLC and LC-MS. Upon completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with DCM (2 x 75 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography, eluting with 0 - 5% EtOAc / hexane, to give 5-methyl-1H-indol-4-yl acetate as a white solid (yield: 1.1 g, 77.78%). HRMS m / z 190.05 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 11.14 (s, 1H), 7.28 (t, J = 2.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 6.25 (t, J = 2 Hz, 1H), 2.36 (s, 3H), 2.15 (s, 3H) ppm.

[0466] Step 2: Preparation of 3-(2-chloro-2-oxoacetyl)-5-methyl-1H-indol-4-yl acetate.

[0467] To a stirred solution of 5-methyl-1H-indol-4-yl acetate (0.500 g, 2.64 mmol) in MTBE (15 mL) at 0 °C was added dropwise (COCl)2 (0.33 mL, 3.96 mmol) over 5 minutes, and the reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 5 hours. The progress of the reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure to give 3-(2-chloro-2-oxoacetyl)-5-methyl-1H-indol-4-yl acetate as a pale yellow liquid (yield: 0.650 g, 87.95%). Note: The crude compound was used directly in the next step without further purification.

[0468] Step 3: Preparation of 3-(2-(ethylamino)-2-oxoacetyl)-5-methyl-1H-indol-4-yl acetate.

[0469] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-5-methyl-1H-indol-4-yl acetate (0.650 g, 2.32 mmol) in anhydrous THF (20 mL) at 0 °C was added ethylamine (2 M in THF; 1.74 mL, 3.49 mmol). Then Et3N (0.97 mL, 6.97 mmol) was added dropwise to the reaction mixture at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the reaction mass was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound, which was triturated with n-pentane (5 mL) and diethyl ether (1 mL) to give 3-(2-(ethylamino)-2-oxoacetyl)-5-methyl-1H-indol-4-yl acetate as a yellow solid (yield: 0.500 g, 74.62%). HRMS m / z 289.00 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 12.30 (s, 1H), 8.63 (t, J = 5.6 Hz, 1H), 8.55 (s, 1H), 7.32 (d, J = 8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.25 - 3.16 (m, 2H), 2.39 (s, 3H), 2.19 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H) ppm.

[0470] Step 4: Preparation of 3-(2-(ethylamino)ethyl)-5-methyl-1H-indol-4-ol (37).

[0471] To a stirred solution of LiAlH4 solution (2.0 M in THF; 13.01 mL, 26.01 mmol) in anhydrous THF (25 mL) at 0 °C was added 3-(2-(ethylamino)-2-oxoacetyl)-5-methyl-1H-indol-4-yl acetate (0.500 g, 1.73 mmol) in THF (50 mL) over 10 minutes, and then the resulting mixture was heated to 70 °C for 9 hours. The reaction progress was monitored by TLC and LC-MS. Once completed, the reaction was cooled to room temperature and then to 0 °C, and quenched with THF / water (1:1) until the evolution of gas ceased. The quenched reaction mixture was diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to afford 3-(2-(ethylamino)ethyl)-5-methyl-1H-indol-4-ol (37) as a gray solid (yield: 0.140 g, 36.98%). HRMS m / z 219.22 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.42 (s, 1H), 6.86 (d, J = 2 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 6.64 (d, J = 8 Hz, 1H), 3.41 - 3.36 (m, 3H), 2.82 - 2.76 (m, 4H), 2.56 - 2.51 (m, 2H), 2.15 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H) ppm.

[0472] Step 5: Preparation of 3-(2-(ethylamino)ethyl)-5-methyl-1H-indol-4-ol (37) hemifumarate.

[0473] At 0 °C, fumaric acid (0.037 g, 0.320 mmol) was added to a stirred solution of 3-(2-(ethylamino)ethyl)-5-methyl-1H-indol-4-ol (37; 0.140 g, 0.641 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes, and the reaction mixture was stirred at room temperature for 4 hours. At this point, the reaction mixture was concentrated under reduced pressure to give a crude product, which was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to give 3-(2-(ethylamino)ethyl)-5-methyl-1H-indol-4-ol (37) hemifumarate as a grey solid (yield: 0.111 g, 59.82%). HRMS m / z 219.30 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.53 (s, 2H), 9.36 (br s, 2H), 6.91 (d, J = 2 Hz, 2H), 6.74 (d, J = 8 Hz, 2H), 6.69 (d, J = 8 Hz, 2H), 6.43 (s, 2H), 2.98 (s, 8H), 2.78 - 2.72 (m, 4H), 2.18 (s, 6H), 1.11 (t, J = 7.2 Hz, 6H) ppm.

[0474] Example 21. Preparation of Compound 38 Hemifumarate

[0475]

[0476] Step 1: Preparation of 2-(4-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride.

[0477] To a stirred solution of 4-methoxy-1H-indole (5.0 g, 33.97 mmol) in MTBE (50 mL) at 0 °C was added dropwise (COCl)2 (4.37 mL, 50.96 mmol) over 5 minutes, and the reaction mixture was stirred at 0 °C for 30 minutes. Then, the reaction mixture was warmed to room temperature and stirred for 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under N2 atmosphere to give 2-(4-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride as a dark yellow liquid (yield: 5.7 g, 70.60%). Note: The crude compound was used directly in the next step without further purification.

[0478] Step 2: Preparation of N-ethyl-2-(4-methoxy-1H-indol-3-yl)-2-oxoacetamide.

[0479] At 0 °C, ethylamine (2 M in THF; 17.99 mL, 35.98 mmol) was added dropwise to a stirred solution of 2-(4-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (5.7 g, 23.99 mmol) in anhydrous THF (50 mL) at 0 °C, followed by dropwise addition of Et3N (10 mL, 71.96 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (25 mL) and extracted with DCM (2 x 20 mL). The organic solvents were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound, which was triturated with n-pentane (5 mL) and diethyl ether (1 mL) to give N-ethyl-2-(4-methoxy-1H-indol-3-yl)-2-oxoacetamide as a yellow solid (crude) (yield: 3.5 g, 59.25%). HRMS m / z 246.90 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 12.10 (s, 1H), 8.60 (t, J = 4.8 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1H), 7.17 (t, J = 8 Hz, 1H), 7.09 (d, J = 8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.26 - 3.19 (m, 2H), 1.11 (t, J = 7.2 Hz, 3H) ppm.

[0480] Step 3: Preparation of 2-(7-bromo-4-methoxy-1H-indol-3-yl)-N-ethyl-2-oxoacetamide.

[0481] At 0 °C under a N2 atmosphere, NBS (0.970 g, 17.05 mmol) was added portionwise to a stirred solution of N-ethyl-2-(4-methoxy-1H-indol-3-yl)-2-oxoacetamide (3.5 g, 14.21 mmol) in anhydrous ACN (20 mL) and then the resulting mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography, eluting with 0 - 15% EtOAc / hexane to give 2-(7-bromo-4-methoxy-1H-indol-3-yl)-N-ethyl-2-oxoacetamide as a yellow solid (yield: 2.2 g, 47.61%). HRMS m / z 326.85 [M+2] + ; 11H NMR (400 MHz, DMSO-d6): δ = 12.27 (s, 1H), 8.65 (s, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.24 - 3.20 (m, 2H), 1.10 (t, J = 7.2 Hz, 3H) ppm.

[0482] Step 4: Preparation of 2-(7-bromo-5-chloro-4-methoxy-1H-indol-3-yl)-N-ethyl-2-oxoacetamide.

[0483] At 0 °C under a N2 atmosphere, NCS (0.471 g, 8.12 mmol) was added portionwise to a stirred solution of 2-(7-bromo-4-methoxy-1H-indol-3-yl)-N-ethyl-2-oxoacetamide (2.2 g, 6.77 mmol) in anhydrous ACN (20 mL) and then the resulting mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (15 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography, eluting with 10 - 25% EtOAc / hexane, to give 2-(7-bromo-5-chloro-4-methoxy-1H-indol-3-yl)-N-ethyl-2-oxoacetamide as a yellow solid (yield: 1.3 g, 53.43%). HRMS m / z 360.85 [M+2] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.62 (s, 1H), 8.80 (s, 1H), 8.59 (d, J = 2.8 Hz, 1H), 7.64 (s, 1H), 3.79 (s, 3H), 3.27 - 3.20 (m, 2H), 1.17 - 1.09 (m, 3H) ppm.

[0484] Step 5: Preparation of 2-(5-chloro-4-methoxy-1H-indol-3-yl)-N-ethylacetamide.

[0485] At room temperature under a N2 atmosphere, 10% Pd / C (0.856 g, 0.723 mmol) was added to a stirred solution of 2-(7-bromo-5-chloro-4-methoxy-1H-indol-3-yl)-N-ethyl-2-oxoacetamide (1.3 g, 3.62 mmol) in methanol (25 mL). The reaction mixture was degassed with N2 for 2 - 3 minutes and stirred at room temperature for 12 hours under a H2 atmosphere (balloon). After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography, eluting with 0 - 5% MeOH / DCM, to give 2-(5-chloro-4-methoxy-1H-indol-3-yl)-N-ethylacetamide as a brown viscous solid (yield: 0.520 g, 53.93%). HRMS m / z 267.05 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.26 (s, 1H), 8.65 (t, J = 5.6 Hz, 1H), 8.29 (d, J = 3.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.25 - 3.19 (m, 2H), 2.56 (s, 1H), 1.10 (t, J = 7.2 Hz, 3H) ppm.

[0486] Step 6: Synthesis of 5-chloro-3-(2-(ethylamino)ethyl)-1H-indol-4-ol (38).

[0487] At 0 °C, H2SO4 (0.20 mL, 3.90 mmol) was added dropwise to a stirred solution of LiAlH4 (2.0 M in THF; 3.90 mL, 7.80 mmol) in anhydrous THF (15 mL), and the mixture was stirred at 0 °C for 30 minutes. Then, a solution of 2-(5-chloro-4-methoxy-1H-indol-3-yl)-N-ethylacetamide (0.520 g, 1.95 mmol) in THF (50 mL) was added at 0 °C over 10 minutes, and the resulting mixture was heated to 70 °C for 5 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was cooled to room temperature, then to 0 °C, and then quenched with THF / H2O (1:1) at 0 °C until bubbling ceased. The reaction mixture was then diluted with THF (100 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, filtered through celite, and the filter cake was washed with THF (100 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 5-chloro-3-(2-(ethylamino)ethyl)-1H-indol-4-ol (38) as a grey solid (yield: 0.17 g, 36.53%). HRMS m / z 239.05 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 10.69 (s, 1H), 9.89 - 9.40 (m, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 3.56 - 3.36 (m, 1H), 2.96 - 2.79 (m, 4H), 2.59 (q, J = 7.2 Hz, 2H), 1.07 (t, J = 7.2 Hz, 3H) ppm.

[0488] Step 7: Synthesis of 5-chloro-3-(2-(ethylamino)ethyl)-1H-indol-4-ol (38) hemifumarate.

[0489] At 0 °C, fumaric acid (0.041 g, 0.356 mmol) was added to a stirred solution of 5-chloro-3-(2-(ethylamino)ethyl)-1H-indol-4-ol (38; 0.170 g, 0.712 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes, and the reaction mixture was stirred at room temperature for 4 hours. At this time, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was triturated with n-pentane (4 mL) and diethyl ether (2 mL) to give 5-chloro-3-(2-(ethylamino)ethyl)-1H-indol-4-ol (38) hemifumarate as an off-white solid (yield: 0.180 g, 71.65%). HRMS m / z 239.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.79 (s, 2H), 10.06 (br.s, 3H), 6.99 (d, J = 2.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.46 (s, 2H), 2.93 (s, 8H), 2.73 - 2.66 (m, 4H), 1.10 (t, J = 7.2 Hz, 6H) ppm.

[0490] Example 22. Preparation of Compound 39 Hemifumarate

[0491]

[0492] Step 1: Preparation of 6-methyl-1H-indol-4-yl acetate.

[0493] At 0 °C under a N2 atmosphere, pyridine (0.41 mL, 5.10 mmol) was added dropwise to a stirred solution of 6-methyl-1H-indol-4-ol (0.50 g, 3.40 mmol) in anhydrous DCM (10 mL), and the mixture was stirred for 15 minutes. Then acetic anhydride (0.50 mL, 4.08 mmol) was added dropwise at 0 °C over 5 minutes, the reaction mixture was warmed to room temperature and stirred at room temperature for an additional 3 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched by the slow addition of ice-cold water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic extracts were washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was triturated with diethyl ether (2 mL) and n-pentane (10 mL) to give 6-methyl-1H-indol-4-yl acetate as a brown solid (yield: 0.500 g, 77.78%). HRMS m / z 189.9 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 11.11 (s, 1H), 7.24 (t, J = 2.8 Hz, 1H), 7.07 (s, 1H), 6.56 (s, 1H), 6.24 (s, 1H), 2.37 (s, 3H), 2.32 (s, 3H) ppm.

[0494] Step 2: Preparation of 3-(2-chloro-2-oxoacetyl)-6-methyl-1H-indol-4-yl acetate.

[0495] To a stirred solution of 6-methyl-1H-indol-4-yl acetate (0.500 g, 2.64 mmol) in MTBE (10 mL) at 0 °C was added dropwise (COCl)2 (0.33 mL, 3.96 mmol) over 5 minutes, and the resulting mixture was stirred at 0 °C for 30 minutes. Then the reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure (and backfilled with N2 atmosphere) to give 3-(2-chloro-2-oxoacetyl)-6-methyl-1H-indol-4-yl acetate as a dark yellow liquid (yield: 0.600 g, 81.19%). Note: The crude compound was used directly in the next step without further purification.

[0496] Step 3: Preparation of 6-methyl-3-(2-(methylamino)-2-oxoacetyl)-1H-indol-4-yl acetate.

[0497] To a stirred solution of 3-(2-chloro-2-oxoacetyl)-6-methyl-1H-indol-4-yl acetate (0.600 g, 2.15 mmol) in anhydrous THF (10 mL) at 0 °C was added dropwise methylamine (2 M in THF; 1.61 mL, 3.22 mmol), followed by Et3N (0.89 mL, 6.44 mmol). After addition was complete, the reaction mixture was warmed to room temperature and stirred for 2 hours. After the reaction was complete (monitored by TLC), the reaction mass was diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound, which was triturated with n-pentane (5 mL) and diethyl ether (1 mL) to give 6-methyl-3-(2-(methylamino)-2-oxoacetyl)-1H-indol-4-yl acetate as a yellow solid (yield: 0.500 g, 85%). HRMS m / z 274.95 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 12.29 (s, 1H), 8.60 (s, 1H), 8.56 (d, J = 4.4 Hz, 1H), 7.22 (s, 1H), 6.73 (s, 1H), 2.73 (d, J = 4.8 Hz, 3H), 2.40 (s, 3H), 2.34 (s, 3H) ppm.

[0498] Step 4: Preparation of 6-methyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (39).

[0499] To a stirred solution of LiAlH4 (2.0 M in THF; 7.29 mL, 14.58 mmol) in anhydrous THF (30 mL) at 0 °C was added dropwise H2SO4 (0.39 mL, 7.29 mmol) and the reaction mixture was stirred at 0 °C for 30 minutes. Then, a solution of 6-methyl-3-(2-(methylamino)-2-oxoacetyl)-1H-indol-4-yl acetate (0.50 g, 1.82 mmol) in THF (10 mL) was added at 0 °C over 10 minutes. After addition was complete, the reaction mixture was heated to 70 °C and stirred for 9 hours. The progress of the reaction was monitored by TLC and LC-MS. Upon completion, the reaction mixture was cooled to 0 °C and quenched with THF / water (1:1, 14 mL) until bubbling ceased. The quenched reaction mixture was then diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through a pad of Celite, and the filter cake was washed with THF (100 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 6-methyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (39) as a grey solid (Yield: 0.240 g, 64.45%). Note: The crude compound was used directly in the next step without further characterization.

[0500] Step 5: Preparation of 6-methyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (39) hemifumarate.

[0501] At 0 °C, fumaric acid (0.068 g, 0.587 mmol) was added to a stirred solution of 6-methyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (39; 0.240 g, 1.17 mmol) in 10% MeOH / DCM (2 mL) over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was then concentrated under reduced pressure to give the crude compound. The crude material was triturated with n-pentane (2 mL) and diethyl ether (1 mL) to give 6-methyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (39) hemifumarate as an off-white solid (yield: 0.203 g, 65.86%). HRMS m / z 205.20 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 10.51 (s, 2H), 9.42 (br s, 3H), 6.85 (d, J = 2.4 Hz, 2H), 6.54 (s, 2H), 6.38 (s, 2H), 6.13 (s, 2H), 3.00 - 2.94 (m, 8H), 2.43 (s, 6H), 2.24 (s, 6H) ppm.

[0502] Example 23. Preparation of Compound 10

[0503]

[0504] Step 1: Preparation of 4-(benzyloxy)-6-fluoro-1H-indole.

[0505] At 0 °C under a N2 atmosphere, K2CO3 (3.66 g, 26.47 mmol) was added portionwise to a stirred solution of 6-fluoro-1H-indol-4-ol (2 g, 13.23 mmol) in anhydrous DMF (20 mL) and the resulting mixture was stirred for 15 minutes. Then benzyl bromide (2.36 mL, 19.85 mmol) was added dropwise to the reaction mixture at 0 °C over 10 minutes and then the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (2 x 75 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography using a 0 - 5% EtOAc / hexane gradient elution to give 4-(benzyloxy)-6-fluoro-1H-indole as a white solid (yield: 1.9 g, 59%). HRMS m / z 242.10 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 11.15 (s, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.35 - 7.32 (m, 1H), 7.20 (t, J = 2.8 Hz, 1H), 6.78 - 6.75 (m, 1H), 6.51 (dd, J = 2.0 Hz, 12 Hz, 1H), 6.43 (s, 1H), 5.21 (s, 2H) ppm.

[0506] Step 2: Preparation of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride.

[0507] To a stirred solution of 4-(benzyloxy)-6-fluoro-1H-indole (1.9 g, 7.88 mmol) in MTBE (20 mL) at 0 °C was added dropwise oxalyl chloride (1.01 mL, 11.81 mmol) over 5 minutes, and the reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. The progress of the reaction was monitored by TLC. Once completed, the solvent was removed under reduced pressure to give crude 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride as a pale yellow liquid (yield: 1.9 g, 72%). Note: The crude compound was used directly in the next step without further purification.

[0508] Step 3: Preparation of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide.

[0509] To a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (1.9 g, 5.73 mmol) in anhydrous THF (20 mL) at 0 °C was added dimethylamine hydrochloride (0.700 g, 8.59 mmol). Then Et3N (2.40 mL, 17.18 mmol) was added dropwise to the reaction mixture at 0 °C and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude compound which was purified by silica gel chromatography using 0 - 5% MeOH / DCM to give 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide as a yellow solid (yield: 0.90 g, 46%). HRMS m / z 341.00 [M+1] + ; 11H NMR (400 MHz, DMSO-d6): δ = 12.30 (s, 1H), 8.14 (s, 1H), 7.70 - 7.61 (m, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.31 - 7.23 (m, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.64 (d, J = 12 Hz, 1H), 5.27 (s, 2H), 2.89 (d, J = 8.0 Hz, 6H) ppm.

[0510] Step 4: Synthesis of 2-(4-(Benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide.

[0511] Under N2 atmosphere at 0 °C, NaH (0.21 g, 5.29 mmol) was added portionwise to a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (0.9 g, 2.64 mmol) in anhydrous DMF (10 mL), and the mixture was stirred for 15 minutes. Then, 2-iodopropane (0.674 g, 3.97 mmol) was added to the above reaction mixture at 0 °C over 10 minutes, and it was stirred at room temperature for another 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0 - 3% MeOH / DCM, to give 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide as a yellow viscous solid (yield: 0.600 g, 59%). HRMS m / z 383.15 [M + 1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 8.18 (s, 1H), 7.56 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 10 Hz, 2H), 7.38 - 7.31 (m, 1H), 7.29 - 7.13 (m, 1H), 6.62 (dd, J = 2 Hz, 12 Hz, 1H), 5.29 (s, 2H), 4.78 - 4.71 (m, 1H), 2.97 - 2.85 (m, 6H), 1.48 - 1.39 (m, 6H) ppm.

[0512] Step 5: Synthesis of 1-(4-(Benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-2-(dimethylamino)ethan-1-ol.

[0513] At 0 °C, 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (0.600 g, 1.57 mmol) in THF (10 mL) was added to a stirred solution of LiAlH4 solution (2.0 M in THF; 6.28 mL, 12.55 mmol) in anhydrous THF (20 mL) over 10 minutes, and the mixture was heated to 70 °C and maintained for 8 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was cooled to 0 °C and quenched by adding THF / water (1:1) until the evolution of gas ceased. Then the reaction mixture was diluted with THF (100 mL), stirred at room temperature under a N2 atmosphere for 30 minutes, filtered through celite, and the filter cake was washed with THF (200 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 1-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-2-(dimethylamino)ethan-1-ol as a brown liquid (yield: 0.40 g, 68.8%). HRMS m / z 371.10 [M+1] + 。

[0514] Step 6: Synthesis of 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine.

[0515] At 0 °C under a N2 atmosphere, triethylsilane (1.39 mL, 8.64 mmol) and boron trifluoride-ether complex (0.53 mL, 4.32 mmol) were added to a stirred solution of 1-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-2-(dimethylamino)ethan-1-ol (0.40 g, 1.08 mmol) in DCM (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with saturated aqueous NaHCO3 solution (5 mL) and extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography, eluting with 0 - 5% MeOH / DCM to give 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine as a yellow viscous solid (yield: 0.335 g, 87%). HRMS m / z 355.10 [M+1] + 。

[0516] Step 7: Synthesis of 3-(2-(dimethylamino)ethyl)-6-fluoro-1-isopropyl-1H-indol-4-ol (10).

[0517] Under a N2 atmosphere at room temperature, 10% Pd / C (0.22 g, 0.189 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (0.335 g, 0.945 mmol) in methanol (10 mL). The reaction mixture was degassed by bubbling N2 for 2 - 3 minutes and then stirred at room temperature for 12 hours under a H2 atmosphere (balloon). After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the insoluble catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give the crude product, which was triturated with n-pentane (5 mL) and diethyl ether (1 mL) to afford 3-(2-(dimethylamino)ethyl)-6-fluoro-1-isopropyl-1H-indol-4-ol (10) as a light brown solid (yield: 0.117 g, 46.8%). HRMS m / z 265.30 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.01 (br.s, 1H), 7.05 (s, 1H), 6.66 (dd, J = 2.4 Hz, 10.4 Hz, 1H), 6.10 (dd, J = 2 Hz, 11.6 Hz, 1H), 4.53 - 4.46 (m, 1H), 2.84 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 1.6 Hz, 2H), 2.24 (s, 6H), 1.35 (t, J = 6.8 Hz, 6H) ppm.

[0518] Example 24. Preparation of Compound 12

[0519]

[0520] Step 1: Synthesis of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide.

[0521] To a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-2-oxoacetyl chloride (see Example 23; 1.8 g, 5.43 mmol) in anhydrous THF (20 mL) at 0 °C was added CH3NH2 (2.0 M in THF; 4.07 mL, 8.14 mmol). Then, Et3N (2.27 mL, 16.28 mmol) was added dropwise to the reaction mixture at 0 °C and the resulting mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by silica gel chromatography using a 0 - 5% MeOH / DCM gradient to afford 2-(4-(benzyloxy)-6-fluoro-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a yellow solid (yield: 1.1 g, 62.12%). HRMS m / z 327.05 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 12.15 (s, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.32 - 7.18 (m, 1H), 6.90 - 6.88 (m, 1H), 6.70 (d, J = 11.6 Hz, 1H), 5.25 (s, 2H), 2.70 - 2.67 (m, 3H) ppm.

[0522] Step 2: Synthesis of 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide.

[0523] At 0 °C under N2 atmosphere, NaH (0.269 g, 6.74 mmol) was added portionwise to a stirred solution of N-methyl-2-oxoacetamide (1.1 g, 3.37 mmol) in anhydrous DMF (10 mL), and the resulting mixture was stirred for 15 minutes. Then, 2-iodopropane was added to the above reaction mixture at 0 °C over 10 minutes, and it was stirred at room temperature for another 3 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was quenched with ice-cold water (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layers were combined, washed with brine (2 x 15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography using 0 - 5% MeOH / DCM as eluent to give 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide as a yellow viscous solid (yield: 1.0 g, 80%). HRMS m / z 369.05 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 8.58 (d, J = 4.4 Hz, 1H), 8.40 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.39 - 7.36 (m, 2H), 7.31 - 7.27 (m, 1H), 7.17 (d, J = 9.2 Hz, 1H), 6.72 (d, J = 11.6 Hz, 1H), 5.24 (s, 2H), 4.78 - 4.71 (m, 1H), 2.67 (d, J = 4.4 Hz, 3H), 1.47 (d, J = 6.4 Hz, 6H) ppm.

[0524] Step 3: Synthesis of 2-(6-fluoro-4-hydroxy-1-isopropyl-1H-indol-3-yl)-N-methylacetamide.

[0525] At room temperature under a N2 atmosphere, 10% Pd / C (0.642 g, 0.542 mmol) was added to a stirred solution of 2-(4-(benzyloxy)-6-fluoro-1-isopropyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (1.0 g, 2.71 mmol) in methanol (10 mL). The reaction mixture was degassed by bubbling N2 for 2 - 3 minutes and then stirred at room temperature under a H2 atmosphere (balloon) for 12 hours. After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was passed through a Celite pad to remove the insoluble catalyst and the filter cake was washed with 10% MeOH / DCM (2 x 30 mL). The combined organic filtrates were concentrated under reduced pressure to give the crude product, which was triturated with n-pentane (10 mL) and diethyl ether (3 mL) to afford 2-(6-fluoro-4-hydroxy-1-isopropyl-1H-indol-3-yl)-N-methylacetamide (yield: 0.400 g, 55.7%). HRMS m / z 265.10 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6): δ = 11.68 (s, 1H), 8.20 (br.s, 1H), 7.06 (s, 1H), 6.80 - 6.70 (m, 1H), 6.21 - 6.18 (m, 1H), 4.58 - 4.50 (m, 1H), 3.59 (s, 2H), 2.61 (d, J = 4.8 Hz, 3H), 1.40 (t, J = 6.8 Hz, 6H) ppm.

[0526] Step 4: Synthesis of 6-fluoro-1-isopropyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (12).

[0527] At 0 °C, H2SO4 (0.32 mL, 6.05 mmol) was added dropwise to a stirred solution of LiAlH4 solution (2.0 M, in THF; 6.05 mL, 12.11 mmol) in anhydrous THF (15 mL), and the resulting mixture was stirred at 0 °C for 30 minutes. Then, a solution of 2-(6-fluoro-4-hydroxy-1-isopropyl-1H-indol-3-yl)-N-methylacetamide (0.400 g, 1.51 mmol) in THF (5 mL) was added at 0 °C over 10 minutes, and the reaction mixture was heated to 70 °C for 5 hours. The reaction progress was monitored by TLC and LC-MS. After completion, the reaction was cooled to 0 °C and quenched by adding THF / H2O (1:1) until the evolution of gas ceased. Then, the quenched reaction mixture was diluted with THF (100 mL), stirred at room temperature for 30 minutes under a N2 atmosphere, filtered through Celite, and the filter cake was washed with THF (100 mL). The combined organic filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography using 0 - 10% MeOH / DCM to give 6-fluoro-1-isopropyl-3-(2-(methylamino)ethyl)-1H-indol-4-ol (12) as a brown solid (yield: 0.150 g, 39.6%). HRMS m / z 251.25 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d6): δ = 8.65 (br s, 1H), 7.03 (s, 1H), 6.60 (dd, J = 2 Hz, 10.4 Hz, 1H), 6.03 (dd, J = 2.4 Hz, 12 Hz, 1H), 4.53 - 4.45 (m, 1H), 2.82 (t, J = 4.8 Hz, 2H), 2.74 (t, J = 6 Hz, 2H), 2.28 (s, 3H), 1.36 (d, J = 6.4 Hz, 6H).

[0528] Example 25. Metabolic Stability in Human Liver Microsomes

[0529] The stability of the disclosed compounds in human liver microsomes (HLM) was tested, and the results are summarized in Table 1. The metabolic stability of the disclosed compounds varies widely, but some trends are evident. For example, compounds with a primary amine nitrogen or only a single methyl substitution on the amine are generally the least stable among the tested compounds. Additionally, substitution at this position (as in Compounds 26, 27, 28, 30, 35, 36, 37, and 38) generally reduces stability compared to the closest analogs having a hydrogen at the 6-position of the indole. This variable metabolic stability causes certain disclosed compounds (such as Compounds 4, 7, 27, 28, 35, and 36) to exhibit higher metabolic stability than extremely short-acting compounds such as N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and 5-fluoro-N,N-dimethyltryptamine (5-F-DMT) and lower metabolic stability than longer-acting compounds such as psilocybin and 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET).

[0530] Test compounds. The disclosed compounds were prepared as described above. All other compounds were obtained commercially.

[0531] HLM stability. Confluent HLM (Corning 452117) from adult male and female donors was used. Microsomal incubations were performed in multi-well plates. The liver microsomal incubation medium consisted of PBS (100 mM, pH 7.4), MgCl2 (1 mM), and NADPH (1 mM), containing 0.50 mg of liver microsomal protein per mL. Control incubations were performed by replacing the NADPH-cofactor system with PBS. Test compounds (1 μM, final solvent concentration 1.0%) were incubated with microsomes at 37 °C with constant shaking. Six time points were analyzed within 60 minutes, and 60 μL aliquots of the reaction mixture were withdrawn at each time point. The reaction aliquots were terminated by adding 180 μL of cold (4 °C) acetonitrile containing 200 ng / mL tolbutamide and 200 ng / mL propranolol as internal standards (IS), followed by shaking for 10 minutes, and then the proteins were sedimented by centrifugation at 4,000 rpm for 20 minutes at 4 °C. The supernatant samples (80 μL) were diluted with water (240 μL), and the remaining parent compound was analyzed using an appropriate liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0532] Data analysis. Using linear regression analysis, the elimination constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (CL int ) were determined in the ln(AUC)-time curve graph.

[0533] Table 1. Intrinsic clearance (CL int ) and half-life (t 1 / 2 ) of the compounds in the presence of HLM.

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] Example 26. Pharmacokinetics in Mice

[0540] After subcutaneous (SC) administration, the pharmacokinetics (PK) of the disclosed compounds were studied in the plasma of mice (Table 2 and Figure 1 ). The peak concentration reached by Compound 4 was much higher than that of 5-F-DMT, and it exhibited a half-life intermediate between the very short-acting compound 5-F-DMT and the longer-acting compound 4-HO-MET.

[0541] Animals. Male C57BL / 6 mice, 8 - 12 weeks old, were used in these studies. Four mice were housed per cage. The temperature and humidity were maintained at 22 ± 3 °C and 30 - 70%, respectively, and the lighting was controlled to provide a 12-hour light and 12-hour dark cycle. Temperature and humidity were recorded by an automated data logging system. All animals were provided with laboratory rodent diet. Reverse osmosis water treated with ultraviolet light was provided ad libitum. The animals were randomly assigned to treatment groups.

[0542] Drugs. Compound 4 was prepared as described above. All other compounds were obtained commercially. The test compounds were dissolved in a vehicle consisting of normal saline (for salts) or saline acidified with 1.3 molar equivalents of acetic acid (for free bases). Then they were administered subcutaneously (SC) at a dose of 10 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight.

[0543] Sample collection and bioanalysis. At 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (4 animals per time point), under light isoflurane anesthesia Blood samples (approximately 60 μL) were collected from the orbital posterior plexus below. After blood collection, plasma was harvested immediately by centrifugation at 4,000 rpm for 10 minutes at 4 °C, and the samples were stored at -70 ± 10 °C until bioanalysis. The animals were sacrificed immediately after blood collection. For bioanalysis, 25 μL aliquots of plasma study samples or spiked plasma calibration standards were added to separate pre-labeled microcentrifuge tubes, followed by the addition of 100 μL of internal standard solution (glipizide, 500 ng / mL, in acetonitrile), except for the blank group, which was added 100 μL of acetonitrile. The samples were vortexed for 5 minutes and then centrifuged at 4,000 rpm for 10 minutes at 4 °C. After centrifugation, 100 μL of each clear supernatant was transferred to a 96-well plate and analyzed using the applicable LC-MS / MS method, where true samples of each analyte were used for calibration and identification.

[0544] Data analysis. Pharmacokinetic parameters were estimated using the non-compartmental analysis tool of WinNonlin software (version 8.0).

[0545] Table 2. Selected pharmacokinetic parameters of the compound in plasma of male C57BL / 6 mice after subcutaneous (SC) administration (10 mg / kg).

[0546]

[0547] Example 27. Stability in the presence of monoamine oxidase

[0548] The stability of the disclosed compounds in a human liver mitochondrial preparation in the presence of monoamine oxidase A and B (MAO-A and MAO-B) was tested, and the results are summarized in Table 3. The stability in this preparation is determined by the combination of both the indole and amine substituents. For compounds lacking a 4-hydroxy substituent on the indole, compounds with two methyl groups on the amine (e.g., DMT, 5-F-DMT, and 5-MeO-DMT) were rapidly metabolized by MAO, while those with at least one non-methyl substituent on the amine were more stable (e.g., N-methyl-N-ethyltryptamine (MET) and N-ethyl-N-propyltryptamine (EPT)). In contrast, 4-hydroxy compounds were generally more stable, as all such compounds with two alkyl groups on the amine (e.g., psilocin and 4-HO-MET) were stable, even when both groups were methyl. However, 4-hydroxy compounds with only one amine substituent showed different stabilities. For example, the N-methyl compound 2 was highly unstable, while the N-propyl compound 3 was highly stable. Additionally, substitution at this position (as in compounds 26, 27, 28, 30, 35, 36, 37, and 38) generally decreased stability compared to the closest analogous compounds with a hydrogen at the 6-position of the indole. Interestingly, compound 4 had moderate stability, consistent with its PK profile in mice and suggesting it could be used as a psychedelic with a moderate duration of action. Several other compounds met this moderate stability criterion, including compounds 27, 28, 31, 32, 35, 38, and 10, but the exact substituents that placed the compounds in this moderate stability range were generally unpredictable.

[0549] Test compounds. The disclosed compounds were prepared as described above. All other compounds were obtained commercially.

[0550] Liver mitochondrial incubation. Human liver mitochondria (Xenotech H0610.M) were used. Mitochondrial incubations were carried out in a multi-well plate. The liver mitochondrial incubation medium consisted of PBS (100 mM, pH 7.4) with 0.30 mg of liver mitochondrial protein per mL. The test compounds (1 μM, final solvent concentration 1.0%) were incubated with liver mitochondrial protein at 37 °C with constant shaking (total reaction volume 100 μL / well). Six time points were analyzed within 60 minutes. At each time point, the reaction was terminated by adding 300 μL of cold (4 °C) acetonitrile containing 200 ng / mL of tolbutamide and 200 ng / mL of labetalol as internal standards (IS), followed by shaking for 10 minutes, and then the proteins were sedimented by centrifugation at 4,000 rpm for 20 minutes at 4 °C. The supernatant samples (100 μL) were diluted with 5% trichloroacetic acid / water (300 μL), and the remaining parent compound was analyzed using an appropriate liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0551] Data analysis. Using linear regression analysis, the elimination constant (k el ), half-life (t 1 / 2 ), and intrinsic clearance (CL int ) were determined in the ln(AUC)-time curve graph.

[0552] Table 3. Intrinsic clearance (CL int ), half-life (t 1 / 2 ), and percentage of remaining compound in the presence of monoamine oxidase (human mitochondrial preparation).

[0553]

[0554]

[0555] Example 28. 5-HT2A Receptor Binding

[0556] The binding affinity of the disclosed compounds at the ketanserin binding site of the 5-HT2A receptor was determined in a radioligand binding experiment.

[0557] Method: WuXi AppTec (Hong Kong) Limited determined the affinity of the test compounds for the 5-HT2A receptor in a radioligand binding experiment with 3 H] ketanserin using a method adapted from the literature and under the conditions described in Table 4.

[0558] Results. The results of the radioligand binding assay are shown in Table 5. Interestingly, the potency of cyclopropyl compound 4 was approximately 3-fold stronger than that of n-propyl compound 3.

[0559] Table 4. Assay conditions for the 5-HT2A receptor radioligand binding assay.

[0560] Receptor source HEK293 stable cell line Vehicle 1.0% DMSO Incubation time 1 hour Incubation temperature 25℃ Incubation buffer 50 mM Tris-HCl, pH 7.4 Ligand <![CDATA[1nM 3 H]Ketanserin]]> Non-specific ligand 1 μM ketanserin

[0561] Table 5. Results of the 5-HT2A receptor binding affinity experiment.

[0562] Compound 5-HT2A Ki (nM) ([3H] ketanserin) MET 127.89 5-F-DMT 181.17 4-HO-MET 106.29 3 1002.41 4 339.23 DMT 415.90 Psilocin 58.58 5-MeO-DMT 39.00 28 318.6 35 445.95 10 1190.1 12 >1225.39

[0563] Example 29. Functional Activity on Serotonin Receptors

[0564] Using Ca 2+The flux functional assays tested the agonist activity of the disclosed compounds against several serotonin receptor subtypes (5-HT2A, 2-HT2B, 5-HT2C, and 5-HT1A), and the results are summarized in Table 6. All compounds showed potent agonist activity against 5-HT2A, indicating potential hallucinogenic activity and possible therapeutic effects. However, even with minor chemical structure changes, there were significant differences in the potency and signaling efficacy against 5-HT2A and the selectivity for this target relative to other serotonin receptors. For example, compared to the n-propyl compound 3 and the isopropyl compound 6, the cyclopropyl compound 4 was more potent against 5-HT2A and more potent and efficacious against 5-HT1A. Similarly, the isopropyl compound 6 showed partial agonism against 5-HT2B, while the cyclopropyl compound 4 did not. Interestingly, both compounds 10 and 12 were highly selective for the 5-HT2C receptor over 5-HT2A, showing potent partial agonism at this target, while they did not show significant agonist activity against 5-HT2A at up to 1,000 nM. This finding for compound 10 contradicts a previous report (WO2006047032), which found that this compound was a selective agonist of the 5-HT2A receptor.

[0565] Test compounds. The disclosed compounds were prepared as described above. All other compounds were obtained commercially.

[0566] Functional assays for 5-HT2A, 5-HT2B, and 5-HT1A. The agonist activity against the 5-HT2A, 5-HT2B, and 5-HT1A receptors was determined using the FLIPR Ca 2+ flux assay at WuXi AppTec (Hong Kong) Limited according to its standard protocol. Briefly, stable transfected cells expressing the receptor of interest (HEK293 for 5-HT2A and 5-HT2B; CHO cells for 5-HT1A) were grown and plated in 384-well plates and incubated overnight at 37 °C and 5% CO2. A fresh solution of 250 mM probenecid in 1 mL of FLIPR assay buffer was prepared. It was combined with the fluorescent dye (Fluo-4 DirectTM) to give a final assay concentration of 2.5 mM. The compounds were diluted 10-fold in a 1:3.16 ratio, and 750 nL was added to the 384-well compound plates together with 30 μL of assay buffer using an ECHO. Then the fluorescent dye was added to the assay plates together with the assay buffer to a final volume of 40 μL. The cell plates were incubated at 37 °C and 5% CO2 for 50 minutes and placed in a FLIPR Tetra together with the compound plates. Then 10 μL of the reference and compounds were transferred from the compound plates to the cell plates, and the fluorescent signals were read.

[0567] Functional assay of 5-HT2C. The agonist activity against 5-HT2C was assayed at Eurofins DiscoverX (Fremont, CA) using the FLIPR Ca 2+ flux assay according to its standard protocol. Briefly, stable transfected cells expressing the human 5-HT2C receptor were grown and plated in 384-well plates and incubated overnight at 37 °C and 5% CO2. The assay was performed in 1x dye loading buffer consisting of 1x dye, 1x additive A and 2.5 mM probenecid in HBSS / 20 mM Hepes. Probenecid was freshly prepared. Cells were loaded with the dye and incubated at 37 °C for 30 - 60 minutes before testing. After dye loading, the cells were removed from the incubator and 10 μL of HBSS / 20 mM Hepes was added. The assay buffer contained 3x vehicle. The cells were incubated at room temperature in the dark for 30 minutes to equilibrate the plate temperature. An intermediate dilution of the sample stock was made to generate 4x samples in the assay buffer. The compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 μL of 4X sample in HBSS / 20 mM Hepes was added to the cells for 5 seconds for the assay.

[0568] Table 6. Agonist activity of compounds against selected serotonin receptors in the Ca 2+ flux functional assay

[0569]

[0570]

[0571] NT = Not tested; ND = Not determined due to lack of measurable agonism.

[0572] Example 30. Stability in mouse brain homogenate

[0573] The stability of the disclosed compounds in mouse brain homogenate was tested (Table 7). Under the experimental conditions, the stability of the test compounds varied widely. Interestingly, Compound 4 had moderate stability, consistent with its PK profile in mice, and suggested that it could be used as a psychedelic with a moderate duration of action. Among the compounds with an N-propyl group, Compound 4 was the most unstable. More generally, there tended to be a rough correlation between the stability in mouse brain homogenate and the stability in the presence of monoamine oxidase (see Example 27).

[0574] Test compounds. The disclosed compounds were prepared as described above. All other compounds were obtained commercially.

[0575] Mouse brain homogenate stability. Immediately before use, thaw the frozen mouse brain homogenate (pooled from male CD-1 mice, BioreclamationIVT, MSE00BRAINMZA) in a 37 °C water bath. Incubate the positive control and test compounds (final concentration in incubation medium = 1 μM (for test compounds) and 2 μM (for control), all with 2% DMSO) at 37 °C in 100 μL total reaction volume of mouse brain homogenate in duplicate for each time point (0, 10, 30, 60, and 120 minutes). At the end of each incubation period, immediately quench the reaction with 400 μL of acetonitrile containing internal standards (200 ng / mL tolbutamide and 200 ng / mL labetalol) and mix well. Then seal the plate, shake for 20 minutes, and centrifuge at 4,000 rpm and 4 °C for 20 minutes. Dilute a 50 μL aliquot of each supernatant to 100 μL in water and then shake the mixture again for 10 minutes. Analyze the remaining parent compound of the resulting mixture using the applicable LC-MS / MS method.

[0576] Table 7. Stability of Compounds in Mouse Brain Homogenate.

[0577]

[0578]

[0579] Example 31. Stability in Rat Brain Homogenate

[0580] The stability of the disclosed compounds in rat brain homogenate was tested (Table 8). Under the experimental conditions, the stability of the test compounds varied widely. Interestingly, Compound 4 had moderate stability, consistent with its PK profile in mice, and suggested that it could be used as a psychedelic with a moderate duration of action. Among the compounds with an N-propyl group, Compound 4 was the least stable. More generally, there tended to be a rough correlation between stability in rat brain homogenate and stability in the presence of monoamine oxidase (see Example 27). In addition, as with stability in the presence of monoamine oxidase (see Example 27), substitution at this position (as in Compounds 26, 27, 28, 30, 35, 36, 37, and 38) generally decreased stability compared to the closest analogs with a hydrogen at the 6-position of the indole.

[0581] Test Compounds. The disclosed compounds were prepared as described above. All other compounds were obtained commercially.

[0582] Stability of rat brain homogenate. Immediately before use, thaw the frozen rat brain homogenate (pooled from male Sprague Dawley rats, Bioreclamation IVT, RAT00BRAINMZA) in a 37 °C water bath. Incubate the positive control and test compounds (final concentration in the incubation medium = 1 μM (for test compounds) and 2 μM (for control), all with 2% DMSO) at 37 °C in 100 μL total reaction volume of rat brain homogenate, in duplicate for each time point (0, 10, 30, 60, and 120 minutes). At the end of each incubation period, immediately quench the reaction with 400 μL of acetonitrile containing internal standards (200 ng / mL tolbutamide and 200 ng / mL labetalol) and mix well. Then seal the plate, shake for 20 minutes, and centrifuge at 4,000 rpm and 4 °C for 20 minutes. Dilute a 50 μL aliquot of each supernatant to 100 μL in water, and then shake the mixture again for 10 minutes. Analyze the remaining parent compound of the resulting mixture using the applicable LC-MS / MS method.

[0583] Table 8. Stability of compounds in rat brain homogenate.

[0584]

[0585]

[0586] Example 32. Serotonin release activity in synaptosomes

[0587] The ability of the disclosed compounds to release serotonin (5-HT) from rat synaptic vesicles was evaluated (Table 9). The potency and efficacy of 5-HT release vary widely depending on the specific compound. Compounds with a 4-hydroxy substituent generally exhibit reduced 5-HT release potency and efficacy compared to compounds without substituents or with only a single fluorine substituent on the indole ring system. However, there are also significant differences among the 4-hydroxy compounds. For example, cyclopropyl compound 4 is more potent than n-propyl compound 3. Similarly, fluorinated compounds 28 and 35 are significantly more potent and efficacious than their non-fluorinated analogs 5 and 6, respectively.

[0588] Test compounds. The disclosed compounds were prepared as described above. All other compounds were obtained commercially.

[0589] Synaptosomal 5-HT Release Assay. The synaptosomal release assay was performed according to a modified version of the previously described procedure (Partilla et al., (2016). Interrogating the Activity of Ligands at Monoamine Transporters in Rat Brain Synaptosomes. In Neurotransmitter Transporters (pp. 41-52). Springer). Briefly, synaptosomes were prepared from rat brains. Male Sprague-Dawley rats were anesthetized with CO2 and their brains were immediately removed. The cerebellum was discarded and the whole brain (minus the striatum) was placed in ice-cold 0.32 M sucrose (10 mL / brain) and gently homogenized by hand. The homogenate of each brain was centrifuged at 1,000 x g for 10 minutes at 4 °C and the resulting supernatant was diluted to a total volume of 10 mL with ice-cold 0.32 M sucrose to provide the synaptosomal solution. Then the synaptosomes were pre-loaded with 5 nM 3 [H]5-HT in the presence of the selective uptake inhibitors DAT (50 nM GBR12935), NET (100 nM nomifensine), and VMAT2 (1 μM reserpine) in Krebs phosphate buffer (KPB). Incubation was allowed to equilibrate at 25 °C for 2 hours. For the release reaction, 425 μL of the pre-loaded synaptosomes were added to a tube containing 75 μL of the test drug, which was diluted in KPB containing 1 mg / mL BSA. After 10 minutes, the release reaction was stopped by rapid vacuum filtration using a cell harvester onto GF / B filters pre-soaked in wash buffer (10 mM Tris-HCl, pH 7.4, 150 mM NaCl) and the filters were washed with additional wash buffer. The filters were dried at 60 °C for 1 hour and the retained radioactivity was quantified using a MicroBeta 2 liquid scintillation counter. The amount of retained radioactivity is inversely proportional to the extent of release.

[0590] Table 9. Effects of Compounds on 5-HT Release from Rat Synaptosomes.

[0591]

[0592] Example 33. Pharmacokinetics in Rats

[0593] The pharmacokinetics (PK) of the disclosed compounds were studied in the plasma of rats after intravenous (IV) administration (Table 10). The half-life in rats generally parallels the stability in the presence of monoamine oxidase (see Example 27), with compounds with very low monoamine oxidase stability such as 5-F-DMT and compound 2 having very short half-lives, and compounds with high monoamine oxidase stability such as dephosphorylation of psilocybin having much longer half-lives. Compounds 28 and 35, which have intermediate monoamine oxidase stability, also exhibit half-lives between the very short-acting compound 5-F-DMT and the longer-acting compound dephosphorylation of psilocybin, indicating their potential utility as medium-duration psychedelic therapeutics.

[0594] Animals. Male Sprague Dawley rats, 8-12 weeks old, were used in these studies. Four rats were housed per cage. Temperature and humidity were maintained at 22 ± 3 °C and 30-70%, respectively, and lighting was controlled to provide a 12-h light and 12-h dark cycle. Temperature and humidity were recorded by an automatically controlled data logging system. All animals were provided with a laboratory rodent diet. Reverse osmosis water treated with UV light was provided ad libitum. Animals were randomly assigned to treatment groups.

[0595] Drugs. The disclosed compounds were prepared as described above. All other compounds were commercially available. The test compounds were dissolved in a vehicle consisting of normal saline (for salts) or saline acidified with 1.3 molar equivalents of acetic acid (for free base). They were then administered intravenously (IV) at a dose of 1 mg / kg (calculated based on the free base) and a volume of 5 mL / kg body weight.

[0596] Sample collection and bioanalysis. Animals were collected under light isoflurane anesthesia at 0.08, 0.25, 0.5, 1, 2, and 4 h (4 animals per time point, 4 h time point only for psilocybin dephosphorylation). Blood samples (approximately 120 μL) were collected from the retroorbital plexus under the microscope. Immediately after blood collection, plasma was harvested by centrifugation at 10,000 rpm for 10 minutes at 4°C, and the samples were stored at -70 ± 10°C until bioanalysis. Animals were sacrificed immediately after blood collection. For bioanalysis, 20 μL aliquots of plasma study samples or spiked plasma calibration standards were added to separate pre-labeled microcentrifuge tubes, followed by 200 μL of internal standard solution (cetrizine or rosuvastatin, 50 ng / mL), except for the blank group, in which 200 μL of acetonitrile was added. The samples were vortexed for 5 minutes and then centrifuged at 2,500 or 4,000 rpm for 10 minutes at 4°C. After centrifugation, 200 μL of each clear supernatant was transferred to a 96-well plate and analyzed with the applicable LC-MS / MS method, in which authentic samples of each analyte were used for calibration and identification.

[0597] Data analysis. The pharmacokinetic parameters were estimated using the non-compartmental analysis tool of WinNonlin software (version 8.0).

[0598] Table 10. Selected pharmacokinetic parameters of the compound in male Sprague-Dawley rat plasma after intravenous (IV) administration (1 mg / kg).

[0599]

[0600] Example 34. 5-HT2C receptor binding

[0601] The binding affinity of the disclosed compounds at the methysergide binding site of the 5-HT2C receptor was determined in a radioligand binding assay.

[0602] Method: WuXi AppTec (Hong Kong) Limited determined the affinity of the test compounds for the 5-HT2C receptor in a radioligand binding assay with 3 [3H]methysergide using a method adapted from the literature and under the conditions described in Table 11.

[0603] Results. The results of the radioligand binding assay are shown in Table 12. Consistent with their high selectivity for the 5-HT2C receptor over the 5-HT2A receptor in functional assays (see Example 29), Compounds 10 and 12 showed potent binding to the 5-HT2C receptor, which was much more potent than the binding observed for the 5-HT2A receptor (see Example 28). Interestingly, this finding for Compound 10 contradicts a previous report (WO2006047032), which found that the compound was a selective agonist for the 5-HT2A receptor.

[0604] Table 11. Assay conditions for the 5-HT2C receptor radioligand binding assay.

[0605]

[0606] Table 12. Results of the 5-HT2C receptor binding affinity experiment.

[0607] Compound 5-HT2C Ki (nM) ([3H] methysergide) 10 10.5 12 30.8

[0608] Example 35. Synthesis of additional compounds

[0609] The additional disclosed compounds can be prepared by standard methods known to those skilled in the art of organic synthesis, such as those presented in Schemes 1-5 and Examples 1-24.

[0610] While the presently considered preferred embodiments of the invention have been shown and described, various changes and modifications can be made by those skilled in the art, which still fall within the scope of the invention as defined by the appended claims.

Claims

1. A compound having the following structure: Wherein: R 1 、R 2 、R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 4 Selected from H and leading to OR 4 An esterifying group that is an ester group; R 5 selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms; R 7 、R 7’ 、R 8 and R 8’ are independently selected from H and F atoms; R a 、R b 、R c and R d are independently selected from H and D atoms; And its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein R 4 is H.

3. The compound according to claim 1, wherein R 4 is an esterifying group that results in OR 4 being an ester group.

4. The compound according to claim 3, wherein R 4 is -C(O)R so as to result in OR 4 is -OC(O)R, where R is as defined in claim 1.

5. The compound according to claim 3, wherein R 4 is -P(O)(OR')2, where R' is independently selected from H and R to result in OR 4 is -OP(O)(OR')2, where R is as defined in claim 1.

6. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

7. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

8. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

9. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

10. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

11. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

12. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

13. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

14. The compound according to claim 1, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

15. A compound having the following structure: Wherein: R 9 、R 10 and R 13 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 11 Selected from H and resulting in OR 11 An esterifying group that is an ester group; R 12 is isopropyl or cyclopropyl, optionally substituted with one or more fluorine atoms; R 14 and R 15 are independently selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms; R a 、R b 、R c and R d are independently selected from H and D atoms; Provided that when R 9 , R 10 , R 11 , R 13 , R a , R b , R c , and R d are H and R 12 is isopropyl, then R 14 and R 15 are not both methyl; And its pharmaceutically acceptable salts.

16. The compound according to claim 15, wherein R 11 is H.

17. The compound according to claim 15, wherein R 11 is an esterification group that results in OR 11 being an ester group.

18. The compound according to claim 17, wherein R 11 is -C(O)R to result in OR 11 is -OC(O)R, wherein R is as defined in claim 15.

19. The compound according to claim 17, wherein R 11 is -P(O)(OR')2, where R' is independently selected from H and R such that OR 11 is -OP(O)(OR')2, where R is as defined in claim 15.

20. The compound according to claim 15, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

21. The compound according to claim 15, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

22. The compound according to claim 15, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

23. The compound according to claim 15, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

24. The compound according to claim 15, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

25. The compound according to claim 15, wherein the compound is selected from the following compounds: And its pharmaceutically acceptable salts.

26. A compound having the following structure: Wherein: R 1 、R 2 、R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 4 Selected from H and leading to OR 4 An esterifying group that is an ester group; R 5 selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms; R a 、R b 、R c and R d are independently selected from H and D atoms; R 16 is an allyl or propargyl group; Provided that when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , R c and R d are all H, then R 16 is not allyl; And its pharmaceutically acceptable salts.

27. The compound according to claim 26, wherein R 4 is H.

28. The compound according to claim 26, wherein R 4 is an esterifying group that results in OR 4 being an ester group.

29. The compound according to claim 28, wherein R 4 is -C(O)R so as to result in OR 4 is -OC(O)R, wherein R is as defined in claim 26.

30. The compound according to claim 28, wherein R 4 is -P(O)(OR')2, where R' is independently selected from H and R such that OR 4 is -OP(O)(OR')2, where R is as defined in claim 26.

31. The compound according to claim 26, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

32. The compound according to claim 26, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

33. The compound according to claim 26, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

34. The compound according to claim 26, wherein the compound has the following structure: And its pharmaceutically acceptable salts.

35. The compound according to claim 26, wherein the compound has the following structure: wherein R 5’ is selected from hydrocarbon groups (R) having 1 to 5 carbon atoms; And its pharmaceutically acceptable salts.

36. The compound according to claim 26, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

37. A compound having the following structure: Wherein: R 1 Selected from: F, Cl, and methyl; R 2 、R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 4 Selected from H and resulting in OR 4 An esterifying group which is an ester group; R 5 selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms; R a 、R b 、R c and R d are independently selected from H and D atoms; R 19 selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms; Provided that when R 1 is F or methyl and R 2 , R 3 , R 4 , R 6 , R 19 , R a , R b , R c and R d are all H, then R 5 is not H or methyl; A further prerequisite is that when R 1 is Cl and R 2 , R 3 , R 4 , R 6 , R 19 , R a , R b , R c , and R d are all H, then R 5 is not H, methyl or ethyl; A further prerequisite is that when R 1 is F and R 2 , R 3 , R 4 , R 6 , R a , R b , R c and R d are all H, then R 5 and R 19 are not both methyl; And its pharmaceutically acceptable salts.

38. The compound according to claim 37, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

39. The compound according to claim 37, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

40. The compound according to claim 37, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

41. A compound according to any one of claims 37 - 40, wherein R 4 is H.

42. A compound according to any one of claims 37 - 40, wherein R 4 is an esterifying group that results in OR 4 being an ester group.

43. The compound according to claim 42, wherein R 4 is -C(O)R to result in OR 4 is -OC(O)R, wherein R is a hydrocarbon group having 1 to 5 carbon atoms and optionally substituted with one or more fluorine atoms.

44. The compound according to claim 42, wherein R 4 is -P(O)(OR')2, where R' is independently selected from H and R such that OR 4 is -OP(O)(OR')2, where R is a hydrocarbon group having 1 to 5 carbon atoms and is optionally substituted by one or more fluorine atoms.

45. The compound according to any one of claims 37 - 44, wherein R1 is F.

46. The compound according to any one of claims 37 - 44, wherein R1 is Cl.

47. The compound according to any one of claims 37 - 44, wherein R1 is methyl.

48. The compound according to claim 37, wherein the compound is selected from the following compounds: and its pharmaceutically acceptable salts.

49. A compound having the following structure: wherein: R 1 、R 3 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 2 Selected from: F, Cl, and methyl; R a 、R b 、R c and R d are independently selected from H and D atoms; R 20 selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms; Provided that when R 2 is F, R 3 is not methyl or OH; and its pharmaceutically acceptable salts.

50. The compound according to claim 49, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

51. The compound according to claim 49, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

52. The compound according to any one of claims 49 - 51, wherein R2 is F.

53. The compound according to any one of claims 49 - 51, wherein R2 is Cl.

54. The compound according to any one of claims 49 - 51, wherein R2 is methyl.

55. The compound according to claim 49, wherein the compound is selected from the following compounds: and its pharmaceutically acceptable salts.

56. A compound having the following structure: wherein: R 1 、R 2 and R 6 are independently selected from: (i) H; (ii) a hydrocarbon group (R) having 1 to 5 carbon atoms; (iii) an alkoxy group (OR); (iv) a thioalkoxy group (SR); (v) CN; (vi) NH2; (vii) OH; and (viii) a halogen atom; R 3 Selected from: F, Cl, and methyl. R a 、R b 、R c and R d are independently selected from H and D atoms; R 21 selected from H and hydrocarbon groups (R) having 1 to 5 carbon atoms, which are optionally substituted by one or more fluorine atoms; Provided that when R 3 is methyl, R 2 is not F and R 6 is not methyl; A further prerequisite is that when R 3 is methyl and R 1 , R 2 , R 6 , R a , R b , R c and R d are all H, then R 21 is not H, methyl or ethyl; A further prerequisite is that when R 3 is F or Cl and R 1 , R 2 , R 6 , R a , R b , R c and R d are all H, then R 21 is not H; and its pharmaceutically acceptable salts.

57. The compound according to claim 56, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

58. The compound according to claim 56, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

59. The compound according to any one of claims 56 - 58, wherein R3 is F.

60. The compound according to any one of claims 56 - 58, wherein R3 is Cl.

61. The compound according to any one of claims 56 - 58, wherein R3 is methyl.

62. The compound according to claim 56, wherein the compound has the following structure: and its pharmaceutically acceptable salts.

63. A compound having the following structure: and its pharmaceutically acceptable salts.

64. A pharmaceutical composition comprising the compound according to any one of claims 1 - 63 and a pharmaceutically acceptable carrier.

65. A method for treating mood disorders, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 - 63 or the pharmaceutical composition according to claim 64.

66. The method according to claim 65, wherein the mood disorder is selected from depressive disorder and bipolar disorder.

67. The method according to claim 65, wherein the mood disorder is depressive disorder.

68. The method according to claim 67, wherein the depressive disorder is a treatment-resistant depressive disorder.

69. The method according to claim 65, wherein the mood disorder is selected from major depressive disorder, persistent depressive disorder, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, psychotic depression, disruptive mood dysregulation disorder, substance / medication-induced depressive disorder, and depressive disorder due to another medical condition.

70. The method according to claim 65, wherein the mood disorder is a substance-related disorder.

71. The method according to claim 65, wherein the mood disorder is a substance use disorder.

72. The method according to claim 65, wherein the mood disorder is an anxiety disorder.

73. The method according to claim 65, wherein the mood disorder is selected from obsessive-compulsive and related disorders, trauma- and stressor-related disorders, feeding and eating disorders, borderline personality disorder, attention-deficit / hyperactivity disorder, and autism spectrum disorder.

74. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 0.5 mg to 150 mg of the compound according to any one of claims 1 - 63.

75. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 2 mg to 5 mg of the compound according to any one of claims 1 - 63.

76. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 5 mg to 10 mg of the compound according to any one of claims 1 - 63.

77. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 10 mg to 20 mg of the compound according to any one of claims 1 - 63.

78. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 20 mg to 40 mg of the compound according to any one of claims 1 - 63.

79. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 40 mg to 80 mg of the compound according to any one of claims 1 - 63.

80. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 80 mg to 100 mg of the compound according to any one of claims 1 - 63.

81. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 100 mg to 120 mg of the compound according to any one of claims 1 - 63.

82. The method according to any one of claims 65 - 73, wherein the method comprises administering from about 120 mg to 150 mg of the compound according to any one of claims 1 - 63.

83. The method according to any one of claims 65 - 82, wherein the method provides improvement in at least one symptom selected from the group consisting of: sadness or lethargy or fatigue, low mood, loss of feeling, anxious or worried feelings, fear, feeling tense, feeling restless, reduced interest in all or almost all activities, difficulty in starting activities, significant increase or decrease in appetite leading to weight gain or loss, insomnia, irritability, fatigue, feeling worthless or having low self - esteem, strong negative beliefs or pessimistic thoughts about oneself, others or the world, feelings of helplessness, inability to concentrate or distractibility, recurrent thoughts of death or suicide, guilt, memory complaints, difficulty in experiencing positive emotions, feeling isolated or alienated from people, hypervigilance, risk - taking behavior, avoidance of thoughts about stressful or traumatic events, pain, rumination and obsessive thoughts, compulsive behaviors, talking to less familiar people or strangers, being the focus of attention, intrusive and disturbing thoughts, not being able to get through the week without taking the medication, feeling guilty about taking the medication, having problems with friends or family due to taking the medication, and withdrawal symptoms attributed to taking the medication.

84. The method according to any one of claims 65 - 83, wherein the compound according to any one of claims 1 - 63 or the pharmaceutical composition according to claim 64 is administered via a route selected from oral, buccal, sublingual, inhaled mist, topical, intranasal, subcutaneous, intramuscular, and intravenous.

85. The method according to any one of claims 65 - 84, wherein the compound according to any one of claims 1 - 63 or the pharmaceutical composition according to claim 64 is administered one to four times a day.

86. The method according to any one of claims 65 - 84, wherein the compound according to any one of claims 1 - 63 or the pharmaceutical composition according to claim 64 is administered one to ten times a month.

87. The method according to any one of claims 65 - 84, wherein the compound according to any one of claims 1 - 63 or the pharmaceutical composition according to claim 64 is administered one to ten times a year.

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