Therapeutic alkaloid compounds

Abstract

Disclosed are compounds for inhibiting SERT, and related methods of making and using the compounds.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 548,083, filed November 10, 2023, and U.S. Provisional Patent Application Serial No. 63 / 651,580, filed May 24, 2024; the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0002] This disclosure relates to the pharmaceutical field, including the discovery of alkaloid compounds that induce antidepressant and / or anti-anxiety effects by partially inhibiting serotonin transporter protein (5-HT). Background Technology

[0003] Serotonin (5-HT) is an essential neurotransmitter for the normal functioning of the central nervous system. This neurotransmission system in the brain controls a variety of important behaviors, including the sleep-wake cycle, mood, body temperature, and appetite. It is also involved in several commonly used anti-anxiety medications.

[0004] Some SERT inhibitors, including selective serotonin transporter inhibitors (SSRIs), are used as therapeutic antidepressants. They are believed to work by increasing extracellular 5-HT levels in serotonergic terminal regions such as the hippocampus and prefrontal cortex.

[0005] A fundamental evaluation in drug development involves assessing absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME / PK). One of the main ADME screenings that new chemical entities undergo is in vitro metabolic stability screening. Drug stability after exposure to human liver hepatocytes or microsomes is a common in vitro assay to approximate in vivo liver-based drug metabolism.

[0006] There remains a need for therapeutic compounds that inhibit SERT, possessing the desired ADME and PK properties, such as extended half-life and metabolic stability, to provide sufficient duration of action for therapeutic use. Summary of the Invention

[0007] This article describes compounds of formula (I) or pharmaceutically acceptable salts thereof: (I), in Ring A is , , or , where * denotes the junction of ring A with the compound of formula (I), and where Each R 1Independently, it can be deuterium, halogenated, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, or -OR. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups is optionally replaced by a halogroup, alkyl, alkanol, aryl, or -OR group. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b replace; m is 0, 1, 2, or 3; R 2 and R 3 Each of these groups is independently H, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in the alkyl, cycloalkyl, alkenyl, ynyl, and aryl groups is optionally replaced by a halogroup, deuterium, cycloalkyl, aryl, or OR group. a Replace; or R 2 and R 3 Together with the atoms they are attached to, they form heterocyclic or heteroaryl groups, wherein each hydrogen atom in the heterocyclic and heteroaryl groups is optionally replaced by a halogenated or OR group. a replace; R a and R b Independently, it is H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if R 1 An example is -NR a R b Then R a and R b They can combine with the nitrogen atoms they are attached to to form heterocyclic alkyl or heteroaryl groups; R4 is hydrogen, C 1-4 Alkyl or C 1-6 Halogenated alkyl groups; and R5 is C 1-4 alkyl.

[0008] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-A) or a pharmaceutically acceptable salt thereof: (II-A), R1, m, R2, R3 and R5 are as disclosed in this paper with respect to equation (I).

[0009] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-B) or a pharmaceutically acceptable salt thereof: (II-B), R1, m, R2, R3 and R5 are as disclosed in this paper with respect to equation (I).

[0010] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-C) or a pharmaceutically acceptable salt thereof: (II-C), R1, m, R2, R3 and R5 are as disclosed in this paper with respect to equation (I).

[0011] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-D) or a pharmaceutically acceptable salt thereof: (II-D), R1, m, R2, R3 and R5 are as disclosed in this paper with respect to equation (I).

[0012] In some embodiments, the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof: (III) Among them, rings A, R1, m, and R a And R5 as disclosed herein with respect to equation (I) or equations (II-A), (II-B), (II-C) and (II-D); X and Y are each independently O, NR7, or S; x is 1 or 2; R 6a and R 6b Each of these is independently H, halogenated group, C. 1-4 Alkyl or C 1-4 Halogenated alkyl; or R 6a and R 6bTogether with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a Replace; and R7 is H or C 1-4 alkyl.

[0013] In some aspects, the present invention relates to compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein Ring A is , , or , where * denotes the junction of ring A with the compound of formula (I), and where Each R 1 Independently, it is deuterium, halogenated group, C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, 3-6 membered heterocyclic, 5-10 membered aryl, 5-10 membered heteroaryl, -OR a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups is optionally replaced by a halogroup, alkyl, alkanol, aryl, or -OR group. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b replace; m is 0, 1, 2, or 3; R4 is hydrogen, C 1-4 Alkyl or C 1-6 Halogenated alkyl groups; and R5 is arbitrarily assigned to C. 3-6 C-substituted with cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups 1-4Alkyl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each independently and optionally radically bonded by one or more deuterium, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, cyano, amino, carboxyl, acetyl, or amide substitutions; R 6a and R 6b Each of these is independently H, a halogroup, or an optionally substituted alkyl group, wherein each hydrogen atom in the alkyl group is optionally replaced by a halogroup, deuterium, cycloalkyl, or OR. a Replace; or R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a replace; R7 is H or C 1-4 Alkyl; and R a and R b H and C independently 1-4 Alkyl (e.g., methyl) or C 1-4 Alkyl group.

[0014] In some respects, the present invention relates to compounds of formula (IV) or pharmaceutically acceptable salts thereof: (IV) in Ring A is , , or , where * denotes the junction of ring A with the compound of formula (I), and where Each R 1 Independently, it is a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl, methoxy, acetyl, cyano, C 2-4 alkenyl, C 2-4 Alkyne, amino, amide, or carboxyl groups; Each of R2 and R3 is independently H or optionally H by one or more halogenated groups, C 3-6 C-substituted with cycloalkyl, alkenyl or ynyl groups 1-4 Alkyl; or R2 and R3, together with the atoms they are attached to, form -(CR) 6a R 6b ) x -; x is 1 or 2; R4 is a methyl group; R 6a and R 6b Each of them independently is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a Replace; and R a It is H, C 1-4 Alkyl (e.g., methyl), C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0015] In some embodiments, a pharmaceutical composition is also provided comprising a compound of formula (I) (including compounds of formula (II-A), formula (II-B), formula (II-C) and formula (II-D), a compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0016] In some embodiments, this disclosure provides a method for treating central nervous system disorders, comprising administering an effective amount of the compound of this disclosure to a subject in need.

[0017] In some embodiments, this disclosure provides a method of treating a disease by administering a SERT inhibitor, which includes administering an effective amount of the compound of this disclosure to a subject in need.

[0018] Numerous implementation schemes are also provided, which can be applied to any aspect of the invention described herein. Detailed Implementation

[0019] This invention is based, at least in part, on analogues of mesembrine and mesembrenone. While (-)mesembrine possesses biological activity and certain desired pharmacological effects, some other properties are not ideal for use as a therapeutic agent. For example, the pharmacokinetics described for (-)mesembrine show rapid metabolism and excretion, with an undesirably low plasma half-life of less than 2 hours. Compounds have been developed and described herein to utilize the desired properties of mesembrine and mesembrenone.

[0020] The compounds of the present invention In some respects, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof: (I), in Ring A is , , or , where * denotes the junction of ring A with the compound of formula (I), and where Each R1 is independently deuterium, halogroup, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, or -OR. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups is optionally replaced by a halogroup, alkyl, alkanol, aryl, or -OR group. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b replace; m is 0, 1, 2, or 3; Each of R2 and R3 is independently H, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in the alkyl, cycloalkyl, alkenyl, ynyl, and aryl groups is optionally replaced by a halogroup, deuterium, cycloalkyl, aryl, or OR group. a Replace; or R 2 and R 3 Together with the atoms they are attached to, they form heterocyclic or heteroaryl groups, wherein each hydrogen atom in the heterocyclic and heteroaryl groups is optionally replaced by a halogenated or OR group. a replace; R a and R b Independently, it is H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if R 1 An example is -NR a Rb Then R a and R b They can combine with the nitrogen atoms they are attached to to form heterocyclic alkyl or heteroaryl groups; R4 is hydrogen, C 1-4 Alkyl or C 1-6 Halogenated alkyl groups; and R5 is arbitrarily assigned to C. 3-6 C-substituted with cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups 1-4 Alkyl group, wherein the alkyl group, cycloalkyl group, heterocyclic aryl group, or heteroaryl group is each independently and optionally converted by one or more deuterium, C 1-4 Alkoxy, C 1-4 The alkyl, halogenated, cyano, amino, carboxyl, acetyl, or amide groups are substituted.

[0021] In some embodiments, the compound of formula (I) is also a compound of formula (II-A), (II-B), (II-C), or (II-D). In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-A) or a pharmaceutically acceptable salt thereof: (II-A), R1, m, R2, R3 and R5 are as defined in this paper with respect to equation (I).

[0022] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-B) or a pharmaceutically acceptable salt thereof: (II-B), R1, m, R2, R3 and R5 are as defined in this paper with respect to equation (I).

[0023] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-C) or a pharmaceutically acceptable salt thereof: (II-C), R1, m, R2, R3 and R5 are as defined in this paper with respect to equation (I).

[0024] In some embodiments, the compound is a compound of formula (I), wherein the compound is a compound of formula (II-D) or a pharmaceutically acceptable salt thereof: (II-D), R1, m, R2, R3 and R5 are as defined in this paper with respect to equation (I).

[0025] In some embodiments, a pharmaceutical composition is also provided comprising a compound of formula (I) (including compounds of formula (II-A), formula (II-B), formula (II-C) and formula (II-D)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0026] In some respects, the present invention relates to compounds of formula (III) or pharmaceutically acceptable salts thereof: (III) Wherein rings A, R1, m and R5 are as disclosed herein with respect to equation (I) or equations (II-A), (II-B), (II-C) and (II-D); X and Y are each independently O, NR7, or S; x is 1 or 2; R 6a and R 6b Each of them independently is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a replace; R a It is H, C 1-4 Alkyl (e.g., methyl), C 1-4 Halogenated alkyl or C 1-4 alkoxy groups; and R7 is H or C 1-4 alkyl.

[0027] In some aspects, the present invention relates to compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein Ring A is , , or , where * denotes the junction of ring A with the compound of formula (III), and where Each R 1 Independently, it is deuterium, halogenated group, C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 3-6 cycloalkyl, C 4-6Cycloalkenyl, 3-6 membered heterocyclic, 5-10 membered aryl, 5-10 membered heteroaryl, -OR a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups is optionally replaced by a halogroup, alkyl, alkanol, aryl, or -OR group. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b replace; m is 0, 1, 2, or 3; R a and R b Independently, it is H or C 1-4 Alkyl groups (e.g., methyl groups); R4 is a methyl group; R5 is C 1-4 alkyl; R 6a and R 6b Each of them is independently H or an optional substituted C. 1-4 Alkyl group, wherein each hydrogen atom in the alkyl group is optionally replaced by a halogroup, C 3-6 cycloalkyl or OR a Replace; or R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a Replace, and R7 is H or C 1-4 alkyl.

[0028] In some aspects, the present invention relates to compounds of formula (III) or pharmaceutically acceptable salts thereof, wherein Ring A is , where * denotes the junction of ring A with the compound of formula (III), and where Each R 1 Independently, it is a halogenated group, C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 3-6 cycloalkyl, C 1-4 Halogenated alkyl or C 1-4 Alkoxy; m is 0, 1, 2, or 3; R a and R b Independently, it is H or C 1-4 Alkyl groups (e.g., methyl groups); R4 is a methyl group; and R5 is a methyl group; R 6a and R 6b Each of them is independently H or an optionally substituted alkyl group, wherein each hydrogen atom in the alkyl group is optionally replaced by a halogroup, deuterium, cycloalkyl group, or OR. a Replace; or R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a replace, R a As defined above with respect to R1 in equation (I) or equations (II-A), (II-B), (II-C) or (II-D); and R7 is H or C 1-4 alkyl.

[0029] In some respects, the present invention relates to compounds of formula (IV) or pharmaceutically acceptable salts thereof: (IV) in Ring A is , , or , where * denotes the junction of ring A with the compound of formula (I), and where Each R1 is independently a halogenated group, C 1-4 Alkyl, C 1-4 Halogenated alkyl, methoxy, acetyl, cyano, C 2-4 alkenyl, C 2-4 Alkyne, amino, amide, or carboxyl groups; Each of R2 and R3 is independently H or optionally H by one or more halogenated groups, C 3-6 C-substituted with cycloalkyl, alkenyl or ynyl groups 1-4 Alkyl; or R2 and R3, together with the atoms they are attached to, form -(CR) 6a R 6b ) x -; x is 1 or 2; R4 is a methyl group; R 6a and R 6b Each of them independently is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl; or R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a Replace; and R a It is H, C 1-4 Alkyl (e.g., methyl), C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0030] Ring A In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), or formula (II-D), wherein ring A is .

[0031] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), or formula (II-D), wherein ring A is .

[0032] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), or formula (II-D), wherein ring A is .

[0033] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), or formula (II-D), wherein ring A is .

[0034] R 1 and m In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) or a pharmaceutically acceptable salt thereof, wherein each R1 is independently hydrogen, a halogroup, C 1-4 Alkyl or C 3-6 cycloalkyl; wherein C 1-4 Alkyl or C 3-6 Each hydrogen atom in the cycloalkyl group is optionally replaced by a halogroup or C. 1-4 Alkyl substitution; and m is 0 or 1. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein: each R1 is independently hydrogen, a halogroup, methyl, ethyl, or cyclopropyl; wherein each hydrogen atom in the methyl, ethyl, or cyclopropyl group is optionally substituted with a halogroup, methyl, or halomethyl; and m is 0 or 1. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is independently hydrogen, fluorine, a methyl or cyclopropyl group optionally substituted with one or more fluorine groups; and m is 0 or 1.

[0035] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R1 is a halogroup. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R1 is fluorinated. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R1 is cyclopropyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein m is 0 or 1.

[0036] In some embodiments, R1 is a halogroup, haloalkyl, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, or -OR. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b In some implementations, R 1It is a halogenated group, a halogenated alkyl group, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a heterocyclic alkyl group, an aryl group, a heteroaryl group, or -OR. a (e.g., alkoxy), -NR a R b (e.g., -NH2), -CHO, -C(O)R a (e.g., -C(O)alkyl, such as -C(O)CH3), -CN, or nitro. In some embodiments, R1 is a halogroup, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, -OR a -NR a R b -CHO, C(O)R a -CN or nitro. In some other embodiments, R1 is an alkyl group. In some other embodiments, R1 is a haloalkyl group. In some embodiments, R1 is an acetyl group. In some embodiments, R1 is an amide group. In some embodiments, R1 is -C(O)NH2. In some embodiments, R1 is a cyano group. In some embodiments, R1 is C 1-4 Alkenyl. In some embodiments, R1 is C 1-4 Alkyne group. In some embodiments, R1 is C 1-4 Alkyl group. In some embodiments, R1 is C 1-4 Methoxy group. In some embodiments, R1 is methyl. In some embodiments, R1 is fluorinated. In some embodiments, R1 is -(CH2)-(C 3-6 (cycloalkyl).

[0037] In some embodiments, R1 is a halogroup, cycloalkyl group, or -OR group. a (e.g., alkoxy), -NR a R b (e.g., -NH2), C(O)R a (e.g., -C(O)alkyl, such as -C(O)CH3), -CN, or nitro. For example, R1 can be a halogroup, cycloalkyl, alkoxy, -NH2, C(O)alkyl, -CN, or nitro. In some embodiments, R1 is a -C(O)alkyl, such as -C(O)CH3. In some embodiments, R1 is an alkoxy, such as methoxy. In some embodiments, R1 is a cycloalkyl, such as cyclopropyl.

[0038] In some embodiments, R1 is a halogroup, cyclopropyl group, -OCH3, -NH2, -C(O)CH3, -CN, or nitro group. In some embodiments, R1 is a halogroup. In some embodiments, R1 is -CN. In some embodiments, R1 is nitro group. In some embodiments, R1 is -NH2. In some embodiments, R1 is a halogroup, haloalkyl group, alkyl group, cyclopropyl group, -NH2, -NO2, -C(O)R a Or -CN. In some embodiments, R1 is a halogroup. In some embodiments, R1 is a haloalkyl group. In some embodiments, R1 is an alkyl group. In some embodiments, R1 is a cyclopropyl group. In some embodiments, R1 is -NH2. In some embodiments, R1 is -NO2. In some embodiments, R1 is -C(O)R. a , where R a It is hydrogen or alkyl. In some embodiments, R1 is -C(O)R a , where R a It is hydrogen or methyl. In some embodiments, R1 is -CN.

[0039] In some implementations, each R a and R b Independently, it is H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an example of R1 is -NR. a R b Then R a and R b They can combine with the nitrogen atoms to which they are attached to form heterocyclic alkyl or heteroaryl groups. For example, if R1 is -NR a R b Then R a and R b They can combine with the nitrogen atoms they are attached to to form In some implementations, each R a and R b Independently, it is H. In some implementations, each R a and R b It is either H or methyl on its own.

[0040] R 2 and R 3 In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R2 is a halomethyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R2 is -CHF2 or -CF3.

[0041] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R2 and R3, together with the atoms to which they are attached, combine to form a heterocyclic or heteroaryl group, wherein each hydrogen atom in the heterocyclic or heteroaryl group is optionally replaced by a halogenated group or an OR group. a Replacement. In some implementations, each R a It is H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments, R a Is it H or C? 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some embodiments, R a It is H. In some implementations, each R a It is H or a methyl group optionally substituted with one or more fluorine molecules. In some embodiments, R a It's CF3.

[0042] In some embodiments, R2 is a methyl group. In further embodiments, R2 is a halomethyl group, such as a methyl group substituted with at least one fluorine molecule (e.g., CHF2 or CF3).

[0043] In some embodiments, R3 is a methyl group. In other embodiments, R3 is a halomethyl group, such as a methyl group substituted with at least one fluorine molecule (e.g., CHF2 or CF3). In some embodiments, R3 is a benzyl group.

[0044] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a C-shaped compound optionally substituted with one or more halogenated groups. 1-4 Alkyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a C-aryl group optionally substituted with one or more fluorine molecules. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a C-aryl group optionally substituted with cyclopropyl, cyclobutyl, or cyclohexyl.1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a C-aryl group optionally substituted with a cyclopropyl group. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is optionally separated by one or more C2 groups. 1-4 alkoxy-substituted C 1-4 alkyl.

[0045] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a C-terminal molecule optionally substituted with a phenyl group. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is C2. 1-4 Alkyl or benzyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 is methyl and R3 is benzyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 is benzyl and R3 is C 1-4 alkyl.

[0046] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 is a C-shaped compound optionally substituted with one or more halogenated groups. 1-4 Alkyl group, and R3 is a C group optionally substituted with a 5-6-membered heteroaryl group. 1-4 Alkyl group, wherein the 5-6 membered heteroaryl group is bonded by one or more C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, cyano, amino, acetyl, or amide substitutions.

[0047] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 is a C-shaped compound optionally substituted with one or more halogenated groups. 1-4 Alkyl group, and R3 is a C group optionally substituted with one or more 5-6 heteroaryl groups. 1-4Alkyl group, wherein the 5-6 membered heteroaryl group is bonded by one or more C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, cyano, amino, acetyl, or amide substitutions.

[0048] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a C-terminal molecule optionally substituted with one or more fluorine molecules. 1-4 alkyl.

[0049] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), or formula (II-D), wherein each of R2 is C 1-4 Alkenyl group, and R3 is C 1-4 Alkyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 is C 1-4 Alkyne group, and R3 is C 1-4 Alkyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R3 is C 1-4 Alkenyl group, and R2 is C 1-4 Alkyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R3 is C 1-4 Alkyne group, and R2 is C 1-4 alkyl.

[0050] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 and R3 is a hydroxyl group or optionally a C-aryl group substituted with one or more halogen groups. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R2 is a hydroxyl group, and R3 is a C-aryl group optionally substituted with one or more halogen groups. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each of R3 is a hydroxyl group, and R2 is a C-aryl group optionally substituted with one or more halogen groups. 1-4 alkyl.

[0051] R 4 In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R4 is H, C 1-4 Alkyl or C 1-6 Halogenated alkyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R4 is methyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein C 1-4 alkyl.

[0052] R 5 In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R5 is C 1-4 alkyl.

[0053] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), formula (II-D), formula (III), or formula (IV), wherein R5 is optionally C 3-6 C-substituted with cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups 1-4 Alkyl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is each independently and optionally radically bonded by one or more deuterium, C 1-4 Alkoxy, C 1-4 The alkyl, halogenated, cyano, amino, carboxyl, acetyl, or amide groups are substituted.

[0054] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R5 is a C-terminal substituted with cyclopropyl, cyclobutyl, or cyclohexyl. 1-4 alkyl.

[0055] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R5 is a C-terminal molecule optionally substituted with a phenyl group. 1-4 Alkyl or methoxy, wherein the phenyl group is optionally substituted with one or more methyl groups, and the methyl group is optionally substituted with one or more halogroups.

[0056] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R5 is a C molecule optionally substituted with one or more fluorine molecules. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R5 is a C group optionally substituted with one or more deuterium groups. 1-4 alkyl.

[0057] R 6a and R 6b and x In some embodiments, the compound is a compound of formula (III), where x is 1. In some embodiments, the compound is a compound of formula (III), where x is 2.

[0058] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of them is independently an H, a halogenated group, or an optionally substituted C. 1-4 Alkyl, wherein C 1-4 Each hydrogen atom in the alkyl group is optionally replaced by a halogroup, deuterium, or C. 3-6 cycloalkyl or OR a Replace, where R a As defined herein with respect to formula (I). In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of them is independently H or an optional substituted C. 1-4 Alkyl, wherein C 1-4 Each hydrogen atom in the alkyl group is optionally replaced by a halogroup, deuterium, or C. 3-6 cycloalkyl or OR a Replace, where R a It is optionally halogenated or C 1-4 alkoxy-substituted C 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of them is independently H or an optional substituted C. 1-4 Alkyl, wherein C 1-4 Each hydrogen atom in the alkyl group is optionally replaced by a halogroup, C 3-6 cycloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkyl substitution.

[0059] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a Replace, where R a It is C 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O), C=O, ... 3-6 Spirocyclic-cycloalkyl or 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally halogenated or OR- a Replace, where R a It is methyl. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of them is independently an optional substitution of C. 1-4 Alkyl group, wherein each hydrogen atom in the alkyl group is optionally distilled by fluorine, C 3-6 cycloalkyl or OR a Replace; where R a It is C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

[0060] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of these components is independently hydrogen, a halogenated group, or a C group. 1-4 Alkyl or C 1-4 Halogenated alkyl group. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each is H. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each is fluorinated. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each is a methyl group. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of them is independently a C that is hydrogen, fluorine, or optionally substituted with one or more fluorine molecules.1-4 Alkyl group. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Each of them is independently hydrogen, fluorine, or a methyl group optionally substituted with one or more fluorine molecules.

[0061] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form carbonyl groups (C=O).

[0062] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form C 3-6 Spirocyclic-cycloalkyl. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form C 3-6 Spirocyclic-cyclopropyl. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form C 3-6 Spirocyclic-cyclobutyl. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form C 3-6 Spirocyclic-cyclohexyl.

[0063] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form 3-6 membered spirocyclic heterocyclic groups containing one or more O, N, or S heteroatoms; wherein each hydrogen atom in the cycloalkyl and heterocyclic groups is optionally replaced by a halogenated group or an OR group. a Replace, where R a It is C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form lactones or lactams.

[0064] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6bTogether with the atoms they are attached to, they form α-lactones. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form β-lactones. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form γ-lactones. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form δ-lactones. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form γ-lactones.

[0065] In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form α-lactams. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form β-lactams. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form γ-lactams. In some embodiments, the compound is a compound of formula (III), wherein R 6a and R 6b Together with the atoms they are attached to, they form caprolactam.

[0066] R 7 In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R7 is H. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R7 is C. 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV), wherein R7 is a methyl group.

[0067] Other compounds In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein R2 and R3, together with the atoms to which they are attached, combine to form a heterocyclic or heteroaryl group, wherein each hydrogen atom in the heterocyclic or heteroaryl group is optionally replaced by a halogenated group or an OR group. a Substitute; R4 is H, C 1-4 Alkyl or C 1-6 Haloalkyl; and R5 is C 1-4 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is independently hydrogen, a halogroup, or a C-aryl group. 1-4 Alkyl or C 3-6 cycloalkyl; wherein C 1-4 Alkyl or C 3-6 Each hydrogen atom in the cycloalkyl group is optionally replaced by a halogroup or C. 1-4 Alkyl substitution; m is 0 or 1; R2 and R3, together with the atoms they are attached to, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally replaced by a halogenated group, C... 1-4 Alkyl or C 1-4 Halogenated alkyl substitution; R4 is H or C 1-4 Alkyl or C 1-4 Haloalkyl; and R5 is C 1-2 Alkyl group. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein: each R1 is independently hydrogen, a halogroup, methyl, ethyl, or cyclopropyl; wherein each hydrogen atom in the methyl, ethyl, or cyclopropyl group is optionally substituted with a halogroup, methyl, or halomethyl; m is 0 or 1; R2 and R3, together with the atoms to which they are attached, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with a halogroup, C, or alkyl group. 1-4 Alkyl or C 1-4 Halogenated alkyl substitution; R4 is H or C 1-4 Alkyl or C 1-4 The compound is a haloalkyl group; and R5 is methyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is independently hydrogen, fluorine, a methyl group optionally substituted with one or more fluorine atoms, or a cyclopropyl group; m is 0 or 1; R2 and R3, together with the atoms to which they are attached, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with fluorine or a methyl group optionally substituted with one or more fluorine atoms; R4 is H, C 1-4 Alkyl or C 1-4 Haloalkyl; and R5 is methyl.

[0068] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is a halogroup (e.g., fluorine) or cyclopropyl; m is 0 or 1; R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with fluorine or optionally substituted with one or more fluorine-substituted methyl groups; R4 is H, C 1-4 Alkyl or C 1-4 The compound is a haloalkyl group; and R5 is methyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is a halogroup (e.g., fluorine) or cyclopropyl; m is 0 or 1; R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with fluorine or optionally substituted with one or more fluorine-substituted methyl groups; R4 is methyl; and R5 is methyl.

[0069] In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is a halogroup (e.g., fluorine) or cyclopropyl; m is 0 or 1; R2 and R3, together with the atoms to which they are attached, form a 6-membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with fluorine or optionally substituted with one or more fluorine-substituted methyl groups; R4 is H, C 1-4 Alkyl or C 1-4 The compound is a haloalkyl group; and R5 is methyl. In some embodiments, the compound is a compound of formula (I), (II-A), (II-B), (II-C), or (II-D), wherein each R1 is a halogroup (e.g., fluorine) or cyclopropyl; m is 0 or 1; R2 and R3, together with the atoms to which they are attached, form a 6-membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with fluorine or optionally substituted with one or more fluorine-substituted methyl groups; R4 is methyl; and R5 is methyl.

[0070] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C) or formula (II-D), wherein R3 is a methyl group.

[0071] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C) or formula (II-D), wherein R2 is methyl or halomethyl; and R3 is methyl, halomethyl or benzyl.

[0072] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C), or formula (II-D), wherein R4 is a methyl group.

[0073] In some embodiments, the compound is a compound of formula (I), formula (II-A), formula (II-B), formula (II-C) or formula (II-D), wherein R5 is a methyl group.

[0074] In some embodiments, the compound is a compound of formula (III), wherein In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0075] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0076] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0077] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0078] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0079] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0080] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0081] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0082] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0083] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0084] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0085] In some implementations, the compound is Or its pharmaceutically acceptable salt.

[0086] In some implementation schemes, the compound is selected from: , , , , , , , , , , , , , , , , and or its pharmaceutically acceptable salt.

[0087] In some implementation schemes, the compound is selected from: , and Or, or a pharmaceutically acceptable salt thereof.

[0088] In some implementation schemes, the compound is selected from: , ,and or its pharmaceutically acceptable salt.

[0089] In some implementation schemes, the compound is selected from: , ,and .

[0090] In some implementation schemes, the compound is selected from: , , , , , and or its pharmaceutically acceptable salt.

[0091] In some implementation schemes, the compound is selected from: , , and or its pharmaceutically acceptable salt.

[0092] In some implementation schemes, the compound is selected from: , and Or, or a pharmaceutically acceptable salt thereof.

[0093] In some implementation schemes, the compound is selected from: , and Or, or a pharmaceutically acceptable salt thereof.

[0094] In some implementation schemes, the compound is selected from: , and Or, or a pharmaceutically acceptable salt thereof.

[0095] In some implementation schemes, the compound is selected from: , and Or, or a pharmaceutically acceptable salt thereof.

[0096] In some implementation schemes, the compound is selected from: , and Or, or a pharmaceutically acceptable salt thereof.

[0097] In some implementation schemes, the compound is selected from: , , , and or its pharmaceutically acceptable salt.

[0098] In some embodiments, the compound is selected from the following:

[0099] In some embodiments, this application relates to a pharmaceutical composition comprising an active pharmaceutical ingredient. In some embodiments, the pharmaceutical composition comprises a compound as disclosed herein as the active pharmaceutical ingredient (API) and a pharmaceutically acceptable carrier comprising one or more excipients. In some embodiments, the pharmaceutical composition optionally further comprises an additional therapeutic compound (i.e., an agent) with a pharmaceutically acceptable carrier. The pharmaceutical composition may be a pharmaceutical agent.

[0100] Pharmaceutically acceptable carriers include those known in the art. The choice of a pharmaceutically acceptable carrier may depend on, for example, the desired route of administration of the composition. A pharmaceutical composition (formulation) may be administered to a subject via any of a variety of routes of administration, including, for example, parenteral administration (e.g., intravenous, subcutaneous, or intramuscular), oral administration (e.g., tablets and capsules); absorption through the oral mucosa (e.g., sublingual), or transdermal administration (e.g., as a patch applied to the skin), or topical administration (e.g., as a cream, ointment, or spray applied to the skin).

[0101] In some embodiments, pharmaceutical compositions comprising compounds of formula (I), (II-A), (II-B), (II-C), or (II-D), or pharmaceutically acceptable salts thereof, may be formulated for oral administration. For example, the compounds provided herein may be combined with suitable pharmacopoeia excipients to form oral unit dosage forms, such as capsules or tablets, containing a target dose of a compound of formula (I), (II-A), (II-B), (II-C), or (II-D). Pharmaceutical products may be prepared by first manufacturing a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) as an active pharmaceutical ingredient (API), followed by rolling / milling with an in-particle excipient and blending with an out-of-particle excipient. Pharmaceutical products may contain, in tablets at a desired dose strength, compounds selected from formulas (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) as both API and excipient components. The blended materials may be compressed to form tablets and then film-coated. Excipients may be selected from materials suitable for inclusion in the pharmaceutical composition for the intended purpose and route of delivery, including those providing the pharmaceutical composition with desired manufacturing and stability properties and / or desired in vivo characteristics or other properties. In some embodiments, the pharmaceutical composition may contain a compound of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) as an API, combined with a filler (e.g., in the form of microcrystalline cellulose), a dry binder or disintegrant (e.g., a cross-linked polymer), a flow aid (e.g., colloidal silica), and / or a lubricant (e.g., magnesium stearate). In some embodiments, the pharmaceutical composition may include materials (such as sustained-release agents or disintegrants) that participate in carrying or transporting the API agent from one organ or body part of the subject to another organ or body part, including materials intended to control the absorption of the API in the intestine.

[0102] The formulation can be readily available in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration method. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. For use in the methods of the present invention, the active compound may be administered alone or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0103] Methods for preparing these formulations or compositions include the step of associating an active compound (such as the compound of the present invention) with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and tightly associating the compound of the present invention with a liquid carrier or a finely dispersed solid carrier, or both, and then (if necessary) shaping the product.

[0104] To prepare a solid dosage form for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: (1) a filler or expander, (2) a binder, (3) a humectant, (4) a disintegrant, (5) a dissolution inhibitor, (6) an absorption enhancer, (7) a wetting agent, (8) an absorbent, (9) a lubricant, (10) a complexing agent, and (11) a colorant. In the case of capsules (including dispersible capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffer. Similar types of solid compositions may also use suitable excipients as fillers in soft-filled or hard-filled gelatin capsules. Pharmaceutical compositions according to the invention may contain conventional pharmaceutical carriers and / or excipients. In some embodiments, pharmaceutical compositions according to the invention may contain conventional carrier agents, including binders, lubricants, and / or flow aids, selected from those products and materials commonly used in the pharmaceutical industry to prepare pharmaceutical compositions for the intended route of administration.

[0105] Tablets can be prepared by compression or molding, optionally containing one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0106] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable carriers and active ingredients, the active ingredient being provided in a solid form for reconstitution prior to administration or in a liquid form (e.g., solution, suspension, or emulsion). In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art. For example, formulations of pharmaceutically acceptable compositions for injection may comprise aqueous solutions, such as water or physiologically buffered saline, or other solvents or media suitable for the intended route of administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0107] The therapeutically effective amount of a pharmaceutical composition can be determined through human clinical trials to identify a safe and effective dose for patients with the relevant diagnosis. It should generally be understood that the effective amount of a compound can vary depending on the subject's weight, sex, age, and medical history. Other factors affecting the effective amount may include, but are not limited to, the severity of the patient's condition, the condition being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered in conjunction with the compound of the present invention. A larger total dose can be delivered by administering the pharmaceutical composition multiple times at dose intervals to determine a dose and dosing interval that are safe and effective for the patient.

[0108] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt can be an organic or inorganic acid. The base added to the compound to form the base addition salt can be an organic or inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt, and in some embodiments, the pharmaceutically acceptable salt is an ammonium salt. For example, pharmaceutically acceptable acid addition salts can exist as various solvates such as those with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of such solvates can be a solvent from which crystallization is performed, inherent in the solvent used for preparation or crystallization, or incidental to such a solvent.

[0109] In some embodiments, compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) may provide additional beneficial properties. For example, the compounds described herein may provide beneficial therapeutic properties while minimizing vomiting. For example, compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) may have improved metabolic stability and SERT-inhibiting activity. In some embodiments, compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) described herein inhibit SERT and have desired metabolic stability and / or other desired ADME properties. Furthermore, compounds with high brain exposure are most desirable, wherein the brain:plasma ratio (expressed as Kp) > 0.3, and ideally > 0.7. In some embodiments, in the determination of Example A1, compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) can be expressed at an IC50 concentration of less than about 1 micromolar. 50 Suppress SERT.

[0110] definition Unless otherwise defined herein, the scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. Generally, the names and techniques used herein in conjunction with chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry are those well-known and commonly used in the art.

[0111] Unless otherwise indicated, the methods and techniques disclosed herein are generally performed in accordance with conventional methods well known in the art and described in various general and more specific references cited and discussed throughout this specification. See, for example, “Principles of Neural Science”, McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th Edition”, WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition”, WH Freeman & Co., NY (1999); and Gilbert et al., “Developmental Biology, 6th Edition”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0112] All references to the foregoing and any other publications, patents, and published patent applications mentioned in this application are expressly incorporated herein by reference. In the event of any conflict, this specification (including its specific definitions) shall prevail.

[0113] This document uses the term "agent" to refer to compounds (such as organic or inorganic compounds, mixtures of compounds), biological macromolecules (such as nucleic acids, antibodies, including their portions and humanized, chimeric and human antibodies and monoclonal antibodies, proteins or portions thereof, such as peptides, lipids, carbohydrates), or extracts made from biological materials such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Agents include, for example, agents with known structures and agents with unknown structures.

[0114] The terms “patient,” “subject,” or “individual” are used interchangeably and refer to humans or non-human animals. These terms include mammals such as humans, primates, livestock (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0115] "Treatment" of a disease or patient refers to taking measures to obtain a beneficial or desired outcome, including clinical outcomes. As used herein and as is well known in the art, "treatment" is a method used to obtain a beneficial or desired outcome (including clinical outcomes). Beneficial or desired clinical outcomes may include, but are not limited to, the reduction or improvement of one or more symptoms or disorders, a decrease in the severity of the disease, stabilization of the disease state (i.e., no worsening), prevention of disease spread, delay or slowing of disease progression, improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonged survival compared to expected survival without treatment.

[0116] The term "prevention" is recognized in the art and is well known in the art when used in relation to conditions such as local recurrence (e.g., pain), diseases such as cancer, symptoms such as heart failure, or any other medical condition, and includes administering a composition that, relative to a subject not receiving the composition, reduces the frequency of symptoms of the subject's medical condition or delays its onset. Thus, cancer prevention includes, for example, reducing, in statistically and / or clinically significant amounts, the number of detectable cancerous growths in a patient population receiving prophylactic treatment relative to an untreated control population, and / or delaying the occurrence of detectable cancerous growths in the treated population relative to the untreated control population.

[0117] The administration of a substance, compound, or agent to a subject may be carried out using one of a variety of methods known to those skilled in the art. For example, the compound or agent may be administered intravenously, intra-arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, via the eyes, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., via a skin tube). The compound or agent may also be suitably introduced via a rechargeable or biodegradable polymer device or other device (e.g., a patch or pump) or formulation that provides an extended, slow, or controlled release of the compound or agent. Administration may also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0118] The appropriate method of administering a substance, compound, or agent to a subject will also depend on factors such as the subject's age and / or physical condition, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered orally to the subject, for example, by ingestion. In some embodiments, the compound or agent is administered orally in a prolonged-release or slow-release formulation, or using a device for such slow or prolonged release.

[0119] As used herein, the phrase "combined administration" refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered agent remains effective in the body (e.g., both agents are effective simultaneously in the patient, which may include the synergistic effect of the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effect of the different therapeutic agents.

[0120] The "therapeutic effective amount" or "therapeutic dose" of a drug or agent is the amount of drug or agent that will have the expected therapeutic effect when administered to a subject. A complete therapeutic effect does not necessarily occur with a single dose, but may only occur after a series of doses. Therefore, a therapeutic effective amount can be administered in one or multiple doses. The precise effective amount required by the subject will depend on factors such as the subject's size, health, and age, as well as the nature and extent of the condition being treated (such as cancer or MDS). Technicians can easily determine the effective amount for a given situation through routine experiments.

[0121] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both cases in which the event or situation occurs and cases in which the event or situation does not occur. For example, “optionally substituted alkyl” means an alkyl group that can be substituted, as well as cases in which the alkyl group is not substituted.

[0122] It should be understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to obtain chemically stable compounds that can be readily synthesized from readily available raw materials using techniques known in the art and the methods described below. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups can be located on the same carbon or on different carbons, as long as a stable structure is obtained.

[0123] As used herein, the term "optionally substituted" means replacing one to six hydrogen groups in a given structure with a specified substituent, including but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or –CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means replacing one to four hydrogen groups in a given structure with the substituents mentioned above. More preferably, one to three hydrogen groups are replaced by the substituents mentioned above. It should be understood that the substituents may be further substituted.

[0124] As used herein, the term "alkyl" refers to a saturated aliphatic group, including but not limited to C1-C1 groups. 10 Straight-chain alkyl, C1-C 10 Branched alkyl, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl, and cycloalkyl-substituted alkyl groups. Preferably, "alkyl" refers to a C1-C7 straight-chain alkyl or a C1-C7 branched alkyl. Most preferably, "alkyl" refers to a C1-C3 straight-chain alkyl or a C1-C3 branched alkyl. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl, etc. "Alkyl" may optionally be substituted.

[0125] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted on a carbon atom replaced by a halogen. Illustrative halogens include fluorine, chlorine, bromine, and iodine. Illustrative haloalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0126] The term "alkoxyalkyl" refers to an alkyl group that has been substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl.

[0127] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "C" is used. x-y "or "C x -C y This refers to groups containing x to y carbons in the chain. C0 alkyl indicates hydrogen, where the group is at the terminal position; if internal, it is a bond. For example, AC 1-6 Alkyl groups contain one to six carbon atoms in their chains.

[0128] As used herein, the term "alkylamino" refers to an amino group that is substituted with at least one alkyl group.

[0129] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula alkylS-.

[0130] As used herein, the term "amide" refers to a group. , Where R e and R f Each can independently represent a hydrogen or hydrocarbon group, or R e and R f Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure.

[0131] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbon C(O)-, preferably alkyl C(O)-.

[0132] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, and can be represented, for example, by the formula alkyl group C(O)NH-.

[0133] The term "acyloxy group" is recognized in the art and refers to a group represented by the general formula hydrocarbon C(O)O-, preferably alkyl C(O)O-.

[0134] The term "alkoxy" refers to an alkyl group linked to an oxygen atom. Preferably, "alkoxy" refers to a C1-C7 straight-chain alkoxy or a C1-C7 branched-chain alkoxy. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0135] The terms "amine" and "amino" are recognized in the art and refer to unsubstituted and substituted amines and their salts, such as portions that can be represented by the following formula. , Where R e R f and R g Each can independently represent a hydrogen or hydrocarbon group, or R e and R f Together with the N atoms they are attached to, they form heterocycles with 4 to 8 atoms in the ring structure.

[0136] As used herein, the term "aminoalkyl" refers to an alkyl group that has been substituted with an amino group.

[0137] As used herein, the term "aralkyl" refers to an alkyl group that has been substituted with an aryl group.

[0138] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring, such as a phenyl ring. The term "aryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more carbons are common to two adjacent rings, and wherein at least one ring is aromatic; for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0139] The term "carbamate" is recognized in the art and refers to the following groups , Where R e and R f Independently represents either hydrogen or hydrocarbon groups.

[0140] As used herein, the term "carbocyclic alkyl" refers to an alkyl group that has been substituted with a carbocyclic group.

[0141] The term "carbocyclic ring" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. Carbocyclic rings include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring can be selected from saturated rings, unsaturated rings, and aromatic rings. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, where valence allows. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The “carbocyclic ring” can be substituted at any one or more positions capable of carrying hydrogen atoms.

[0142] As used herein, the term "carbocyclic alkyl" refers to an alkyl group that has been substituted with a carbocyclic group.

[0143] The term "carbonate" is recognized in the art and refers to the group -OCO2-.

[0144] As used herein, the term "carboxyl" refers to a group represented by the formula -CO2H.

[0145] As used herein, the term "ester" refers to the group -C(O)OR 9 , where R 9 It indicates a hydrocarbon group.

[0146] As used herein, the terms “halogenated group” and “halogen” refer to halogens and include chlorine, fluorine, bromine and iodine.

[0147] As used herein, the terms “hetaralkyl” and “heteroaralkyl” refer to alkyl groups that have been substituted with heteroaryl groups.

[0148] The terms "heteroaryl" and "hetaryl" encompass substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, and wherein at least one ring is heteroaromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0149] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0150] As used herein, the term "heterocyclic alkyl" refers to an alkyl group that has been substituted with a heterocyclic group.

[0151] The terms "heterocyclic group," "heterocyclic," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3 to 10-membered rings, more preferably 3 to 7-membered rings, whose ring structure contains at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclic group" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are common to two adjacent rings, and wherein at least one ring is heterocyclic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0152] As used herein, the term "hydrocarbon group" refers to a group bonded by carbon atoms without =O or =S substituents and typically has at least one carbon-hydrogen bond and a predominantly carbon backbone, but may optionally contain heteroatoms. Therefore, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbon groups, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked by oxygen rather than carbon) are not. Hydrocarbon groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, ynyl, and combinations thereof.

[0153] As used herein, the term "hydroxyalkyl" refers to an alkyl group that has been substituted with a hydroxyl group.

[0154] When used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" means a group comprising ten or fewer atoms, preferably six or fewer, of which the substituents. For example, "lower alkyl" refers to an alkyl group containing six or fewer, preferably four or fewer carbon atoms. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the description of hydroxyalkyl and aralkyl (in which case, for example, when calculating the carbon atoms in the alkyl substituents, the atoms in the aryl group are not counted).

[0155] The terms "polycyclic," "polycyclic," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic) in which two or more atoms are shared by two adjacent rings; for example, the rings are "fused rings." Each ring of a polycyclic compound may be substituted or unsubstituted. In some embodiments, each ring of the polycyclic compound contains 3 to 10 atoms, preferably 5 to 7 atoms.

[0156] The term "sulfate" is recognized in the art and refers to the group –OSO3H or its pharmaceutically acceptable salt.

[0157] The term "sulfonamide" is recognized in the art and refers to a group represented by the following general formula. , Where R e and R f Independently represents either hydrogen or hydrocarbon groups.

[0158] The term "sulfoxide" is recognized in the art and refers to the group –S(O)-.

[0159] The term "sulfonate" is recognized in the art and refers to the group SO3H or its pharmaceutically acceptable salt.

[0160] The term "sulfone" is recognized in the art and refers to the group –S(O)2-.

[0161] The term "substituted" refers to a portion having a substituent replacing hydrogen on one or more carbons of the main chain. It should be understood that "substituted" or "replaced by" includes the implicit condition that such substitution is based on the permissible valence of the substituted atom and the substituent, and that said substitution produces a stable compound, for example, which does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is considered to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. Permissible substituents can be one or more substituents and can be the same or different for a suitable organic compound. For the purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents in the organic compounds described herein that satisfy the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonate groups, hypophosphonate groups, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonate groups, sulfonamide groups, sulfinamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that, where appropriate, the substituted portion on the hydrocarbon chain may itself be substituted.

[0162] As used herein, the term "thioalkyl" refers to an alkyl group that has been substituted with a mercapto group.

[0163] As used herein, the term "thioester" refers to the group -C(O)SR. e Or –SC(O)R e , where R e It indicates a hydrocarbon group.

[0164] As used in this article, the term "thioether" is equivalent to ether, in which oxygen is replaced by sulfur.

[0165] The term "urea" is recognized in the art and can be represented by the following general formula. , Where R e and R f Independently represents either hydrogen or hydrocarbon groups.

[0166] As used herein, the term “regulation” includes both inhibiting or suppressing functions or activities (such as cell proliferation) and enhancing functions or activities.

[0167] "Pharmaceutically acceptable salt" or "salt" as used in this article refers to an acid addition salt or base addition salt that is suitable for treating the patient or is compatible with the treatment of the patient.

[0168] As used herein, the term "pharmaceutically acceptable acid addition salt" means any non-toxic organic or inorganic salt of any base compound represented by formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV). Illustrative inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monocarboxylic or dicarboxylic acid salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts of compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) are more soluble in water and various hydrophilic organic solvents and typically exhibit higher melting points compared to their free base forms. The selection of suitable salts is known to those skilled in the art. Other non-pharmaceuticalally acceptable salts, such as oxalates, may be used, for example, to isolate compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0169] As used herein, the term "pharmaceutically acceptable base addition salt" means any non-toxic organic or inorganic base addition salt of any acid compound or any intermediate thereof represented by formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV). Illustrative inorganic bases forming suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Illustrative organic bases forming suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and methylpyridine or ammonia. The selection of suitable salts will be known to those skilled in the art.

[0170] This article uses the phrase "pharmaceutically acceptable" to refer to compounds, materials, compositions, and / or dosage forms that, within the bounds of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0171] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation and does not harm the patient.

[0172] As used herein, the phrases “parenteral administration” and “extraterrestrial administration” refer to administration methods that are typically administered by injection, other than enteral and local administration, and include, but are not limited to, intravenous, intraocular (e.g., intravitreal), intramuscular, intra-arterial, intrasheath, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds and one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use. These compositions may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0173] Many compounds that can be used in the methods and compositions of this disclosure have at least one stereocenter in their structure. This stereocenter may be present in an R or S configuration, the R and S symbols being used according to the rules described in Pure Appl. Chem. (1976), 45, 11-30. This disclosure considers all stereoisomers, such as enantiomers and diastereomers (including all possible mixtures of stereoisomers) of compounds, salts, prodrugs, or mixtures thereof. See, for example, WO 01 / 062726.

[0174] Furthermore, certain alkenyl-containing compounds can exist as Z (isolateral) or E (isolateral) isomers. In each case, this disclosure includes both mixtures and individual isomers.

[0175] Some compounds may also exist as tautomers. Although not explicitly indicated in the formulas described herein, such forms are intended to be included within the scope of this disclosure.

[0176] A “prodrug” or “pharmaceutically acceptable prodrug” is a compound that, upon administration, is metabolized (e.g., hydrolyzed or oxidized) in a host to form the compounds of this disclosure (e.g., compounds of formula (I), (II-A), (II-B), (II-C), or (II-D)). Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protective) group on the functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation, or dephosphorylation to produce the active compound. Examples of prodrugs include those using esters or aminophosphates as biologically unstable or cleavable (protective) groups. The prodrugs of this disclosure are metabolized to produce compounds of formula (I), (II-A), (II-B), (II-C), or (II-D). This disclosure includes prodrugs of the compounds described herein within its scope. For example, “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985 describes the routine procedures for the selection and preparation of suitable prodrugs.

[0177] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filter aid, diluent, excipient, solvent, or encapsulating material, that can be used to formulate a medicament for medical or therapeutic purposes.

[0178] As used herein, the terms “logarithm of solubility,” “LogS,” or “logS” are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is often accompanied by poor absorption. The LogS value is the unit stripping logarithm (base 10) of solubility measured in moles per liter.

[0179] Methods of using the compounds disclosed herein are also provided. This disclosure also includes pharmaceutical compositions comprising one or more SERT-inhibiting compounds as described herein, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical compositions reported herein may be provided in unit dosage forms (e.g., capsules, tablets, etc.). Pharmaceutical compositions comprising compounds of formula (I), (II-A), (II-B), (II-C), or (II-D) may be provided in oral dosage forms (such as capsules or tablets). Oral dosage forms optionally comprise one or more fillers, disintegrants, lubricants, flow aids, anti-adhesion agents, and / or antistatic agents. In some embodiments, the oral dosage form is prepared via dry mixing. In some embodiments, the oral dosage form is a tablet and is prepared via dry granulation. For example, the SERT inhibitor compounds of formula (I), (II-A), (II-B), (II-C), (II-D), (III), or (IV) of this disclosure can be formulated as test articles for evaluation in animal models and (if appropriate) subsequent human clinical trials to determine the effective dose and frequency of administration for human treatment. The pharmaceutical compositions can be administered orally in any orally acceptable dosage form. Therefore, patients and / or subjects treated with the compounds described herein can be selected by first evaluating patients and / or subjects to determine whether a subject requires SERT inhibition, and if determined that a subject requires SERT inhibition, by administering to the subject a pharmaceutical composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts thereof.

[0180] The compounds described herein may be used to treat CNS disorders and / or inflammatory conditions. Exemplary CNS disorders include generalized anxiety disorder, acute anxiety and panic attacks, social anxiety, panic disorder, major depressive disorder, cognitive impairment, including Alzheimer's disease and other neurodegenerative disorders, neurodevelopmental disorders, schizophrenia, bipolar disorder, obsessive-compulsive disorder, multiple sclerosis, attention deficit hyperactivity disorder, bulimia nervosa, Huntington's disease, stroke, autism, and premenstrual anxiety disorder. Exemplary inflammatory conditions include chronic obstructive pulmonary disease (COPD), asthma, and rheumatoid arthritis.

[0181] In some embodiments, a method of treating a patient with a disorder includes administering to the patient a composition comprising a compound disclosed herein for the treatment or prevention of a mental health disorder. In some embodiments, a method of treating a patient with a disorder includes administering to the patient a composition comprising a compound disclosed herein for the treatment or prevention of a diagnosed disorder selected from anxiety and depression. In some embodiments, the compounds disclosed herein are administered to the patient in a unit dose. In some embodiments, the method includes administering to a patient in need a therapeutically effective amount of a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) for the treatment of a disorder selected from the group consisting of mild to moderate depression and major depressive episodes. In some embodiments, the method includes administering to a patient in need a therapeutically effective amount of a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) for the treatment of anxiety. In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) to a patient in need for the treatment of depression. In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) to a patient in need for the treatment of a disorder selected from the group consisting of: anxiety associated with depression, anxiety with depression, mixed anxiety, and depressive disorder. In some embodiments, the method includes administering a therapeutically effective amount of a compound of formula (I), (II-A), (II-B), (II-C), or (II-D) to a patient in need for the treatment of anxiety and hysteria or anxiety and depression.

[0182] Unless otherwise stated in the compound table herein, the abbreviations RAC or rac indicate racemic mixtures, and DIAST indicates a specific diastereomer. In the illustrative embodiments, although the compounds may be used... or The term "bond" is used to describe this, but such descriptions can be expressed based on the relative stereochemistry of elution peaks derived from chiral separation.

[0183] In some embodiments, this disclosure provides one or more of the following embodiments or variations thereof: 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I), in Ring A is , , or , where * denotes the connection point between ring A and the compound of formula (I), and where Each R1 is independently deuterium, halogroup, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, or -OR. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups is optionally replaced by a halogroup, alkyl, alkanol, aryl, or -OR group. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b replace; m is 0, 1, 2, or 3; Each of R2 and R3 is independently H, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in the alkyl, cycloalkyl, alkenyl, ynyl, and aryl groups is optionally replaced by a halogroup, deuterium, cycloalkyl, aryl, or OR group. a Replace; or R2 and R3, together with the atoms they are attached to, combine to form a heterocyclic group or a heteroaryl group, wherein each hydrogen atom in the heterocyclic group or heteroaryl group is optionally replaced by a halogenated group or an OR group. a replace; R a and R b Independently, it is H, alkyl (e.g., methyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an example of R1 is -NR. a R b Then R a and R b They can combine with the nitrogen atoms they are attached to to form heterocyclic alkyl or heteroaryl groups; R4 is hydrogen, C 1-4 Alkyl or C 1-6 Halogenated alkyl groups; and R5 is C 1-4 alkyl.

[0184] 2. The compound as described in embodiment 1, wherein ring A is .

[0185] 3. The compound as described in embodiment 1, wherein ring A is .

[0186] 4. The compound as described in embodiment 1, wherein ring A is .

[0187] 5. The compound as described in embodiment 1, wherein ring A is .

[0188] 6. The compound as described in embodiment 1, wherein the compound is a compound of formula (II-A), (II-A) Or its pharmaceutically acceptable salt.

[0189] 7. The compound as described in Embodiment 1, wherein the compound is a compound of formula (II-B), (II-B) Or its pharmaceutically acceptable salt.

[0190] 8. The compound as described in Embodiment 1, wherein the compound is a compound of formula (II-C). (II-C) Or its pharmaceutically acceptable salt.

[0191] 9. The compound as described in Embodiment 1, wherein the compound is a compound of formula (II-D). (II-D) Or its pharmaceutically acceptable salt.

[0192] 10. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 9, wherein: a. Each R1 is independently hydrogen, halide, C 1-4 Alkyl or C 3-6 cycloalkyl; wherein C 1-4 Alkyl or C 3-6 Each hydrogen atom in the cycloalkyl group is optionally replaced by a halogroup or C. 1-4 Alkyl substitution; b. m is 0 or 1; c. Each of R2 and R3 is independently hydrogen, halogroup, C 1-4 Alkyl or C 3-6 cycloalkyl; wherein C 1-4 Alkyl or C3-6 Each hydrogen atom in the cycloalkyl group is optionally replaced by a halogroup or C. 1-4 Alkyl substitution; d. R4 is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and e. R5 is C 1-2 alkyl.

[0193] 11. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 10, wherein: a. Each R1 is independently hydrogen, halogroup, methyl, ethyl or cyclopropyl; wherein each hydrogen atom in the methyl, ethyl or cyclopropyl group is optionally substituted with a halogroup, methyl or halomethyl; b. m is 0 or 1; c. Each of R2 and R3 is independently hydrogen, a halogroup, a methyl group, or a halomethyl group; wherein each hydrogen atom in the methyl, ethyl, or cyclopropyl group is optionally substituted with a halogroup, a methyl group, or a halomethyl group; d. R4 is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and e. R5 is methyl.

[0194] 12. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 11, wherein: a. Each R1 is independently hydrogen, fluorine, or optionally a methyl or cyclopropyl group substituted with one or more fluorine groups; b. m is 0 or 1; c. Each of R2 and R3 is independently hydrogen, fluorine, or a methyl group optionally substituted with one or more fluorine molecules; d. R4 is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and e. R5 is methyl.

[0195] 13. The compound as described in any one of embodiments 1 to 12, wherein R1 is a halogroup.

[0196] 14. The compound as described in any one of embodiments 1 to 12, wherein R1 is fluorinated.

[0197] 15. The compound as described in any one of embodiments 1 to 12, wherein R1 is cyclopropyl.

[0198] 16. The compound as described in any one of embodiments 1 to 15, wherein m is 0 or 1.

[0199] 17. The compound as described in any one of embodiments 1 to 16, wherein R2 is a halomethyl group.

[0200] 18. The compound as described in embodiment 17, wherein R2 is -CHF2 or -CF3.

[0201] 19. The compound as described in any one of embodiments 1 to 18, wherein R5 is a methyl group.

[0202] 20. The compound as described in any one of embodiments 1 to 19, wherein R3 is a methyl group.

[0203] 21. The compound as described in any one of embodiments 1 to 20, wherein R4 is a methyl group.

[0204] 22. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0205] 23. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0206] 24. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0207] 25. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0208] 26. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0209] 27. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0210] 28. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0211] 29. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0212] 30. The compound of any one of embodiments 1 to 9, wherein R2 and R3, together with the atoms to which they are attached, combine to form a heterocyclic group or a heteroaryl group, wherein each hydrogen atom in the heterocyclic group and the heteroaryl group is optionally halogenated or OR a replace; R4 is H, C 1-4 Alkyl or C 1-6 Halogenated alkyl groups; and R5 is C 1-4 alkyl.

[0213] 31. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 30, wherein: a. Each R1 is independently hydrogen, halide, C 1-4 Alkyl or C 3-6 cycloalkyl; wherein C 1-4 Alkyl or C 3-6 Each hydrogen atom in the cycloalkyl group is optionally replaced by a halogroup or C. 1-4 Alkyl substitution; b. m is 0 or 1; c. R2 and R3, together with the atoms they are attached to, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally replaced by a halogenated group, C... 1-4 Alkyl or C 1-4 Halogenated alkyl substitution; d. R4 is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and e. R5 is C 1-2 alkyl.

[0214] 32. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 31, wherein: a. Each R1 is independently hydrogen, halogroup, methyl, ethyl or cyclopropyl; wherein each hydrogen atom in the methyl, ethyl or cyclopropyl group is optionally substituted with a halogroup, methyl or halomethyl; b. m is 0 or 1; c. R2 and R3, together with the atoms they are attached to, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally replaced by a halogenated group, C... 1-4 Alkyl or C 1-4 Halogenated alkyl substitution; d. R4 is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and e. R5 is methyl.

[0215] 33. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 32, wherein: a. Each R1 is independently hydrogen, fluorine, or optionally a methyl or cyclopropyl group substituted with one or more fluorine groups; b. m is 0 or 1; c. R2 and R3, together with the atoms to which they are attached, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally substituted with fluorine or optionally substituted with one or more fluorine-substituted methyl groups; d. R4 is H, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and e. R5 is methyl.

[0216] 34. The compound as described in any one of embodiments 30 to 33, wherein R1 is a halogroup.

[0217] 35. The compound as described in any one of embodiments 30 to 33, wherein R1 is fluorinated.

[0218] 36. The compound as described in any one of embodiments 30 to 33, wherein R1 is cyclopropyl.

[0219] 37. The compound as described in any one of embodiments 30 to 33, wherein m is 0 or 1.

[0220] 38. The compound of any one of embodiments 30 to 33, wherein R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group.

[0221] 39. The compound of any one of embodiments 30 to 38, wherein R2 and R3, together with the atoms to which they are attached, combine to form an unsubstituted 5-membered heterocyclic group.

[0222] 40. The compound of any one of embodiments 30 to 38, wherein R2 and R3, together with the atoms to which they are attached, form a 6-membered heterocyclic group.

[0223] 41. The compound of any one of embodiments 30 to 38, wherein R2 and R3, together with the atoms to which they are attached, combine to form an unsubstituted 6-membered heterocyclic group.

[0224] 42. The compound as described in any one of embodiments 30 to 41, wherein R5 is methyl.

[0225] 43. The compound as described in any one of embodiments 30 to 42, wherein R4 is a methyl group.

[0226] 44. The compound as described in embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0227] 45. The compound as described in embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0228] 46. ​​The compound as described in embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0229] 47. The compound as described in embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0230] 48. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0231] 49. A pharmaceutical composition comprising a compound as described in any one of embodiments 1 to 48 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0232] 50. A method of treating a mental health disorder, comprising administering to a mammal in need an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 48, or a pharmaceutical composition as described in embodiment 49.

[0233] 51. The method as described in embodiment 50, wherein the mental health disorder is anxiety, stress, or depression.

[0234] 52. The method of embodiment 50, wherein the mental health disorder is anxiety.

[0235] 53. The method of embodiment 50, wherein the mental health disorder is stress.

[0236] 54. The method as described in embodiment 50, wherein the mental health disorder is depression.

[0237] 55. The method as described in any one of embodiments 50 to 54, wherein the mammal is a human.

[0238] 56. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0239] 57. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0240] 58. The compound as described in embodiment 1, wherein the compound is Or its pharmaceutically acceptable salt.

[0241] 59. The compound as described in embodiment 1, wherein said compound is Or its pharmaceutically acceptable salt.

[0242] 60. The compound of embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0243] 61. The compound as described in embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0244] 62. The compound as described in embodiment 30, wherein said compound is Or its pharmaceutically acceptable salt.

[0245] Example Some compounds in the following examples are labeled using MDL-enhanced stereo notation. For example, the label “ABS” indicates absolute stereochemistry at a specific stereocenter. The labels “or n” or “or n (orn)” (where n is an integer (e.g., “or 1”)) indicate stereoisomers having the drawn stereochemistry, or epimers at a specific stereocenter. The labels “and n” or “and n (&n)” (where n is an integer (e.g., “and 1 (and 1)” or “and 1 (&1)”)) indicate a mixture of two epimers at the stereocenter, i.e., the drawn structure and epimers in which the stereocenters have opposite configurations (e.g., racemic mixtures).

[0246] LC / MS spectra were acquired using an Agilent 1200 / G1956A or SHIMADZU LCMS-2020. Standard LC / MS conditions were as follows (run time 1.55 minutes): Acidic conditions: Mobile phase A: 0.0375% TFA (v / v) in water. Mobile phase B: 0.01875% TFA (v / v) in acetonitrile; Column: Kinetex EVO C 18 30*2.1mm, 5 μ m.

[0247] Alkaline conditions: Mobile phase A: 0.025% NH3·H2O (v / v) in water. Mobile phase B: Acetonitrile; Column: Kinetex EVOC 18 2.1X30mm, 5 μ m.

[0248] Abbreviation Table

[0249] General synthetic method A: Synthesizing methylenecyclohexane and methylcyclohexene compounds from the corresponding cyclohexanone compounds. Step 1 At 0°C, methyl(triphenyl)phosphonium bromide (740 mg, 2.07 mmol) was added to a solution of methyl(triphenyl)phosphonium bromide in 6.0 mL of THF over 0.5 hours. t- BuOK (1M in THF, 2.07 mL). Add 1 mL of THF containing the corresponding cyclohexanone compound (1.04 mmol) to the mixture. Stir the reaction mixture at 25 °C for 16 hours, then pour into water (50 mL). Extract the mixture with ethyl acetate (100 mL). Dry the organic solution over sodium sulfate, filter, and concentrate. Purify the crude product by reversed-phase HPLC (0.1% FA conditions).

[0250] Step 2 TfOH (1.39 mmol) was added to a solution of methylenecyclohexane compound (696 μmol) in dioxane (10 mL). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC. The residue was then separated into the corresponding methylcyclohexene compounds by SFC.

[0251] General Synthesis Method B: Methylenecyclohexane and Methylcyclohexene Compounds Treating a ketone compound (such as A) with a phosphonium salt (such as a phosphonium salt formed by treating methyl(triphenyl)phosphonium bromide with an alkoxide (such as tert-BuOK)) in a solvent (such as THF) at a low temperature (such as 0°C) is a method that can be used to prepare a methylenecyclohexane compound (such as B).

[0252] Treating methylenecyclohexane compounds (such as B) with an acid (such as trifluoromethanesulfonic acid (TfOH)) in a solvent (such as dioxane) at a high temperature (such as 80°C) is a method that can be used to prepare methylcyclohexene compounds (such as C and D).

[0253] General synthesis method C: Step 1At 0°C, t-BuOK (1M in THF, 2.07 mL) was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL) over 0.5 hours. THF (1 mL) containing 1.04 mmol of O16 was added to the mixture. The reaction mixture was stirred at 25°C for 16 hours and then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0254] Step 2 TfOH (1.39 mmol) was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0255] Example 1: Synthesis of (+ / -)-pinene (016) and (+ / -)-pinene (022) Step 1: Synthesis of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxynitrile NaH (18.0 g, 451 mmol, 60% purity) was added fractionally to a solution of 2-(3,4-dimethoxyphenyl)acetonitrile (20 g, 112 mmol) in DMF (93 mL). The mixture was stirred at 25 °C for 20 min. 1-Bromo-2-chloroethane (16.1 g, 112 mmol) was added, and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by adding a MeOH / water mixture (1:1, 1000 mL), and the resulting solution was extracted with EtOAc (3 × 500 mL). The organic solutions were combined, washed with water (4 × 500 mL) and brine (1 × 200 mL), and dried over Na₂SO₄. The solution was filtered, and the solvent was evaporated under reduced pressure. The solid obtained by column chromatography (SiO2, petroleum ether / EtOAc = 10 / 1 to 3 / 1) yielded 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxynitrile (15 g, 65%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H),6.82 (d, J= 1.2 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 1.68 - 1.65 (m, 2H), 1.35(d, J = 2.4 Hz, 2H).

[0256] Step 2: Synthesis of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxaldehyde A solution of 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxynitrile (11 g, 54.1 mmol) in THF (160 mL) was added to DIBAL-H (1 M in toluene, 81.2 mL). The mixture was stirred at 25 °C for 3 hours, and the reaction was carefully quenched by adding 2 M HCl aqueous solution. The solution was extracted with DCM (3 × 200 mL). The organic solutions were combined, washed with water (2 × 200 mL) and brine (2 × 200 mL), and dried over Na₂SO₄ to give 1-(3,4-dimethoxyphenyl)cyclopropane-1-carboxaldehyde (9.6 g, 85%) as a yellow oil. LC-MS (ESI+) m / z 207.0 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 6.94 - 6.61 (m, 3H), 3.89 (d, J = 2.8 Hz, 6H), 1.61 -1.52 (m, 2H), 1.42 - 1.37 (m, 2H) Step 3: ( Z )-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)- N Synthesis of methylmethyleneamine MeNH2 (2 M, 121 mL) and Na2SO4 (15.5 g, 109 mmol, 11.0 mL) were added to a solution of 1-(3,4-dimethoxyphenyl)-cyclopropaneformaldehyde (5.0 g, 24.2 mmol) in DCM (50 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a white solid ( Z )-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)- N 1,3-methylmethyleneamine (5.1 g, 99%). LC-MS (ESI) + ) m / z 219.9 (M+H) + ; 1 HNMR (400 MHz, CDCl3) δ 7.55 (q, J= 1.2 Hz, 1H), 6.93 - 6.77 (m, 3H), 3.88 (d, J = 7.2 Hz, 6H), 3.24 (d, J = 1.6 Hz, 3H), 1.29 - 1.23 (m, 2H), 1.18 - 1.12 (m, 2H).

[0257] Step 4: 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1 H Synthesis of pyrrole Towards( Z )-1-(1-(3,4-dimethoxyphenyl)cyclopropyl)- N 4-Methylmethyleneamine (5.4 g, 24.6 mmol) was dissolved in DMF (19 mL) with NaI (366 mg, 2.44 mmol) and TMSCl (267 mg, 2.46 mmol). The mixture was stirred at 90 °C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The organic solutions were combined, washed with water and brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a yellow oily substance: 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1-methyl-2,3-dihydro-1-methyl-2,3-dihydro-2,4-dimethyl ... H -Pyrrole (6.25 g, 80%). LC-MS (ESI) + ) m / z 220.0 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 6.90 - 6.66 (m, 3H), 6.31 (t, J =1.6 Hz, 1H), 3.95 - 3.80 (m, 6H), 3.18 - 3.11 (m, 2H), 2.79 (dt, J = 1.2, 9.0Hz, 2H), 2.65 (s, 3H).

[0258] Step 5: racemic -3a-(3,4-dimethoxyphenyl)-1-methyl-1,2,3,3a,7,7a-hexahydro-6 H -Indole- Synthesis of 6-keto(016) 4-(3,4-dimethoxyphenyl)-1-methyl-2,3-dihydro-1 H1-Pyrrole (6.25 g, 28.5 mmol) was dissolved in DCM (100 mL). HCl (1 M in dioxane, 25 mL, 100 mmol) was added to this solution. The mixture was evaporated to dryness and then dissolved in ACN (90 mL). (E)-4-methoxybut-3-en-2-one (4.28 g, 42.7 mmol) was added to this solution. The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The analysis was performed by HPLC (column: Phenomenex Luna C). 18 (250*70mm, 10 μm); Mobile phase: [water (NH4HCO3)-ACN]; B%: 22%-52%, 20 min) Purify the residue. Acidify the eluent with aqueous HCl to give O16 (3.0 g, 30%) as a white solid. LC-MS (ESI) + ) m / z 288.3 (M+H) + . 1 H NMR (400 MHz, CDCl3)δ 6.90 - 6.88 (m, 1H), 6.87 - 6.83 (m, 2H), 6.74 (dd, J = 2.0, 10.1 Hz, 1H), 6.11 (d, J = 10.0 Hz, 1H), 3.89 (d, J = 4.0 Hz, 6H), 3.33 (dt, J = 2.4, 8.8 Hz, 1H), 2.69 - 2.66 (m, 1H), 2.58 - 2.51 (m, 2H), 2.50 - 2.41 (m, 2H), 2.33 (s, 3H), 2.27 - 2.18 (m, 1H) Step 6: racemic -3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6 H Synthesis of -indole-6-one (022) The mixture of 016 (12.0 g, 43.9 mmol) and 10% Pd / C (300 mg) in EtOAc (120 mL) was degassed and then purged three times with H2. The mixture was stirred at 25 °C and 15 psi H2 for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give 022 (10 g, 80%) as a brown oil. LC-MS (ESI) + ) m / z 290.4 (M+H) + . 1HNMR (400 MHz, CDCl3) δ 6.99- 6.89 (m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J =7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, J = 3.6 Hz, 1H), 2.69 - 2.56 (m,2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0259] Example 2: racemic -3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-6 H SFC separation of -indole-6-one (022) yielded (-)-pinene (001) and (+)-pinene (002). Compound 022 (15 g, 90% purity) was subjected to separation by SFC (column: DAICEL CHIRALCEL OD (250 mm * 50 mm, 10 μm); mobile phase: [Neu-MeOH]; B%: 25%-25%, 2; 1230 min); yielding 001 (peak 1, 5.4 g, free base, 36%) and 002 (peak 2, 5.6 g, free base, 37%), both of which were yellow oily.

[0260] 001: LC-MS (ESI + ) m / z 290.4 (M+H) + 1 H NMR (400 MHz, CDCl3) δ 6.99 - 6.89(m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J = 7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, J = 3.6 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0261] 002: LC-MS (ESI + ) m / z 290.4 (M+H)+ 1 H NMR (400 MHz, CDCl3) δ 6.99 - 6.89(m, 2H), 6.89 - 6.84 (m, 1H), 3.91 (d, J = 7.6 Hz, 6H), 3.20 - 3.11 (m, 1H), 2.97 (t, J = 3.6 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.51 - 2.31 (m, 5H), 2.27 - 2.18 (m, 3H), 2.18 - 2.07 (m, 2H).

[0262] Example 3: (3a) S 7a S )-3a-(3,4-dimethoxyphenyl)-1,6-dimethyl-2,3,3a,4,5,7a-hexahydro-1 H Synthesis of indole Step 1: (3a) S 7a S )-3a-(3,4-dimethoxyphenyl)-1-methyl-6-methyleneoctahydro-1 H -Indole become At 0°C, methyl(triphenyl)phosphonium bromide (740 mg, 2.07 mmol) was added to a solution of methyl(triphenyl)phosphonium bromide in THF (6.0 mL) over 0.5 hours. t- BuOK (1M in THF, 2.07 mL). Add 1 mL of THF containing 001 (300 mg, 1.04 mmol) to the mixture. Stir the reaction mixture at 25 °C for 16 hours, then pour into water (50 mL). Extract the mixture with ethyl acetate (100 mL). Dry the organic solution over sodium sulfate, filter, and concentrate. Purify the crude product by reversed-phase HPLC (0.1% FA conditions) to give a yellow gelatinous substance (3a). S 7a S )-3a-(3,4-dimethoxyphenyl)-1-methyl-6-methyleneoctahydro-1 H -Indole (137.7 mg). LC-MS (ESI) + ) m / z 288.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 6.88 - 6.79 (m, 2H), 6.78 - 6.72 (m, 1H), 4.70 (s, 2H), 3.81 (d, J =6.0 Hz, 6H), 3.37 (ddd, J= 5.2, 8.4, 9.8 Hz, 1H), 2.90 (t, J = 4.0 Hz, 1H), 2.45(s, 2H), 2.42 - 2.35 (m, 4H), 2.16 - 2.08 (m, 1H), 1.98 (d, J = 3.6 Hz, 2H),1.96 - 1.86 (m, 3H).

[0263] The compounds in the table below were prepared using a similar procedure:

[0264] Step 2: (3a) S 7a S )-3a-(3,4-dimethoxyphenyl)-1-methyl-6-methyleneoctahydro-1 H -Indole become To (3a) S 7a S )-3a-(3,4-dimethoxyphenyl)-1-methyl-6-methyleneoctahydro-1 H - Indole (200 mg, 696 μmol) was added to a solution of dioxane (10 mL) with TfOH (209 mg, 1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The solution was then analyzed by preparative HPLC (column: Welch Ultimate C). 18 150*25mm*5um; Mobile phase: [water (TFA)-ACN]; Gradient: 6%-36% within 13 minutes. B) Purify the residue to obtain the residue. The residue was separated by SFC ("Column: Chiralcel OX-3 50x4.6mm ID, 3µm; Mobile phase: Phase A of CO2 and Phase B of IPA (0.05% DEA); Gradient elution: B in A from 5% to 40%; Flow rate: 3mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100Bar") to obtain 243(3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1,6-dimethyl-2,3,3a,4,5,7a-hexahydro-1H-indole (52 mg) as a yellow gel and 242(3aS,7aS)-3a-(3,4-dimethoxyphenyl)-1,6-dimethyl-2,3,3a,4,7,7a-hexahydro-1H-indole (7 mg) as a yellow gel." LC-MS (ESI) was used to separate the residue. + ) m / z 288.1 (M+H) + ; 1H NMR (400 MHz, CDCl3) δ 6.85 - 6.66 (m, 3H), 5.74 (s, 1H), 3.86 (d, J = 4.0 Hz, 6H), 3.25 - 3.12 (m, 1H), 2.62 (d, J = 2.4 Hz, 1H), 2.41 (s,3H), 2.32 - 2.17 (m, 1H), 2.16 - 1.99 (m, 3H), 1.81 - 1.69 (m, 5H), 1.49 (d, J = 13.6 Hz, 1H).

[0265] The compounds listed in the table below can be prepared using a similar method:

[0266] Example 4A - 1-Methyl-3a-(3,4,5-trimethoxyphenyl)-2,3,7,7a-tetrahydroindole-6-one (144) Step 1 1-(3,4,5-trimethoxyphenyl)cyclopropaneformonitrile (3) A mixture of 2-(3,4,5-trimethoxyphenyl)acetonitrile (10 g, 48.2 mmol) CAS#13338-63-1, 1,2-dibromoethane (10.8 g, 57.9 mmol, 4.37 mL) CAS#106-93-4, and LDA (2 M, 60.3 mL) in THF (200 mL) was degassed and purged three times with N2. The mixture was then stirred at -78 to 25 °C for 4 hours under N2 atmosphere. Upon completion, the mixture was quenched with saturated NH4Cl (80 mL) and extracted with ethyl acetate (220 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 30 / 1) to give the title compound (4.5 g, 38% yield) as a yellow solid.

[0267] LC-MS (ESI+) m / z 234.1 (M+H)+.

[0268] 1H NMR (400 MHz, chloroform- d) δ 6.53 (s, 2H), 3.92 - 3.80 (m, 9H), 1.73 -1.66 (m, 2H), 1.41 - 1.36 (m, 2H).

[0269] Step 2 1-(3,4,5-trimethoxyphenyl)cyclopropaneformaldehyde (4) A mixture of 1-(3,4,5-trimethoxyphenyl)cyclopropaneformonitrile (4.5 g, 19.3 mmol), DIBAL-H (1 M, 28.9 mL), and THF (50 mL) was degassed and purged three times with N2. The mixture was then stirred at -78 to 25 °C for 8 hours under N2 atmosphere. Upon completion, the reaction was carefully quenched by adding 2 M HCl, and the organic components were extracted into ethyl acetate (3 × 65 mL). The combined extracts were washed with water (2 × 20 mL) and brine (2 × 20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 5 / 1) to give the title compound (3.7 g, 79% yield) as a yellow solid.

[0270] LC-MS (ESI+) m / z 236.8 (M+H)+.

[0271] 1 H NMR (400 MHz, chloroform-) d ) δ 9.28 (s, 1H), 6.53 (s, 2H), 3.94 - 3.78 (m,9H), 1.60 - 1.54 (m, 3H), 1.44 - 1.37 (m, 2H).

[0272] Step 3 (E)-N-methyl-1-[1-(3,4,5-trimethoxyphenyl)cyclopropyl]methyleneamine (5) A mixture of 1-(3,4,5-trimethoxyphenyl)cyclopropaneformaldehyde (3.7 g, 15.6 mmol), Na₂SO₄ (33.4 g, 235 mmol, 23.8 mL), methylamine hydrochloride (5.29 g, 78.3 mmol), and Na₂CO₃ (6.64 g, 62.6 mmol) in DCM (250 mL) was degassed and purged three times with N₂. The mixture was then stirred at 25 °C for 24 hours under N₂ atmosphere. Upon completion, the reaction liquid was dried over a rotary evaporator after filtration. The crude compound was used in the next step without further purification to give the title compound (2.7 g, 90% yield) as a yellow solid.

[0273] LC-MS (ESI+) m / z 249.9 (M+H)+.

[0274] 1 H NMR (400 MHz, chloroform-) d ) δ 7.59 (d, J = 1.2 Hz, 1H), 6.56 (s, 2H), 3.97- 3.74 (m, 9H), 3.26 (d, J = 1.2 Hz, 3H), 1.31 - 1.26 (m, 2H), 1.19 - 1.14 (m, 2H).

[0275] Step 4 1-Methyl-4-(3,4,5-trimethoxyphenyl)-2,3-dihydropyrrole (6) A mixture of (E)-N-methyl-1-[1-(3,4,5-trimethoxyphenyl)cyclopropyl]methyleneamine (2 g, 8.0 mmol) and TMSI (1.61 g, 8.0 mmol, 1.09 mL) in DMF (15 mL) was degassed and purged three times with N2. The mixture was then stirred at 60 °C for 0.5 h under N2 atmosphere. Upon completion, the mixture was quenched with H2O (18 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The pH of the aqueous phase was then adjusted to 8 with saturated NaHCO3 (8 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The crude compound was used in the next step without further purification to give the title compound (1 g, 30% yield) as a yellow oil.

[0276] LC-MS (ESI+) m / z 250.0 (M+H)+.

[0277] 1 H NMR (400 MHz, chloroform-) d ) δ 8.03 (s, 1H), 6.47 - 6.40 (m, 2H), 6.37 (Brd, J = 1.2 Hz, 1H), 3.90 - 3.80 (m, 9H), 3.17 (Br t, J = 9.2 Hz, 2H), 2.67 (s, 2H).

[0278] Step 5 1-Methyl-3a-(3,4,5-trimethoxyphenyl)-2,3,7,7a-tetrahydroindole-6-one (144) A mixture of 1-methyl-4-(3,4,5-trimethoxyphenyl)-2,3-dihydropyrrole (1 g, 4.0 mmol), (E)-4-methoxybut-3-en-2-one (401 mg, 4.0 mmol, 402.79 μL), HCl / dioxane (4 M, 3 mL), and ACN (6.24 g, 152 mmol, 8 mL) in DCM (9 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 12 hours under N2 atmosphere. Upon completion, the reaction mixture was filtered. The sample was analyzed by preparative HPLC (basic conditions: column: Welch Ultimate C). 18 150*25mm*5um; mobile phase: [water(NH3H2O)-ACN]; B%: 18%-48%, 8min) The residue was purified to give the title compound as a white solid (570 mg, 45% yield).

[0279] LC-MS (ESI+) m / z 317.9 (M+H) + .

[0280] 1 H NMR (400 MHz, chloroform-) d ) δ 6.62 (dd, J = 2.0, 10.1 Hz, 1H), 6.45 (s,2H), 6.02 (d, J = 10.0 Hz, 1H), 3.84 - 3.69 (m, 9H), 3.29 - 3.17 (m, 1H), 2.58(br s, 1H), 2.50 - 2.43 (m, 2H), 2.42 - 2.32 (m, 2H), 2.23 (s, 3H), 2.12 (td, J = 8.4, 13.0 Hz, 1H).

[0281] Step 6: Compound 144 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0282] Step 7: The product from Step 6 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0283] Example 4B - Compounds 145, 188 and 189 Step 1: 1-Methyl-3a-(3,4,5-trimethoxyphenyl)-2,3,4,5,7,7a-hexahydroindole-6-one (145) A mixture of 1-methyl-3a-(3,4,5-trimethoxyphenyl)-2,3,7,7a-tetrahydroindole-6-one (190 mg, 598 µmol) and Pd / C (10.0 mg, 59.9 µmol, 10% purity) in EtOAc (4 mL) was degassed and purged three times with H2. The mixture was then stirred at 25 °C for 12 hours under H2 atmosphere. The reaction mixture was filtered. The filtrate was concentrated and analyzed by preparative HPLC (basic conditions: column: Welch Ultimate C). 18 150*25mm*5um; Mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 21%-51%, 2 min) Purification yielded 145 (232 mg, 90% yield) as a yellow solid. LC-MS (ESI+) m / z 320.2 (M+H)+. 1 H NMR (400 MHz, CDCl3) δ 6.60 (s, 2H), 3.95 - 3.81 (m, 9H), 3.18 - 3.11 (m, 1H), 2.95 (t, J = 3.2 Hz, 1H), 2.62 (d, J= 3.6 Hz, 2H), 2.52 -2.41 (m, 1H), 2.38 - 2.29 (m, 4H), 2.25 (s, 1H), 2.23 - 2.19 (m, 2H), 2.18 -2.10 (m, 2H).

[0284] Step 2 (3aS,7aS)-1-methyl-3a-(3,4,5-trimethoxyphenyl)-2,3,4,5,7,7a-hexahydroindole- 6-keto (188) and (3aR,7aR)-1-methyl-3a-(3,4,5-trimethoxyphenyl)-2,3,4,5,7,7a-hexahydroindole-6- Ketones (189) Racemic compound 145 was separated by SFC (conditions: column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: [Neu-MeOH]; B%: 25%-25%, C14.55; 146min) to give 188 (100 mg, 45% yield) as a white solid and 189 (95.0 mg, 43% yield) as a yellow solid.

[0285] 189:LC-MS (ESI+) m / z 320.1 (M+H)+. 1 H NMR (400 MHz, CDCl3) 6.59 (s,2H), 3.96 - 3.80 (m, 9H), 3.20 - 3.10 (m, 1H), 2.95 (Br s, 1H), 2.62 (Br d, J =3.2 Hz, 2H), 2.33 (s, 3H), 2.25 (s, 1H), 2.23 - 2.19 (m, 2H), 2.18 - 2.10 (m,2H), 1.58 (s, 2H).

[0286] 188:LC-MS (ESI+) m / z 320.3 (M+H)+. 1 H NMR (400 MHz, CDCl3) δ 6.59 (s,2H), 3.96 - 3.80 (m, 9H), 3.16 (t, J = 6.8 Hz, 1H), 2.96 (s, 1H), 2.63 (s, 2H), 2.34 (s, 3H), 2.24 (s, 1H), 2.23 - 2.19 (m, 2H), 2.18 - 2.09 (m, 2H), 1.57(s, 2H).

[0287] Step 3: Compounds 188 and / or 189 were added to a solution of methyl (triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0°C. 1 mL of THF containing 1.04 mmol of O16 was added to the mixture. The reaction mixture was stirred at 25°C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0288] Step 4: The product from Step 3 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0289] Example 5A - (3aR,7aS)-3a-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3,7,7a-tetrahydroindole-6-one (133) Step 1 - (3-fluoro-4,5-dimethoxy-phenyl)methanol At 0 °C, a mixture of 3-fluoro-4,5-dimethoxy-benzaldehyde (4.20 g, 22.81 mmol, CAS: 71924-61-3) in EtOH (60 mL) was added to NaBH4 (949 mg, 25.1 mmol), and the mixture was stirred at 25 °C for 3 hours. Upon completion, the mixture was poured into ammonium chloride (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give (3-fluoro-4,5-dimethoxy-phenyl)methanol (4.00 g, 89.50% yield, 95% purity) as a yellow oil.

[0290] 1 H NMR (400 MHz, CDCl3) δ = 6.80 - 6.56 (m, 2H), 4.55 (s, 2H), 3.90 -3.77 (m, 6H).

[0291] Step 2 --(chloromethyl)-1-fluoro-2,3-dimethoxy-benzene At 0 °C, SOCl2 (6.39 g, 53.7 mmol) was added to a mixture of (3-fluoro-4,5-dimethoxy-phenyl)methanol (4.00 g, 21.5 mmol) in DCM (40 mL), and the mixture was stirred at 25 °C for 3 hours. Upon completion, the mixture was poured into sodium bicarbonate (10 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give 5-(chloromethyl)-1-fluoro-2,3-dimethoxy-benzene (4.00 g, 91% yield) as a yellow oil.

[0292] 1 H NMR (400 MHz, CDCl3) δ = 6.88 - 6.56 (m, 2H), 4.44 (s, 2H), 3.91 -3.80 (m, 6H).

[0293] Step 3 - 2-(3-fluoro-4,5-dimethoxy-phenyl)acetonitrile To a mixture of 5-(chloromethyl)-1-fluoro-2,3-dimethoxy-benzene (4.00 g, 19.6 mmol) in DMSO (40 mL), NaCN (1.92 g, 39.1 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. Upon completion, the mixture was poured into a saturated sodium bicarbonate solution (40 mL) to adjust the pH to >7 and extracted with ethyl acetate (100 mL x 3), followed by washing the organic layer with brine (50 mL). The organic layer was dried over sodium sulfate, and the residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 2-(3-fluoro-4,5-dimethoxy-phenyl)acetonitrile (3.6 g, 90% yield) as a yellow oil.

[0294] 1 H NMR (400 MHz, CDCl3) δ = 6.80 - 6.50 (m, 2H), 3.90 - 3.75 (m, 6H), 3.62 (s, 2H).

[0295] Step 4 - 1-(3-bromo-4,5-dimethoxy-phenyl)cyclopropaneformonitrile LDA (2 M, 23.0 mL) was added to a mixture of 2-(3-fluoro-4,5-dimethoxy-phenyl)acetonitrile (3.60 g, 18.4 mmol) in THF (36 mL), followed by the addition of 1,2-dibromoethane (4.16 g, 22.1 mmol, 1.67 mL). The mixture was stirred at 25 °C for 2 hours. Upon completion, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropaneformitrile (3.70 g, 14.38 mmol, 78% yield) as a yellow oil.

[0296] 1 H NMR (400 MHz, CDCl3) δ = 6.67 (t, J = 1.8 Hz, 1H), 6.49 (dd, J = 2.2,12.0 Hz, 1H), 3.99 - 3.74 (m, 6H), 1.72 - 1.60 (m, 2H), 1.34 - 1.25 (m, 2H).

[0297] Step 5: 1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropaneformaldehyde A mixture of 1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropaneformitrile (3.70 g, 16.7 mmol), DIBALH (1 M, 25.1 mL), and THF (37 mL) was degassed and purged three times with N2. The mixture was then stirred at 25 °C for 16 hours under N2 atmosphere. Upon completion, the mixture was poured into HCl (2 M, 50 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give 1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropaneformaldehyde (3.70 g, 13.2 mmol, 79% yield) as a brown oil.

[0298] 1H NMR (400 MHz, CDCl3) δ = 9.11 (s, 1H), 7.15 - - 6.52 (m, 2H), 4.07- 3.60 (m, 6H), 1.61 - 1.40 (m, 2H), 1.37 - 1.23 (m, 2H).

[0299] Step 6 - (E)-1-[1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropyl]-N-methyl-methyleneamine A mixture of 1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropaneformaldehyde (3.70 g, 16.5 mmol), methylamine hydrochloride (5.57 g, 82.5 mmol), Na₂CO₃ (5.25 g, 49.5 mmol), and Na₂SO₄ (35.10 g, 247 mmol, 25.1 mL) in DCM (40 mL) was degassed and purged three times with N₂. The mixture was then stirred at 25 °C for 16 hours under N₂ atmosphere. Upon completion, the reaction mixture was filtered and concentrated under vacuum to give (E)-1-[1-(3-bromo-4,5-dimethoxy-phenyl)cyclopropyl]-N-methyl-methyleneamine (4.45 g, 86% yield) as a yellow liquid.

[0300] 1 H NMR (400 MHz, CDCl3) δ = 7.61 - 7.47 (m, 1H), 6.71 (d, J = 1.9 Hz, 2H), 3.91 - 3.86 (m, 6H), 3.25 (d, J = 1.5 Hz, 3H), 1.36 - 1.22 (m, 2H), 1.20 -1.11 (m, 2H).

[0301] Step 7 - 4-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3-dihydropyrrole A mixture of (E)-1-[1-(3-fluoro-4,5-dimethoxy-phenyl)cyclopropyl]-N-methyl-methyleneamine (1.00 g, 4.21 mmol), NaI (63.1 mg, 421 µmol), and TMSI (843 mg, 4.21 mmol) in DMF (5 mL) was degassed and purged three times with N2. The mixture was then stirred at 60 °C for 0.5 h under N2 atmosphere. Upon completion, the reaction mixture was filtered and concentrated under vacuum to give 4-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3-dihydropyrrole (1.00 g, crude product) as a brown oil. LC-MS (ESI) + ) m / z 238.8 (M+H).

[0302] Step 8 - (3aR,7aS)-3a-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3,7,7a-tetrahydroindene Indo-6-one At 25 °C, HCl / dioxane (4 M, 10.0 mL) was added to a solution of 4-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3-dihydropyrrole (1.00 g, 1.14 mmol, 27% purity) in DCM (1 mL) for 10 minutes. After the addition, the mixture was concentrated under vacuum to obtain a residue, and then (E)-4-methoxybut-3-en-2-one (227 mg, 2.28 mmol, 228 µL) in ACN (10 mL) was added to the residue. The mixture was stirred at 80 °C for 16 hours. Upon completion, the reaction mixture was filtered and concentrated under vacuum to obtain a residue. The residue was purified by reverse-phase (0.1% FA) to give a crude product. The crude product was purified by preparative HPLC (column: Waters xbridge 150*25mm 10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 9 min) to obtain (3aR,7aS)-3a-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3,7,7a-tetrahydroindole-6-one (9.94 mg, 2.83% yield) as a yellow solid.

[0303] LC-MS (ESI + ) m / z 306.1(M+H) + .

[0304] 1 H NMR (400 MHz, CDCl3) δ = 6.67 (dd, J = 2.2, 12.8 Hz, 1H), 6.63 - 6.59(m, 1H), 6.58 (d, J = 1.6 Hz, 1H), 6.05 (d, J = 10.4 Hz, 1H), 3.86 (s, 3H), 3.81(s, 3H), 3.24 (dt, J = 2.4, 8.8 Hz, 1H), 2.61 - 2.56 (m, 1H), 2.56 - 2.47 (m,1H), 2.46 - 2.40 (m, 2H), 2.38 - 2.30 (m, 1H), 2.25 (s, 3H), 2.19 - 2.08 (m,1H).

[0305] Step 9: Compound 133 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0306] Step 10: The product from Step 9 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0307] Example 5B - Compounds 134, 194, 195 Step 1 - 3a-(3-fluoro-4,5-dimethoxy-phenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindole-6-one (134) The mixture of 133 (70.00 mg, 229 µmol), Pd / C (10 mg, 10% purity) in ethyl acetate (2 mL) was degassed and purged three times with N2. The mixture was then stirred at 25 °C for 1 hour under H2 atmosphere. The reaction mixture was filtered, concentrated under vacuum, and analyzed by preparative HPLC (column: Welch Xtimate C). 18 150*25mm*5um; mobile phase: [water (NH3H2O)-ACN]; B%: 30%-60%, 8min) purification, yielding 134 as a white solid (20 mg, 61.8 µmol, 26% yield, 95% purity). LC-MS (ESI) + ) m / z 308.2 (M+H) + 1 H NMR (400 MHz, CDCl3) δ = 6.83 – 6.67(m, 1H), 6.62 (s, 1H) 4.07 – 3.69 (m, 6H), 3.15 – 2.95 (m, 1H), 2.91 – 2.80(m, 1H), 2.52 (d, J= 2.8 Hz, 2H), 2.45 - 2.33 (m, 1H), 2.31 - 2.21 (m, 4H), 2.18 - 1.93 (m, 5H).

[0308] Step 2 - (3aS,7aS)-3a-(3-fluoro-4,5-dimethoxy-phenyl)-1,7a-dimethyl-3,4,5,7-tetracycline Hydrogen-2H-indol-6-one (194) and (3aR,7aR)-3a-(3-fluoro-4,5-dimethoxy-phenyl)-1,7a-dimethyl-3,4, 5,7-Tetrahydro-2H-indol-6-one (195) Racemic 134 was purified by SFC (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: [0.1% NH3H2OMEOH]; B%: 20%-20%, C12.05; 109 min) to give 194 (4.09 mg, 18% yield, 97% purity) and 195 (4.92 mg, 22% yield, 94% purity) as white solids.

[0309] 194:LC-MS (ESI + ) m / z 308.2 (M+H) + 1 H NMR (400 MHz, CDCl3) δ = 6.77 (br d,J = 12.8 Hz, 1H), 6.70 (s, 1H), 3.92 (br d, J = 13.6 Hz, 6H), 3.14 (t, J =6.4 Hz, 1H), 2.90 (s, 1H), 2.70 - 2.53 (m, 2H), 2.52 - 2.40 (m, 1H), 2.38 -2.27 (m, 4H), 2.26 - 2.13 (m, 3H), 2.13 - 2.06 (m, 2H) 195:LC-MS (ESI + ) m / z 308.2 (M+H); 1 H NMR (400 MHz, CDCl3) δ = 6.77 (br d,J = 12.8 Hz, 1H), 6.70 (s, 1H), 3.92 (br d, J = 13.6 Hz, 6H), 3.14 (t, J =6.4 Hz, 1H), 2.90 (s, 1H), 2.70 - 2.53 (m, 2H), 2.52 - 2.40 (m, 1H), 2.38 -2.27 (m, 4H), 2.26 - 2.13 (m, 3H), 2.13 - 2.06 (m, 2H).

[0310] Step 3: Compound 194 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0311] Step 4: The product from Step 3 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0312] Example 6A: Synthesis of 149 and 150 Step 1: 1-(2,2-difluorobenzo[ d Synthesis of [1,3]dioxacyclopenten-5-yl)cyclopropane-1-carboxynitrile LiHMDS (1 M, 177.5 mL) was added to a solution of 1,2-dibromoethane (19.0 g, 101 mmol, 7.7 mL) in THF (300 mL). The mixture was stirred at -20 °C for 30 min, and then 2-(2,2-difluoro-1,3-benzodioxane-5-yl)acetonitrile (10 g, 50.7 mmol) was added. The reaction mixture was stirred and heated from -20 °C to 25 °C over 2 hours. The reaction mixture was quenched by pouring into a cold, saturated aqueous solution of NH4Cl (300 mL). The aqueous solution was extracted with ethyl acetate (300 mL × 2). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 10 / 1) to give a yellow oily 1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)cyclopropane-1-carboxynitrile (7.5 g, 50%). 1H NMR (400 MHz, CDCl3)δ 7.09 - 6.91 (m, 3H), 1.70 - 1.65 (m, 2H), 1.35 - 1.26 (m, 2H).

[0313] Step 2: 1-(2,2-difluorobenzo[ d Synthesis of [1,3]dioxacyclopenten-5-yl)cyclopropane-1-carboxaldehyde To 1-(2,2-difluorobenzo[ d A solution of [1,3]dioxacyclopenten-5-yl)cyclopropane-1-carboxynitrile (7.5 g, 33.6 mmol) in toluene (70 mL) was added to DIBAL-H (1 M, 40.3 mL). The mixture was stirred at 0–25 °C for 8 hours. The reaction mixture was quenched by pouring into a cold, saturated 2N HCl aqueous solution (50 mL). The aqueous solution was extracted with ethyl acetate (50 mL × 2). The organic solutions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 10 / 1) to give a yellow oily 1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)cyclopropane-1-carboxaldehyde (6.2 g, 85%). 1 H NMR (400 MHz, CDCl3) δ9.33 (s, 1H), 7.64 - 7.38 (m, 1H), 7.35 - 7.27 (m, 1H), 7.24 (d, J = 1.6 Hz,1H), 1.88 - 1.81 (m, 2H), 1.69 - 1.62 (m, 2H).

[0314] Step 3: ( E )-1-(1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)cyclopropyl)- N -methyl Synthesis of Methyleneamine To 1-(2,2-difluorobenzo[ d A solution of [1,3]dioxacyclopenten-5-yl)cyclopropane-1-carboxaldehyde (6.2 g, 27.4 mmol) in DCM (150 mL) was mixed with methylamine (2 M, 137 mL) and Na₂SO₄ (17.5 g, 123 mmol, 12.5 mL). The mixture was stirred at 25 °C for 10 hours. The reaction mixture was quenched by adding a cold, saturated aqueous solution of H₂O (150 mL). The aqueous solution was extracted with ethyl acetate (150 mL × 2). The organic solutions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a yellow oil. E )-1-(1-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)cyclopropyl)-N -Methylmethyleneamine (6.7 g). 1 H NMR (400 MHz, CDCl3) δ 9.02 (s,1H), 6.99 - 6.86 (m, 3H), 3.16 (d, J = 1.2 Hz, 3H), 1.23 - 1.16 (m, 2H), 1.12 -1.05 (m, 2H).

[0315] Step 4: 4-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)-1-methyl-2,3-dihydro-1 H -pyr Synthesis of lye Will( E )-1-(1-(2,2-difluorobenzo[ d [1,3]dioxacyclopentadien-5-yl)cyclopropyl)- N A mixture of 4-methylmethyleneamine (500 mg, 2.09 mmol) and TMSI (418 mg, 2.09 mmol, 284 µL) in DMF (4 mL) was degassed and purged three times with N2. The reaction mixture was then stirred at 60 °C for 1 hour under N2 atmosphere. The reaction mixture was quenched by adding water (10 mL). The aqueous solution was extracted with ethyl acetate (10 mL × 2). The organic solutions were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-(2,2-difluorobenzo[]] as a yellow oil. d [1,3]dioxacyclopentadien-5-yl)-1-methyl-2,3-dihydro-1 H -Pyrrole (1.5 g, 60%). 1 H NMR (400 MHz, CDCl3)δ 6.95 - 6.89 (m, 2H), 6.85 - 6.80 (m, 1H), 6.36 (s, 1H), 2.68 (s, 3H).

[0316] Step 5: Synthesis of 149 4-(2,2-difluorobenzo[ d [1,3]dioxacyclopenten-5-yl)-1-methyl-2,3-dihydro-1 H -pyrrole (1.2 g, 5.02 mmol), ( EThe mixture of 4-methoxybut-3-en-2-one (753 mg, 7.52 mmol, 755 μL), HCl / dioxane (4 M, 123 mL), DCM (5 mL), and ACN (5 mL) was degassed and purged three times with N2. The reaction mixture was then stirred at 90 °C for 8 hours under N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The analysis was performed by preparative HPLC (column: Welch Xtimate C). 18 150*25mm*5um; mobile phase: [water (HCl)-ACN]; B%: 7%-37%, 8min) Purification of the residue yielded 149 (1 g, 46%) as a white solid. LC-MS (ESI) + ) m / z 308.0 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ 10.69 - 10.47 (m, 1H), 7.72 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 1.6, 8.5 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.27 (d, J = 10.4 Hz,1H), 4.06 (s, 1H), 3.57 (dd, J = 7.6, 11.2 Hz, 1H), 3.46 - 3.39 (m, 1H), 2.96(d, J = 4.4 Hz, 3H), 2.84 - 2.71 (m, 2H), 2.49 - 2.41 (m, 2H).

[0317] Step 5B: Compound 149 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0318] Step 5C: The product from Step 5B was added to a solution of 696 mol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0319] Step 6: Synthesis of 150 Add Pd / C (15 mg, 455 µmol, 10% purity) to a solution of 149 (140 mg, 455 mol) in EtOAc (3 mL). Stir the reaction mixture at 25 °C for 2 hours under H2 atmosphere. Filter the reaction mixture and concentrate the filtrate under reduced pressure. Analyze the solution by preparative HPLC (column: Welch Xtimate C). 18 150*25mm*5um; Mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 39%-69%, 2 min) Purify the residue to give 150 (80 mg, 54%) of a white oil. LC-MS (ESI+) m / z 303.1 (M+H)+. 1 H NMR (400 MHz, CDCl3) δ 7.15 - 7.08 (m, 2H),7.06 - 7.02 (m, 1H), 3.19 (d, J = 2.4 Hz, 1H), 2.96 (s, 1H), 2.61 (d, J = 2.4 Hz,2H), 2.52 - 2.42 (m, 1H), 2.35 (s, 3H), 2.30 - 2.22 (m, 1H), 2.20 - 2.09 (m,4H), 1.71 - 1.41 (m, 1H).

[0320] Example 6B: Preparative HPLC separation of 150 yielded 232 and 233. The enantiomers of 150 were separated by preparative HPLC (column: DAICL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [Neu-MeOH]; B%: 25%-25%, C6.0; 54 min) to obtain 232 (34 mg, 42%) as a yellow oil and 233 (35 mg, 53%) as a white oil.

[0321] 232:LC-MS (ESI + ) m / z 310.1 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 7.18 - 7.08(m, 2H), 7.07 - 7.02 (m, 1H), 3.23 - 3.11 (m, 1H), 2.93 (s, 1H), 2.67 - 2.54(m, 2H), 2.53 - 2.42 (m, 1H), 2.40 - 2.29 (m, 4H), 2.26 - 2.22 (m, 1H), 2.21 - 2.16 (m, 1H), 2.16 - 2.07 (m, 3H).

[0322] 233: LC-MS (ESI + ) m / z 310.1 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 7.15 - 7.08(m, 2H), 7.06 - 7.02 (m, 1H), 3.21 - 3.11 (m, 1H), 2.93 (t, J = 3.2 Hz, 1H), 2.60 (dd, J = 3.6, 6.1 Hz, 2H), 2.52 - 2.43 (m, 1H), 2.39 - 2.29 (m, 4H), 2.28- 2.22 (m, 1H), 2.21 - 2.16 (m, 1H), 2.16 - 2.06 (m, 3H).

[0323] Step 7: Compound 232 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0324] Step 8: The product from Step 7 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0325] Example 7: Synthesis of 340, 341, and 342 Step 1 - 2-[4-(difluoromethoxy)-3-methoxy-phenyl]acetonitrile At -70°C, 1-(isocyanomethylsulfonyl)-4-methylbenzene (38.6 g, 197 mmol) in THF (600 mL) was added to a solution of t-BuOK (1 M in THF, 395 mL). The mixture was stirred for 1 hour and treated dropwise with a solution of 4-(difluoromethoxy)-3-methoxybenzaldehyde (25 g, 123 mmol) in THF (100 mL), with stirring continued at 60°C for 2 hours. The mixture was cooled, and then MeOH (500 mL) was added. The reaction mixture was then stirred at 60°C for 2 hours. The reaction mixture was concentrated under vacuum. The mixture was poured into water (500 mL) and extracted with ethyl acetate (1500 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5:1) to give 2-[4-(difluoromethoxy)-3-methoxy-phenyl]acetonitrile (21 g, 38% yield), which was a yellow oil.

[0326] 1 H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 2.0, 8.2 Hz, 1H), 6.47 (t, J = 74.8 Hz, 1H), 3.83 (s, 3H), 3.67 (s, 2H).

[0327] Step 2 - 1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropaneformonitrile A mixture of 2-[4-(difluoromethoxy)-3-methoxy-phenyl]acetonitrile (8.0 g, 37.5 mmol), 1-bromo-2-chloroethane (5.38 g, 37.5 mmol, 3.11 mL), and tetraoctylammonium bromide (4.10 g, 7.5 mmol) in KOH (17.8 M, 10.5 mL) was degassed and purged three times with N2. The mixture was then stirred at 70 °C for 16 hours under N2 atmosphere. The mixture was poured into water (200 mL) and extracted with ethyl acetate (500 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to give 1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropaneformitrile (12.7 g, 67% yield) as a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ 7.17 - 7.11 (m, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.78 (dd, J = 2.0, 8.4 Hz, 1H), 6.55 (t, J = 75.2 Hz, 1H), 3.93 (s, 3H), 1.80 - 1.71 (m, 2H), 1.46 - 1.36 (m, 2H).

[0328] Step 3 - 1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropaneformaldehyde DIBAL-H (1 M, 125 mL) was added over 30 minutes to a solution of 1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropaneformitrile (20 g, 83.6 mmol) in THF (200 mL) at 0 °C and under a N2 atmosphere. The mixture was stirred at 25 °C for 16 hours under a N2 atmosphere. The reaction mixture was poured into a dilute hydrochloric acid solution (2 M, 300 mL) and extracted with ethyl acetate (600 mL). The organic solutions were combined and concentrated under vacuum to give 1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropane-formaldehyde (20 g, 93% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 9.11(s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.47(t, J= 75.2 Hz, 1H), 3.82 (s, 3H), 1.54 - 1.49 (m, 2H), 1.38 - 1.30 (m, 2H).

[0329] Step 4 - (E)-1-[1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropyl]-N-methyl-methyleneamine A mixture of 1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropaneformaldehyde (20 g, 82.5 mmol), Na₂CO₃ (26.2 g, 247 mmol), Na₂SO₄ (117 g, 825 mmol), and methylamine hydrochloride (27.8 g, 412 mmol) in DCM (200 mL) was degassed and purged three times with N₂. The mixture was then stirred at 25 °C for 16 hours under N₂ atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give (E)-1-[1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropyl]-N-methyl-methyleneamine (20 g, 90% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 2.0, 8.0 Hz, 1H), 6.45 (t, J = 75.2 Hz, 1H), 3.80 (s, 3H), 3.17 (d, J = 1.6 Hz, 3H), 1.23 - 1.16 (m, 2H), 1.12 - 1.06 (m, 2H).

[0330] Step 5 - 4-[4-(difluoromethoxy)-3-methoxy-phenyl]-1-methyl-2,3-dihydropyrrole TMSI (1.57 g, 7.84 mmol) and NaI (117 mg, 783 μmol) were added to a solution of (E)-1-[1-[4-(difluoromethoxy)-3-methoxy-phenyl]cyclopropyl]-N-methyl-methyleneamine (2 g, 7.84 mmol) in DMF (20 mL). The reaction mixture was stirred at 60 °C for 30 min. The mixture was poured into water (250 mL) and extracted with ethyl acetate (600 mL). A saturated sodium bicarbonate solution was added to the aqueous phase to adjust the pH to >7, and the solution was extracted with ethyl acetate (300 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give 4-[4-(difluoromethoxy)-3-methoxy-phenyl]-1-methyl-2,3-dihydropyrrole (7 g, 33% yield) as a yellow oil. LC-MS (ESI) + ) m / z 256.1 (M+H) + Step 6 - 3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-1-methyl-2,3,4,5,7,7a-hexahydroindene Indo-6-one (340) HCl / dioxane (4 M, 13.6 mL) was added to a solution of 4-[4-(difluoromethoxy)-3-methoxy-phenyl]-1-methyl-2,3-dihydropyrrole (7 g, 15.6 mmol) in DCM (60 mL). The reaction mixture was stirred at 20 °C for 30 min. The reaction mixture was concentrated under vacuum. The residue was redissolved in ACN (60 mL), and trimethyl(1-methyleneallyloxy)silane (3.34 g, 23.4 mmol, 4.07 mL) was added to this solution. The mixture was stirred at 80 °C for 16 h. The mixture was poured into 4 M NaOH solution (100 mL) and extracted with ethyl acetate (250 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to give 340 (4 g, 76% yield) as a yellow oil. LC-MS (ESI) + ) m / z 326.3 (M+H) + ; 1 H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.0 Hz, 1H), 6.93 - 6.85 (m, 2H), 6.48 (t, J=75.2 Hz, 1H), 3.83 (s, 3H), 3.12 - 3.03 (m, 1H), 2.88 (t, J = 3.2 Hz, 1H), 2.54(d, J = 3.2 Hz, 2H), 2.45 - 2.34 (m, 1H), 2.32 - 2.22 (m, 4H), 2.22 - 2.13 (m,2H), 2.13 - 2.09 (m, 1H), 2.09 - 2.00 (m, 2H).

[0331] Step 7 - (3aS,7aS)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-1-methyl-2,3,4,5,7, 7a-hexahydroindol-6-one (341) and (3aR,7aR)-3a-[4-(difluoromethoxy)-3-methoxy-phenyl]-1-methyl-2, 3,4,5,7,7a-hexahydroindol-6-one (342) Racemic 340 was separated by SFC (column: Daicel ChiralPak IG (250*30mm, 10um); mobile phase: [CO2-MeOH]; B%: 20%, isocratic elution mode) to obtain 341 (1.62 g, 39% yield) and 342 (1.16 g, 28% yield) as yellow gels.

[0332] 341 (Retention time: 0.906 min): LC-MS (ESI) + ) m / z 326.0 (M+H) + ; 1 H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.0 Hz, 1H), 7.04 - 6.90 (m, 2H), 6.80 - 6.32 (m, 1H), 3.92 (d, J = 3.2 Hz, 3H), 3.18 (s, 1H), 2.98 (s, 1H), 2.64 (d, J = 2.4 Hz, 2H), 2.47 (dd, J = 3.6, 12.4 Hz, 1H), 2.35 (s, 4H), 2.30 - 2.18 (m, 3H), 2.17 - 2.08 (m, 2H).

[0333] 342 (Retention time: 1.241 min): LC-MS (ESI) + ) m / z 326.0 (M+H) + ;1 H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.0 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.81 - 6.34 (m, 1H), 3.92 (s, 3H), 3.17 (d, J = 6.0 Hz, 1H), 2.99 (s, 1H), 2.64 (s, 2H), 2.54 - 2.43(m, 1H), 2.42 - 2.31 (m, 4H), 2.30 - 2.21 (m, 2H), 2.20 - 2.07 (m, 3H).

[0334] Step 8: Compound 341 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0335] Step 9: The product from Step 8 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0336] Example 8: Synthesis of compounds 230 and 231 Step 1 - (3-iodo-4,5-dimethoxy-phenyl)methanol At 0 °C, NaBH4 (1.30 g, 34.2 mmol) was added in portions to 10 g of EtOH (100 mL) solution of 10 g of 3-iodo-4,5-dimethoxy-phenylaldehyde. The mixture was stirred at 25 °C for 1.5 h. The mixture was poured into a saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (100 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give (3-iodo-4,5-dimethoxy-phenyl)methanol (10 g, 89% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 6.83 (s, 1H), 4.52 (s, 2H), 3.76 (d, J =17.6 Hz, 7H).

[0337] Step 2 - 5-(chloromethyl)-1-iodine-2,3-dimethoxy-benzene SOCl2 (16.4 g, 137 mmol, 10 mL) was added to a solution of (3-iodo-4,5-dimethoxy-phenyl)methanol (10 g, 34.0 mmol) in DCM (100 mL). The mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under vacuum, and a saturated sodium bicarbonate solution was added to adjust the pH to >7. The solution was extracted with ethyl acetate (600 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give 5-(chloromethyl)-1-iodo-2,3-dimethoxy-benzene (10 g, 84% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 4.42 (s, 2H), 3.78 (d, J = 17.1 Hz, 6H).

[0338] Step 3 - 2-(3-iodo-4,5-dimethoxy-phenyl)acetonitrile NaCN (3.14 g, 63.9 mmol) was added to a solution of 5-(chloromethyl)-1-iodo-2,3-dimethoxy-phenyl (10 g, 32.0 mmol) in DMSO (100 mL). The mixture was stirred at 25 °C for 16 hours. A saturated sodium bicarbonate solution was added to the mixture to adjust the pH to >7. The solution was extracted with ethyl acetate (1000 mL). The organic solutions were combined, washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give 2-(3-iodo-4,5-dimethoxy-phenyl)acetonitrile as a yellow solid (9.0 g, 88% yield). 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 3.60 (s, 2H).

[0339] Step 4 - 1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropaneformonitrile At 0 °C, LDA (2 M, 37.1 mL) was added to a solution of 2-(3-iodo-4,5-dimethoxy-phenyl)acetonitrile (9 g, 29.6 mmol, 1 equivalent) in THF (90 mL). Next, 1,2-dibromoethane (6.69 g, 35.6 mmol, 2.69 mL) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was poured into a saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (450 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 5) to give 1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropaneformitrile (5.8 g, 53% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.90 - 3.68 (m, 6H), 1.63 (d, J = 2.4 Hz, 2H), 1.30 (d, J = 2.4 Hz, 2H).

[0340] Step 5 - 1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropaneformaldehyde DIBAL-H (1 M, 26.4 mL) was added to a solution of 1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropaneformitrile (5.8 g, 17.6 mmol) in THF (60 mL). The mixture was stirred at 0 °C for 16 hours. Upon completion, the mixture was poured into dilute hydrochloric acid (2 M, 20 mL) and extracted with ethyl acetate (60 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give 1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropaneformaldehyde (5.8 g, 94% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.22 - 7.18 (m, 1H), 6.76 (d, J = 2.0 Hz, 1H), 3.78 (d, J = 10.4 Hz, 6H), 1.48 (d, J = 2.8 Hz, 2H), 1.34 - 1.28(m, 2H) Step 6 - (E)-1-[1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropyl]-N-methyl-methyleneamine A solution of 1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropaneformaldehyde (5.8 g, 17.4 mmol) in DCM (60 mL) was added with methylamine hydrochloride (5.90 g, 87.3 mmol), Na₂CO₃ (5.55 g, 52.3 mmol), and Na₂SO₄ (37.2 g, 261 mmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered and concentrated under vacuum to give (E)-1-[1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropyl]-N-methyl-methyleneamine (5.5 g, 85% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 2.0Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 3.76 (d, J = 13.6 Hz, 6H), 3.17 (d, J= 1.6 Hz, 3H), 1.21 - 1.16 (m, 2H), 1.09 - 1.02 (m, 2H).

[0341] Step 7 - 4-(3-iodo-4,5-dimethoxy-phenyl)-1-methyl-2,3-dihydropyrrole A mixture of (E)-1-[1-(3-iodo-4,5-dimethoxy-phenyl)cyclopropyl]-N-methyl-methyleneamine (1 g, 2.90 mmol) and TMSI (579 mg, 2.90 mmol, 394 μL) in DMF (10 mL) was degassed and purged three times with N2. The mixture was then stirred at 60 °C for 0.5 h under N2 atmosphere. The mixture was poured into water (15 mL) and extracted with ethyl acetate (100 mL). A saturated sodium bicarbonate solution was added to the aqueous solution to adjust the pH to >7, and the solution was further extracted with ethyl acetate (200 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give 4-(3-iodo-4,5-dimethoxy-phenyl)-1-methyl-2,3-dihydropyrrole (500 mg, 40% yield) as a yellow oil. LC-MS (ESI) + ) m / z 345.9 (M+H) + ; 1 H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 1.6 Hz, 1H), 6.64 (d, J = 1.6 Hz, 1H), 6.30 (s, 1H), 3.77 (s, 3H), 3.72 (s, 3H), 3.10 (t, J =9.2 Hz, 2H), 2.67 (t, J = 9.2 Hz, 2H), 2.59 (s, 3H).

[0342] Step 8 - (3aR,7aS)-3a-(3-iodo-4,5-dimethoxy-phenyl)-1-methyl-2,3,7,7a-tetrahydroindene Indo-6-one (132) At 25 °C, HCl / dioxane (4 M, 234 μL) was added over 10 minutes to a solution of 4-(3-iodo-4,5-dimethoxy-phenyl)-1-methyl-2,3-dihydropyrrole (400 mg, 938 µmol) in DCM (4.0 mL). After addition, the mixture was filtered and concentrated under vacuum. Then, ACN (4.0 mL) containing (E)-4-methoxybut-3-en-2-one (112 mg, 1.13 mmol, 113 μL) was added to the residue. The mixture was stirred at 60 °C for 2 hours. The reaction mixture was quenched by adding the reaction mixture to a cold, saturated aqueous solution of sodium hydroxide (30 mL) until pH = 8. The aqueous solution was extracted with ethyl acetate (100 mL). The organic solutions were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The solution was analyzed by preparative HPLC (FA conditions: column: Phenomenex luna C). 18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 9%-39%, 10min) The residue was purified to give 132 (80 mg, 19% yield) as a yellow gel. LC-MS (ESI) + ) m / z 413.9 (M+H) + ; 1 H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0Hz, 1H), 6.71 (dd, J = 1.6, 10.0 Hz, 1H), 6.18 (d, J = 10.4 Hz, 1H), 3.87 (d, J =11.2 Hz, 6H), 3.38 (dt, J = 3.2, 9.2 Hz, 1H), 2.85 (s, 1H), 2.71 - 2.60 (m,2H), 2.55 (d, J = 4.0 Hz, 1H), 2.50 (dd, J = 3.6, 11.1 Hz, 1H), 2.40 (s, 3H), 2.32 - 2.19 (m, 1H).

[0343] Step 9 - (3aR,7aS)-3a-(3-cyclopropyl-4,5-dimethoxy-phenyl)-1-methyl-2,3,7,7a-tetra ... Hydroindole-6-one (142) To a solution of 132 (150 mg, 363 µmol) and cyclopropylboronic acid (155 mg, 1.81 mmol) in toluene (3.0 mL) and water (1.0 mL), Na2CO3 (115 mg, 1.09 mmol) and Pd(PPh3)4 (41.9 mg, 36.3 µmol) were added. The mixture was stirred at 90 °C for 12 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL). The organic solutions were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by reversed-phase HPLC (0.1% FA conditions) to give 142 (70 mg, 57% yield) as a colorless gel. LC-MS (ESI) was used to further purify the product. + ) m / z 328.2 (M+H) + . 1 HNMR (400 MHz, CDCl3) δ 6.77 - 6.68 (m, 2H), 6.39 (s, 1H), 6.18 (d, J = 10.4 Hz,1H), 3.88 (s, 6H), 3.48 - 3.32 (m, 1H), 2.94 (br s, 1H), 2.77 - 2.68 (m, 1H),2.65 (br s, 1H), 2.59 - 2.49 (m, 2H), 2.44 (s, 3H), 2.29 - 2.20 (m, 2H), 1.01(br d, J = 8.4 Hz, 2H), 0.72 - 0.58 (m, 2H) Step 10 - 3a-(3-cyclopropyl-4,5-dimethoxy-phenyl)-1-methyl-2,3,4,5,7,7a-hexahydroindene Indo-6-one (143) Under a nitrogen atmosphere, Pd / C (10%, 20 mg) was added to a solution of 142 (200 mg, 610 µmol) in ethyl acetate (1.0 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C under H2 (15 Psi.) for 2 hours. The reaction mixture was filtered and concentrated under vacuum. The analysis was performed by preparative HPLC (column: Welch Ultimate C). 18 150*25mm*5um; mobile phase: [water (NH3H2O)-ACN]; B%: 38%-68%, 8min) The residue was purified to give 143 (80 mg, 39% yield) as a yellow solid. LC-MS (ESI) + ) m / z330.4 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 6.74(d, J = 2.0 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 3.89 (d, J = 5.1 Hz, 6H), 3.19 -3.10 (m, 1H), 2.93 (br s, 1H), 2.61 (d, J = 3.6 Hz, 2H), 2.53 - 2.37 (m, 2H),2.33 (s, 3H), 2.31 - 2.22 (m, 2H), 2.21 - 2.04 (m, 4H), 1.05 - 0.96 (m, 2H),0.72 - 0.64 (m, 2H) Step 11 - (3aS,7aS)-3a-(3-cyclopropyl-4,5-dimethoxy-phenyl)-1-methyl-2,3,4,5,7, 7a-hexahydroindol-6-one (230) and (3aR,7aR)-3a-(3-cyclopropyl-4,5-dimethoxy-phenyl)-1-methyl-2,3, 4,5,7,7a-hexahydroindol-6-one (231) Racemic 143 was separated by SFC (column: DAICL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 30%-30%, C7.85; 71 min) to obtain 230 (37.4 mg, 45% yield) and 231 (40.2 mg, 49% yield) as yellow oil.

[0344] 230:LC-MS (ESI + ) m / z 330.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 6.74 (d, J =2.0 Hz, 1H), 6.41 (d, J = 1.6 Hz, 1H), 3.89 (d, J = 5.4 Hz, 6H), 3.22 - 3.09 (m,1H), 2.94 (br s, 1H), 2.62 (br s, 2H), 2.51 - 2.40 (m, 1H), 2.34 (s, 4H),2.29 - 2.05 (m, 6H), 1.08 - 0.95 (m, 2H), 0.74 - 0.62 (m, 2H).

[0345] 231:LC-MS (ESI + ) m / z 330.2 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ=6.65 (d, J =2.4 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 3.80 (d, J = 5.2 Hz, 6H), 3.06 (br t, J =7.2 Hz, 1H), 2.84 (br s, 1H), 2.52 (br d, J = 3.6 Hz, 2H), 2.42 - 2.30 (m, 1H), 2.29 - 2.22 (m, 4H), 2.21 - 1.96 (m, 6H), 0.95 - 0.88 (m, 2H), 0.62 - 0.55(m, 2H).

[0346] Step 12: Compound 230 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL), and t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 hours at 0 °C. 1 mL of THF containing 0.16 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 hours, then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase HPLC (0.1% FA conditions).

[0347] Step 13: The product from Step 12 was added to a solution of 696 µmol of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole in dioxane (10 mL), followed by the addition of TfOH (1.39 mmol). The mixture was stirred at 80 °C for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0348] The compounds listed in the table below can be prepared using synthetic methods similar to those described above:

[0349] Example 9: Synthesis of 107, 108 and 109 Compound 108 was added to a solution of methyl(triphenyl)phosphonium bromide (2.07 mmol) in THF (6.0 mL). At 0 °C, t-BuOK (1 M in THF, 2.07 mL) was added over 0.5 h. THF (1 mL) containing 016 (1.04 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 16 h and then poured into water (50 mL). The mixture was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse-phase HPLC (0.1% FA conditions).

[0350] The above product was added to a solution of 3a-(3,4-dimethoxyphenyl)-1-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-indole (696 μmol) in dioxane (10 mL), and then TfOH (1.39 mmol) was added. The mixture was stirred at 80 °C for 2 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC.

[0351] Example A1: SERT Inhibition Measurement SERT inhibition can be measured using a neurotransmitter transport fluorescence assay. Briefly, stable 5HTT cells were prepared in 384-well plates. Compounds were prepared in assay buffer (20 mM HEPES, 0.1% BSA). The compounds were added to the plated cells and incubated at 37 °C for 30 min. 25 μL of dye solution (Molecular Devices neurotransmitter transporter uptake assay kit) was added to each well and incubated at 37 °C for 30 min. Then the plate was read on a plate reader.

[0352] Results can be provided as follows: A: IC 50 < / = 50 nM or lower; B: 50 nM < IC 50 < / = 100 nM; C: 100 nM < IC 50 < / = 500 nM; D: 500 nM < IC 50 < / = 1 μmol; E: IC 50 > 1 μmol. The relative SERT IC 50 refers to the ratio of the IC 50 values of the compounds shown in the above table.

[0353] Example B1: Metabolic stability of four compounds in the S9 intestinal tract of humans, monkeys, dogs, and rats. Table B1: Metabolic stability

[0354] Hepatocyte stability: Prepare 10 mM stock solutions of the test compound and positive control in DMSO. Before use, incubate the thawed medium and supplemental incubation medium (serum-free) in a 37°C water bath for at least 15 minutes. Dilute the stock solution to 100 μM by combining 198 μL of acetonitrile and 2 μL of the 10 mM stock solution. Verapamil was used as a positive control in the assay. Remove the frozen vial containing pooled human mixed-sex hepatocytes from storage, ensuring the vial is kept at low temperature. Decompress by loosening and retightening the cap. Thaw the vial by gentle agitation in a 37°C water bath. Keep the vial in the water bath until all ice crystals have dissolved and are no longer visible. Spray the vial with 70% ethanol before transferring it to a biosafety cabinet. Then pour the contents into a 50 mL conical tube containing thawed medium. Centrifuge the vial at 100 g for 10 minutes at room temperature. Aspirate the thawed medium and resuspend the hepatocytes in serum-free incubation medium to obtain approximately 1.5 × 10⁶ cells. 6 Cells / mL. Cell viability and density were counted using Cellometer® Vision, and then the cells were diluted to 0.5 × 10⁶ cells / mL with serum-free incubation medium. 6 Working cell density: viable cells / mL. Aliquots of 198 μL of hepatocytes were dispensed into each well of an uncoated 96-well plate. The plate was incubated on a track shaker at 500 rpm for approximately 10 minutes. An aliquot of 2 μL of 100 μM test compound or verapamil was added to the corresponding well of the uncoated 96-well plate to initiate the reaction. The assay was performed in duplicate. The plate was incubated on a track shaker at 500 rpm for the designed time points. 25 μL of the contents were transferred and mixed with 5 volumes (125 μL) of cold acetonitrile and 150 nmol / mL (100 nM alprazolam, 100 nM labetalol, and 100 nM tolbutamide) to terminate the reaction at time points of 0, 15, 30, 60, 90, and 120 minutes. The sample was centrifuged at 3,220 g for 30 minutes. 100 μL of the supernatant was then transferred to a new 96-well plate for analysis. 100 μL of distilled water was added to each sample and mixed for analysis by LC-MS / MS. Peak areas were determined based on the extracted ion chromatograms. The in vitro half-life (t0.05) of the parent compound was determined by regression analysis of the percentage of parent compound disappearance compared to the time curve. 1 / 2 In vitro half-life (in vitro t) 1 / 2 Determined by the slope value: in vitro t 1 / 2= 0.693 / k. b. Use the following equation to perform in vitro t 1 / 2 (in minutes) in vitro intrinsic clearance rate (in vitro CL) int , at µL / min / 10 6 Transformation of (cell count): In vitro CL int = kV / N V = incubation volume (0.2 mL); N = the number of hepatocytes in each well (0.1 × 10⁻⁶) 6 (cells).

[0355] The hepatocyte stability data in Table B1 are expressed as an improvement of fold (X) relative to compound 001 in CLint.

[0356] Gut stability: Prepare the main solution according to Table B2 below.

[0357] Add 222.5 μL of the main solution and 25 μL of 10 mM NADPH solution to the incubation plate. Preheat for 10 min. Initiate the reaction by adding 2.5 μL of 100 μM control or test compound solution. Verapamil, midazolam, and testosterone were used as positive controls in this study. The final concentration of the control and test compounds was 1 μM. 25 µL aliquots were taken from the reaction solution at 0.5 min, 5 min, 15 min, 30 min, 45 min, and 60 min. The reaction was terminated by adding 5 volumes of cold acetonitrile and IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). The samples were centrifuged at 3,220 g for 30 min. 100 µL of the supernatant aliquot was mixed with 100 µL of ultrapure H2O and then used for LC-MS / MS analysis.

[0358] Data analysis was performed as follows. All calculations were performed using Microsoft Excel. Peak areas were determined based on the extracted ion chromatograms. The slope value k was determined by linear regression of the remaining percentage of parent drug compared to the natural logarithm of the incubation time curve. In vitro half-life (in vitro t...) 1 / 2 Determined by the slope value: The following equation (the average of two measurements) was used for in vitro t 1 / 2 Conversion (in minutes) to in vitro intrinsic clearance (in vitro CLint, in µL / min / mg protein): Compound 243 (Example 3) The metabolic stability of compound 243 was tested in humans, monkeys, dogs, and rats (double-replicated measurements). For comparison, verapamil was tested in humans and monkeys (double-replicated measurements), midazolam was tested in dogs (double-replicated measurements), and testosterone was tested in rats (double-replicated measurements).

[0359] In human metabolic stability tests, compound 243 had a median half-life greater than 24 hours and 33 times that of verapamil, while verapamil had a median CLint (micrograms / min / mg protein) more than 23 times that of compound 243.

[0360] In canine metabolic stability tests, the median half-life of compound 243 was more than 168 times that of midazolam, and the median CLint (micrograms / min / mg protein) of midazolam in dogs was more than 164 times that of compound 243.

[0361] In rat metabolic stability tests, the median half-life of compound 243 was approximately 30 times that of testosterone, and in dogs, the median CLint (micrograms / min / mg protein) of testosterone was approximately 30 times that of compound 243.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: (I)， in Ring A is , , or , where * denotes the connection point between ring A and the compound of formula (I), and where Each R1 is independently deuterium, halogroup, alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, or -OR. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups is optionally replaced by a halogroup, alkyl, alkanol, aryl, or -OR group. a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b replace; m is 0, 1, 2, or 3; Each of R2 and R3 is independently H, alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, or aryl; wherein each hydrogen atom in the alkyl, cycloalkyl, alkenyl, ynyl, and aryl groups is optionally replaced by a halogroup, deuterium, cycloalkyl, aryl, or OR group. a Replace; or R2 and R3, together with the atoms they are attached to, combine to form a heterocyclic group or a heteroaryl group, wherein each hydrogen atom in the heterocyclic group or heteroaryl group is optionally replaced by a halogenated group or an OR group. a replace; R a and R b Independently, it is H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or if an example of R1 is -NR. a R b Then R a and R b They can combine with the nitrogen atoms they are attached to to form heterocyclic alkyl or heteroaryl groups; R4 is H, C 1-4 Alkyl or C 1-6 Halogenated alkyl groups; and R5 is arbitrarily assigned to C. 3-6 C-substituted with cycloalkyl, 3-6-membered heterocyclic, phenyl, or 5-6-membered heteroaryl groups 1-4 Alkyl group, wherein the alkyl group, cycloalkyl group, heterocyclic aryl group, or heteroaryl group is each independently and optionally converted by one or more deuterium, C 1-4 Alkoxy, C 1-4 The alkyl, halogenated, cyano, amino, carboxyl, acetyl, or amide groups are substituted.

2. The compound of claim 1, wherein R4 is a methyl group.

3. The compound of claim 2, wherein R5 is methyl.

4. The compound of claim 3, wherein each R1 is independently a halogroup, C 1-4 Alkyl, C 1-4 alkenyl, C 1-4 alkynyl group, C 3-6 cycloalkyl, -OR a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Each hydrogen atom in the alkyl, alkenyl, ynyl, or cycloalkyl group is optionally replaced by a halogenated group, C... 1-4 Alkyl, C 1-4 Alkyl alcohols, -OR a -NR a R b -CHO, -C(O)R a -CO2R a -C(O)NR a R b -CN, nitro or -P(O)OR a OR b Replace; and R a and R b Each is R independently a and R b Independently, it is H or C 1-4 alkyl.

5. The compound of claim 4, wherein each R1 is independently a halogroup, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, acetyl, cyano, C 3-6 Cycloalkyl, C(O)NR a R b R a and R b Each is C 1-4 alkyl.

6. The compound of claim 5, wherein... a. R2 and R3 are H and C independently, respectively. 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl or optionally C 3-6 cycloalkyl, phenyl, C 2-4 alkenyl or C 2-4 alkynyl-substituted C 1-4 Alkyl; or b. R2 and R3, together with the atoms they are attached to, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally halogenated or OR-substituted. a Replace, and R a It is C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkyl group.

7. The compound of claim 6, wherein one of R2 and R3 is not H.

8. The compound of claim 7, wherein R2 and R3 are each independently H and C. 1-4 Haloalkyl-(CH2)-(C 3-6 cycloalkyl), -(CH2)-(C 1-4 alkoxy), C 3-6 Cycloalkyl or benzyl.

9. The compound of claim 8, wherein ring A is .

10. The compound of claim 9, wherein the compound is a compound of formula (II-C). (II-C) Or its pharmaceutically acceptable salt.

11. The compound of claim 10, wherein R2 and R3 are each independently methyl.

12. The compound of claim 11, wherein m is 0 or 1.

13. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

14. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

15. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

16. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

17. The compound of claim 6, wherein R2 and R3, together with the atoms to which they are attached, form a 5-6 membered heterocyclic group, wherein each hydrogen atom in the heterocyclic group is optionally halogenated or OR-substituted. a Replace, and R a It is C 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

18. The compound of claim 16, wherein R a It is a methyl group, and the halogroup is fluorinated.

19. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

20. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

21. A method of treating a central nervous system disorder, comprising administering to a subject in need an effective amount of the compound as described in any one of claims 1 to 20.

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