Mixed serotonin receptor binders for treatment of psychotic disorders

Abstract

Disclosed herein are compounds having, 5-HT2A antagonism, 5-HT2C agonism, and psychoplastogenic properties. In addition, provided herein are pharmaceutical compositions, and methods for treating brain disorders with the compounds and compositions disclosed herein.

Description

MIXED SEROTONIN RECEPTOR BINDERS FOR TREATMENT OF PSYCHOTIC DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 614,457, filed December 22, 2023, and U.S. Provisional Application No.63 / 735,148, filed December 17, 2024, each of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders. BACKGROUND

[0003] Over the last several decades, predominant interest in serotonergic targets with respect to schizophrenia has centered around 5-HT2A antagonism / inverse agonism.5-HT2C receptor agonists have emerged as additional serotonergic target of interest.5-HT2C agonists have been suggested as treatments for multiple symptom domains of schizophrenia including positive, negative, cognitive, and depressive symptoms without the adverse events or tolerability issues associated with existing agents. The 5-HT2C receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT2C receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT2C receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the utility of either agonists or antagonists in the treatment of schizophrenia. The preclinical profile of 5-HT2C agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy. Selective 5-HT2C agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients. These data suggest that 5-HT2C agonists are potential therapeutics for the treatment of psychiatric disorders, including psychotic disorders. SUMMARY

[0004] In one aspect, disclosed herein are compounds having dual 5-HT2a antagonist and 5-HT2c agonist activity. In one aspect, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I) wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; orR8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; R10is hydrogen or C1-C3alkyl; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; m is 1 or 2; and n is 1 or 2; wherein: (a) at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen; (b) R8is -L-R8a; (c) R2is not hydrogen; (d) at least one of R6a, R6b, R7a, R7b, and R10is not hydrogen; (e) n is 2; or (f) m is 2.

[0005] In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1- C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, - NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, - OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, - C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3-C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, at least at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen. In some embodiments, R2is not hydrogen.

[0006] In some embodiments, each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3-C6cycloalkyl, and C1-C3alkyl(C3- C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituentsselected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3- C4cycloalkyl, or R7aand R7bare taken together to form a C3-C4cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, at least one of R6a, R6b, R7a, R7b, or R10is not hydrogen. In some embodiments, at least one of R6a, R6b, R7a, and R7bis not hydrogen. In some embodiments, R8is -L-R8a. In some embodiments, L is a bond. In some embodiments, L is C1-C6alkylene, or C1-C6heteroalkylene. In some embodiments, R8ais -NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, - C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O.

[0007] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0008] In some embodiments, provided herein is the compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, for use as medicine.

[0009] In one aspect, disclosed herein is a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0010] In one aspect, disclosed herein is a method of treating a disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof. In some embodiments, the disease or disorder is a disease or disorder of the brain. In some embodiments, the neurological disease or disorder is a neurodegenerative, a neuropsychiatric, or substance use disease or disorder. In some embodiments, the neurological disease or disorder is an injury. In some embodiments, the disease or disorder is an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, or a factitious disorder. In some embodiments, the disease or disorder is a psychotic disorder. In some embodiments, the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, paraphrenia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizoid personality disorder, borderline personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorders, or psychosis associated with a neurodegenerative disorders. In some embodiments, the neurodegenerative disorder is selected from Huntington’s disease, Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease In some embodiments, the psychoticdisorder is schizophrenia or bipolar disorder. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0011] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION

[0012] The present disclosure provides non-hallucinogenic compounds useful for the treatment of a variety of brain disorders, including psychotic disorders, as well as for increasing neuronal plasticity.

[0013] Compounds capable of modifying neural circuits have potential for treating neurological diseases and disorders that are mediated by the loss of synaptic connectivity and / or plasticity. Moreover, such compounds are likely to produce sustained therapeutic effects because, for example, of the potential to treat the underlying pathological changes in circuitry. Certain Terminology

[0014] Unless otherwise stated, the following terms used in this application have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. The use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0015] As used herein, C1-Cx (or C1-x) includes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0016] “Alkyl” generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon- carbon double bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” unless otherwise stated. Alkyl groups described herein are generally monovalent but may also be divalent (which may also be described herein as “alkylene” or “alkylenyl” groups). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n- propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso- butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. In general, alkyl groups are each independently substituted or unsubstituted. Each recitation of “alkyl” provided herein, unless otherwise stated, includes a specific and explicit recitation of an unsaturated “alkyl” group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORx, -SRx, -OC(O)-Rx, -N(Rx)2, -C(O)Rx, -C(O)ORx, -C(O)N(Rx)2, - N(Rx)C(O)ORx, -OC(O)-N(Rx)2, -N(Rx)C(O)Rx, -N(Rx)S(O)tRx(where t is 1 or 2), -S(O)tORx(where t is 1 or 2), -S(O)tRx(where t is 1 or 2) and -S(O)tN(Rx)2 (where t is 1 or 2) where each Rxis independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In some embodiments, an alkyl group is substituted with one or more fluorine.

[0017] An “alkylene” group refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, - CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as described for alkyl groups herein.

[0018] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula –C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, - C(CH3)=CHCH3, and –CH2CH=CH2.

[0019] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡C-R, wherein R refers to the remainingportions of the alkynyl group. In some embodiments, R is H or an alkyl. Non-limiting examples of an alkynyl group include -C≡CH, -C≡CCH3-C≡CCH2CH3, -CH2C≡CH.

[0020] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0021] The term “alkylamine” refers to -NH(alkyl), or -N(alkyl)2.

[0022] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl,” e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0023] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Ry-ORx, -Ry-OC(O)-Rx, -Ry- OC(O)-ORx, -Ry-OC(O)-N(Rx)2, -Ry-N(Rx)2, -Ry-C(O)Rx, -Ry-C(O)ORx, -Ry-C(O)N(Rx)2, -Ry-O-Rz- C(O)N(Rx)2, -Ry-N(Rx)C(O)ORx, -Ry-N(Rx)C(O)Rx, -Ry-N(Rx)S(O)tRx(where t is 1 or 2), -Ry-S(O)tRx(where t is 1 or 2), -Ry-S(O)tORx(where t is 1 or 2) and -Ry-S(O)tN(Rx)2 (where t is 1 or 2), where each Rxis independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Ryis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rzis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0024] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Ry-ORx, -Ry-OC(O)-Rx, -Ry-OC(O)-ORx, -Ry- OC(O)-N(Rx)2, -Ry-N(Rx)2, -Ry-C(O)Rx, -Ry-C(O)ORx, -Ry-C(O)N(Rx)2, -Ry-O-Rz-C(O)N(Rx)2, -Ry- N(Rx)C(O)ORx, -Ry-N(Rx)C(O)Rx, -Ry-N(Rx)S(O)tRx(where t is 1 or 2), -Ry-S(O)tRx(where t is 1 or 2), -Ry- S(O)tORx(where t is 1 or 2) and -Ry-S(O)tN(Rx)2 (where t is 1 or 2), where each Rxis independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Ryis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rzis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0025] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, adamantyl, norbornyl, and decalinyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl.

[0026] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo. In some embodiments, halo is fluoro or chloro.

[0027] The term “heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies – for example, -CH2- may be replaced with -NH-, -S-, or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, selenium, or other suitable heteroatom. In some embodiments, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-). In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C18 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12 heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4 heteroalkyl. In some embodiments, a heteroalkyl is or includes one or more cyclic group(s). In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group. In one embodiment, a heteroalkyl is a C1-C6heteroalkyl.

[0028] “Heteroalkylene” refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.

[0029] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl. Unless statedotherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Ry-ORx, -Ry-OC(O)-Rx, -Ry-OC(O)-ORx, -Ry-OC(O)-N(Rx)2, -Ry-N(Rx)2, -Ry-C(O)Rx, -Ry- C(O)ORx, -Ry-C(O)N(Rx)2, -Ry-O-Rz-C(O)N(Rx)2, -Ry-N(Rx)C(O)ORx, -Ry-N(Rx)C(O)Rx, -Ry-N(Rx)S(O)tRx(where t is 1 or 2), -Ry-S(O)tRx(where t is 1 or 2), -Ry-S(O)tORx(where t is 1 or 2) and -Ry-S(O)tN(Rx)2 (where t is 1 or 2), where each Rxis independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Ryis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rzis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0030] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one embodiment, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another embodiment, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0031] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one embodiment, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0032] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0033] In general, optionally substituted groups are each independently substituted or unsubstituted. Each recitation of an optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). Unless otherwise stated, a substituted group provided herein (e.g., substituted alkyl) is substituted by one or more substituent, each substituent being independently selected from the group consisting of: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORx, -SRx, -OC(O)-Rx, -N(Rx)2, -C(O)Rx, -C(O)ORx, -C(O)N(Rx)2, - N(Rx)C(O)ORx, -OC(O)-N(Rx)2, -N(Rx)C(O)Rx, -N(Rx)S(O)tRx(where t is 1 or 2), -S(O)tORx(where t is 1 or 2), -S(O)tRx(where t is 1 or 2) and -S(O)tN(Rx)2 (where t is 1 or 2) where each Rxis independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), - N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, - S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, - NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0034] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0035] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity. In some embodiments. modulation is an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, antagonists, and allosteric modulators (e.g., a positive allosteric modulator) of a G protein-coupled receptor are modulators of the receptor.

[0036] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function of the receptor.

[0037] The term “agonism,” as used herein, generally refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

[0038] The term “agonist,” as used herein, generally refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. In some embodiments, the term “agonist” includes full agonists or partial agonists. “Full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor. “Partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.

[0039] The term “positive allosteric modulator,” as used herein, generally refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.

[0040] The term “antagonism,” as used herein, generally refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and blocks function of the receptor.

[0041] The term “antagonist” or “neutral antagonist,” as used herein, generally refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist may have no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

[0042] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0043] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0044] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

[0045] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0046] The term “pharmaceutically acceptable,” as used herein, generally refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0047] The term “pharmaceutically acceptable salt,” as used herein, generally refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci.1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted. Provided herein are non-hallucinogenic compounds that promote neuronal growth and / or improve neuronal structure. Compounds

[0048] In one aspect, disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I) wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; orR8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; R10is hydrogen or C1-C3alkyl; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; m is 1 or 2; and n is 1 or 2; wherein: (a) at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen; (b) R8is -L-R8a; (c) R2is not hydrogen; (d) at least one of R6a, R6b, R7a, R7b, and R10is not hydrogen; (e) n is 2; or (f) m is 2.

[0049] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-1), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-1).

[0050] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-2), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-2).

[0051] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-3), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-3),

[0052] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-4), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-4).

[0053] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-5), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:

[0054] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-6), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:,

[0055] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-7), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:

[0056] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-11), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-11).

[0057] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-12), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:

[0058] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-13), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:

[0059] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-14), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-14).

[0060] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-15), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-15).

[0061] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-16), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-16).

[0062] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-17), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-17).

[0063] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-18), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-18).

[0064] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-19), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:

[0065] In some embodiments, the compound of Formula (I) has the structure of Formula (I-A-20), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-A-20).

[0066] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I- A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), or (I-A-20), each R1, R2, R3, R4, and R5, when present, is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1- C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, - S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3-C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, halogen, C6-C10aryl, or C3- C7cycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, and cycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogen, -OH, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, - Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independentlyhydrogen,. In some embodiments, at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen.

[0067] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), or (I-A-16), R1is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0068] In some embodiments of Formula (I), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A- 17), (I-A-18), or (I-A-19), R2is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is hydrogen. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or aryl, wherein each of the alkyl, heteroalkyl, and aryl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is C1- C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0069] In some embodiments of Formula (I), (I-A-2), (I-A-5), (I-A-11), (I-A-14), (I-A-15), (I-A-17), (I-A- 18), or (I-A-20), R3is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0070] In some embodiments of Formula (I), (I-A-3), (I-A-6), (I-A-12), (I-A-14), (I-A-16), (I-A-17), (I-A- 19), or (I-A-20), R4is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0071] In some embodiments of Formula (I), (I-A-4), (I-A-7), (I-A-13), (I-A-15), (I-A-16), (I-A-18), (I-A- 19), or (I-A-20), R5is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0072] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I- A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), or (I-A-20), each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, - NO2, -ORb, -SRb, -NRcRd, C3-C6cycloalkyl, and C1-C3alkyl(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy; or R6aand R6bare taken together to form a C3-C4cycloalkyl, or R7aand R7bare taken together to form a C3-C4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen, -ORb, or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, - CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen. In some embodiments, R6ais -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais -OH. In some embodiments, R6ais -CH3. In some embodiments, R6bis hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis hydrogen or - CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis hydrogen. In some embodiments, R6bis -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis -OH. In some embodiments, R6bis -CH3. In some embodiments, R7ais hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7ais hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7ais hydrogen. In some embodiments, R7ais -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R7ais -OH. In some embodiments, R7ais -CH3. In some embodiments, R7bis hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis hydrogen. In some embodiments, R7bis -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis -OH. In some embodiments, R7bis -CH3. In some embodiments, R6aand R6bare taken together to form a cyclopropyl. In some embodiments, R7aand R7bare taken together to form a cyclopropyl. In some embodiments, at least one of R6a, R6b, R7a, and R7bis not hydrogen.

[0073] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I- A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), or (I-A-20), R8is hydrogen or C1-C6alkyl. In some embodiments, R8is hydrogen or C1-C3alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is C1-C3alkyl. In some embodiments, R8is -L-R8a. In some embodiments, L is a bond. In some embodiments, L is C1-C6alkylene or C1-C6heteroalkylene. In some embodiments, L is C1-C6alkylene. In some embodiments, L is ethylene. In some embodiments, R8ais - NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais -NRbC(=O)Rbor heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais 4- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais pyrrolidinyl, or tetrahydropyranyl, wherein each of the pyrrolidinyl and tetrahydropyranyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O. In some embodiments,. some embodiments, R8is, some embodiments, R8is.

[0074] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I- A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), or (I-A-20), R9is hydrogen or C1-C3alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is -CH3. In some embodiments, R9is -CH2CH3.

[0075] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7) (I- A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), or (I-A-20), R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, the heterocycloalkyl is a 5- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl, an imidazolidinyl, a piperidinyl, a piperazinyl, or a morpholino, each of which is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl. In some embodiments, R8and R9are taken together to form an imidazolidinyl. In some embodiments, R8and R9are taken together to form a piperidinyl. In some embodiments, R8and R9are taken together to form a piperazinyl. In some embodiments, R8and R8are taken together to form a morpholino.

[0076] In some embodiments of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I- A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), or (I-A-20), m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0077] In one aspect, the compound of Formula (I) has the structure of Formula (I-B), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:, wherein: R2is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), orC1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; or R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; m is 1 or 2; and n is 1 or 2.

[0078] In some embodiments of Formula (I-B), R2is C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1- C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, - S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), - P(=O)RcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3-C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R2is C1-C6alkyl, C1- C6heteroalkyl, halogen, C6-C10aryl, or C3-C7cycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, and cycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1- C3alkoxy, halogen, -OH, and -CN. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN. In

[0079] In some embodiments of Formula (I-B), each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3-C6cycloalkyl, and C1-C3alkyl(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C4cycloalkyl, or R7aand R7bare taken together to form a C3-C4cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen, -ORb, or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, - CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen or -CH3 optionally substituted with one or more substituents selected fromhalogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen. In some embodiments, R6ais - CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R6ais -OH. In some embodiments, R6ais -CH3. In some embodiments, R6bis hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis hydrogen. In some embodiments, R6bis -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis -OH. In some embodiments, R6bis -CH3. In some embodiments, R7ais hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7ais hydrogen or - CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R7ais hydrogen. In some embodiments, R7ais -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7ais -OH. In some embodiments, R7ais -CH3. In some embodiments, R7bis hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis hydrogen. In some embodiments, R7bis -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R7bis -OH. In some embodiments, R7bis -CH3. In some embodiments, R6aand R6bare taken together to form a cyclopropyl. In some embodiments, R7aand R7bare taken together to form a cyclopropyl. In some embodiments, at least one of R6a, R6b, R7a, and R7bis not hydrogen.

[0080] In some embodiments of Formula (I-B), R8is hydrogen or C1-C6alkyl. In some embodiments, R8is hydrogen or C1-C3alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is C1-C3alkyl. In some embodiments, R8is -L-R8a. In some embodiments, L is a bond. In some embodiments, L is C1- C6alkylene or C1-C6heteroalkylene. In some embodiments, L is C1-C6alkylene. In some embodiments, L is ethylene. In some embodiments, R8ais -NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais 4- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O. In some embodiments, R8ais pyrrolidinyl, or tetrahydropyranyl, wherein each of the pyrrolidinyl and tetrahydropyranyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8is. , . In some embodiments,. some embodiments,.

[0081] In some embodiments of Formula (I-B), R9is hydrogen or C1-C3alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is -CH3. In some embodiments, R9is -CH2CH3.

[0082] In some embodiments of Formula (I-B), R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, the heterocycloalkyl is a 5- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl, an imidazolidinyl, a piperidinyl, a piperazinyl, or a morpholino, each of which is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl. In some embodiments, R8and R9are taken together to form an imidazolidinyl. In some embodiments, R8and R9are taken together to form a piperidinyl. In some embodiments, R8and R9are taken together to form a piperazinyl. In some embodiments, R8and R9are taken together to form a morpholino.

[0083] In some embodiments of Formula (I-B), m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0084] In one aspect, the compound of Formula (I) has the structure of Formula (I-C-1’) or Formula (I-C- 2’) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:wherein:each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy;R8is hydrogen, C1- C6alkyl, or -L-R8a; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; or R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; R10is hydrogen or C1-C3alkyl; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; and each Rcand Rdis independently hydrogen or C1-C6alkyl; orRcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O, wherein at least one of R6a, R6b, R7a, R7b, and R10is not hydrogen.

[0085] In one aspect, the compound of Formula (I) has the structure of Formula (I-C-1) or Formula (I-C-2) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-C-2), wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; or R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O;each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; and each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O.

[0086] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1- C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, - NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, - NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6- C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3- C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, halogen, C6-C10aryl, or C3-C7cycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, and cycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogen, -OH, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1- C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently.

[0087] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R1is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionallysubstituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is C1- C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0088] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R2is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is hydrogen. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or aryl, wherein each of the alkyl, heteroalkyl, and aryl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0089] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R3is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is C1- C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0090] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R4is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is C1- C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0091] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R5is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0092] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R8is hydrogen or C1- C6alkyl. In some embodiments, R8is hydrogen or C1-C3alkyl. In some embodiments, R8is -CH3. In some embodiments, R8is hydrogen. In some embodiments, R8is C1-C3alkyl. In some embodiments, R8is -L-R8a. In some embodiments, L is a bond. In some embodiments, L is C1-C6alkylene or C1-C6heteroalkylene. In some embodiments, L is C1-C6alkylene. In some embodiments, L is ethylene. In some embodiments, R8ais - NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais heterocycloalkyl optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais 4- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais pyrrolidinyl or tetrahydropyranyl, wherein each of the pyrrolidinyl and tetrahydropyranyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments,. some embodiments, R8is. In some embodiments,. some embodiments, R8is.

[0093] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R9is hydrogen or C1- C3alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is -CH3. In some embodiments, R9is -CH2CH3.

[0094] In some embodiments of Formula (I-C-1’), (I-C-1),(I-C-2), or (I-C-2’), R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, the heterocycloalkyl is a 5- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl, an imidazolidinyl, a piperidinyl, a piperazinyl, or a morpholino, each of which is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl. In some embodiments, R8and R9are taken together to form an imidazolidinyl. In some embodiments, R8and R9are taken together to form a piperidinyl. In some embodiments, R8and R9are taken together to form a piperazinyl. In some embodiments, R8and R9are taken together to form a morpholino.

[0095] In some embodiments of Formula (I), (I-C-1’), or (I-C-2’), R10is hydrogen or -CH3. In some embodiments of Formula (I), (I-C-1’), or (I-C-2’), R10is hydrogen. In some embodiments of Formula (I), (I- C-1’), or (I-C-2’), R10is -CH3.

[0096] In one aspect, the compound of Formula (I) has the structure of Formula (I-D), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl,wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; m is 1 or 2; and n is 1 or 2.

[0097] In some embodiments of Formula (I-D), each R1, R2, R3, R4, and R5is independently hydrogen, C1- C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3-C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, halogen, C6-C10aryl, or C3-C7cycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, and cycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogen, -OH, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, - Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independentlyhydrogen,. In some embodiments, at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen.

[0098] In some embodiments of Formula (I-D), R1is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0099] In some embodiments of Formula (I-D), R2is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is hydrogen. In some embodiments, R2is C1-C6alkyl, C1- C6heteroalkyl, -F, -Cl, -Br, or aryl, wherein each of the alkyl, heteroalkyl, and aryl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0100] In some embodiments of Formula (I-D), R3is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0101] In some embodiments of Formula (I-D), R4is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0102] In some embodiments of Formula (I-D), R5is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0103] In some embodiments of Formula (I-D), each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3-C6cycloalkyl, and C1-C3alkyl(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C4cycloalkyl, or R7aand R7bare taken together to form a C3-C4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen, -ORb, or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, - CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, each R6a, R6b, R7a, R7bis independently hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen. In some embodiments, R6ais - CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R6ais -OH. In some embodiments, R6ais -CH3. In some embodiments, R6bis hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis hydrogen. In some embodiments, R6bis -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6bis -OH. In some embodiments, R6bis-CH3. In some embodiments, R7ais hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7ais hydrogen or - CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R7ais hydrogen. In some embodiments, R7ais -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7ais -OH. In some embodiments, R7ais -CH3. In some embodiments, R7bis hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R7bis hydrogen. In some embodiments, R7bis -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R7bis -OH. In some embodiments, R7bis -CH3. In some embodiments, R6aand R6bare taken together to form a cyclopropyl. In some embodiments, R7aand R7bare taken together to form a cyclopropyl. In some embodiments, at least one of R6a, R6b, R7a, and R7bis not hydrogen.In some embodiments of Formula (I-D), L is a bond. In some embodiments, L is C1-C6alkylene or C1- C6heteroalkylene. In some embodiments, L is C1-C6alkylene. In some embodiments, L is ethylene. In some embodiments, R8ais -NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, - C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O. In some embodiments, R8ais heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais 4- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais pyrrolidinyl or tetrahydropyranyl, wherein each of the pyrrolidinyl and tetrahydropyranyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -

[0104] In some embodiments of Formula (I-D), R9is hydrogen or C1-C3alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is -CH3. In some embodiments, R9is -CH2CH3.

[0105] In some embodiments of Formula (I-D), m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2.

[0106] In one aspect, the compound of Formula (I) has the structure of Formula (I-E-1) or Formula (I-E-2), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I-E-2), wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; R6ais selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, - NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; orR8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O.

[0107] In some embodiments of Formula (I-E-1) or (I-E-2), each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, - NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, - NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3-C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, halogen, C6-C10aryl, or C3-C7cycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, and cycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1- C3alkoxy, halogen, -OH, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN. In some embodiments, each R1, R2, R3, R4, and R5is independently hydrogen, -CH3,, , ,some embodiments, atleast one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen.

[0108] In some embodiments of Formula (I-E-1) or (I-E-2), R1is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, - F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is hydrogen. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R1is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0109] In some embodiments of Formula (I-E-1) or (I-E-2), R2is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, - F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is hydrogen. In some embodiments, R2is C1- C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or aryl, wherein each of the alkyl, heteroalkyl, and aryl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0110] In some embodiments of Formula (I-E-1) or (I-E-2), R3is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, - F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R3is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0111] In some embodiments of Formula (I-E-1) or (I-E-2), R4is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, - F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R4is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0112] In some embodiments of Formula (I-E-1) or (I-E-2), R5is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, - F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN. In some embodiments, R5is C1-C6alkyl, C1-C6heteroalkyl, -F, - Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from methyl, -O-CH3, -F, -Cl, -Br, and -CN.

[0113] In some embodiments of Formula (I-E-1) or (I-E-2), R6ais selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3-C6cycloalkyl, and C1-C3alkyl(C3- C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen, -ORb, or C1- C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R6ais hydrogen or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen, - OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1- C3alkoxy. In some embodiments, R6ais hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais hydrogen. In some embodiments, R6ais -CH3 optionally substituted with one or more substituents selected from halogen, - OH, -CN, and C1-C3alkoxy. In some embodiments, R6ais -OH. In some embodiments, R6ais -CH3.

[0114] In some embodiments of Formula (I-E-1) or (I-E-2), R8is hydrogen or C1-C6alkyl. In some embodiments, R8is hydrogen or C1-C3alkyl. In some embodiments, R8is hydrogen. In some embodiments, R8is C1-C3alkyl. In some embodiments, R8is -L-R8a. In some embodiments, L is a bond. In some embodiments, L is C1-C6alkylene or C1-C6heteroalkylene. In some embodiments, L is C1-C6alkylene. In some embodiments, L is ethylene. In some embodiments, R8ais -NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, - NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8ais 4- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, - OH, -CN, and =O. In some embodiments, R8ais pyrrolidinyl or tetrahydropyranyl, wherein each of the pyrrolidinyl and tetrahydropyranyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O. In some embodiments, R8is. , . In some embodiments,. some embodiments,.

[0115] In some embodiments of Formula (I-E-1) or (I-E-2), R9is hydrogen or C1-C3alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9is -CH3. In some embodiments, R9is -CH2CH3.

[0116] In some embodiments of Formula (I-E-1) or (I-E-2), R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, the heterocycloalkyl is a 5- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl, an imidazolidinyl, a piperidinyl, a piperazinyl, or a morpholino, each of which is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O. In some embodiments, R8and R9are taken together to form a pyrrolidinyl. In some embodiments, R8and R9are taken together to form an imidazolidinyl. In some embodiments, R8and R9are taken together to form a piperidinyl. In some embodiments, R8and R9are taken together to form a piperazinyl. In some embodiments, R8and R9are taken together to form a morpholino.

[0117] In one aspect, disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (II) wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; or R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; R10is hydrogen or C1-C3alkyl; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; m is 1 or 2; and n is 1 or 2;wherein: (a) at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen; (b) R8is -L-R8a; (c) R2is not hydrogen; (d) at least one of R6a, R6b, R7a, R7b, and R10is C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, or C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1- C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; (e) n is 2; or (f) m is 2.

[0118] In another aspect, disclosed herein is a compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, selected from:,, ,.

[0119] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, has the structure of:,

[0120] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, has the structure of:.

[0121] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, has the structure of:

[0122] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof has the structure of:

[0123] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, has the structure of:

[0124] In another aspect, disclose herein is a compound disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, for use as medicine.

[0125] Provided in some embodiments herein is a compound of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A- 4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I- A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, having a structure provided in Table 1.Table 1

[0126] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. Pharmaceutical Compositions

[0127] In another aspect, disclose herein is a pharmaceutical composition comprising the compound of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A- 14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof.

[0128] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0129] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound having a structure represented by Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A- 18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, and a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0130] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or morepharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999), herein incorporated by reference for such disclosure.

[0131] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[0132] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0133] The pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such asstarches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0134] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0135] The pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0136] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and pharmaceutical compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. Further Forms of Compounds

[0137] In one embodiment, compounds described herein are in the form of pharmaceutically acceptable salts. In some embodiments, any compound provided herein is a pharmaceutically acceptable salt, such as, for example, any salt described herein.

[0138] As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0139] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A- 14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, with an acid. In some embodiments, the compound of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I- A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I- E-1), (I-E-2), or (II), for example any compound described in Table 1, (i.e., free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2- hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2- disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0140] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound represented by the structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A- 11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I- C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1,with a base. In some embodiments, the compound of represented by the structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A- 4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I- A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1 is acidic and is reacted with a base. In such situations, an acidic proton of the compound represented by the structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A- 11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I- C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0141] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0142] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of compounds of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I- A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I- E-1), (I-E-2), or (II), are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0143] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0144] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36Cl,123I,124I,125I,131I,32P and33P. In one embodiment, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one embodiment, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogens of the compounds of Formula (I), (I-A-1), (I-A- 2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), are replaced with deuterium.

[0145] In some embodiments, a compound represented by the structure of Formula (I), (I-A-1), (I-A-2), (I- A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, possesses one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, a compound represented by the structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A- 13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E- 1), (I-E-2), or (II), for example any compound described in Table 1, exists in the R configuration. In some embodiments, a compound represented by the structure of Form Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A- 4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I- A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0146] In some embodiments, a composition provided herein comprises a racemic mixture of a compound represented by a structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A- 11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I- C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1. In some embodiments, a compound provided herein is a racemate of a compound represented by a structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A- 14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1.

[0147] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, a compound represented by the structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A- 14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, is prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments,separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. See, e.g., Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0148] In some embodiments, compounds described herein are prepared as prodrugs. In some embodiments, a prodrug is an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. In some instances, a prodrug is bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the “prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

[0149] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol.42, p.309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e., the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.

[0150] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I- A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), as set forth herein are included within the scope of the claims.

[0151] In some embodiments, any one of the hydroxyl group(s), amino group(s) and / or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0152] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0153] In some embodiments, a metabolite of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. In some embodiments. an “active metabolite” of a compound provided herein is a biologically active derivative of the compound provided herein that is formed when the compound is metabolized. In some embodiments, metabolism is the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. In some embodiments, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. In some embodiments, a metabolite of a compound disclosed herein is optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. Synthesis of Compounds

[0154] Compounds of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I- A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0155] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0156] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0157] In some embodiments, compounds described herein are synthesized as outlined in the Examples. Methods of Treatment

[0158] In another aspect, disclosed herein is a method of treating a disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I- A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I- E-1), (I-E-2), or (II), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof. In some embodiments, the disease or disorder is a disease or disorder of the brain.

[0159] In some embodiments, the neurological disease or disorder is a neurodegenerative, a neuropsychiatric, or substance use disease or disorder. In some embodiments, the neurological disease or disorder is an injury. In some embodiments, the disease or disorder is an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, or a factitious disorder. In some embodiments, the disease or disorder is a psychotic disorder. In some embodiments, the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, paraphrenia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizoid personality disorder, borderline personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorders, or psychosis associated with a neurodegenerative disorders. In some embodiments, the neurodegenerative disorder is selected from Huntington’s disease, Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease. In some embodiments, the psychotic disorder is schizophrenia or bipolar disorder. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0160] The compounds disclosed herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, are useful for promoting neuronal growth and / or improving neuronal structure.

[0161] In some embodiments, provided herein is a method of promoting neural plasticity (e.g., cortical structural plasticity) in an individual by administering a compound described herein (e.g., a compound represented by the structure of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A- 11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I- C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1, to the individual. In some embodiments, the individual has or is diagnosed with a brain disorder or other conditions described herein.

[0162] In some embodiments, provided herein is a method of promoting neuronal growth in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1).

[0163] In some embodiments, provided herein is a method of improving neuronal structure in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structurerepresented by Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), for example any compound described in Table 1).

[0164] In some embodiments, provided herein is a method of treating a disease or disorder in an individual in need thereof that is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented by Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A-12), (I-A-13), (I-A-14), (I-A- 15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I-D), (I-E-1), (I-E-2), or (II), or for example any compound described in Table 1).

[0165] In some embodiments, provided herein is a method of treating a neurological disease or disorder in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound or pharmaceutical composition provided herein (e.g., a compound having a structure represented Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7), (I-A-11), (I-A- 12), (I-A-13), (I-A-14), (I-A-15), (I-A-16), (I-A-17), (I-A-18), (I-A-19), (I-A-20), (I-B), (I-C-1), (I-C-2), (I- D), (I-E-1), (I-E-2), or (II), or for example any compound described in Table 1).

[0166] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from promoting neuronal growth and / or improving neuronal structure.

[0167] Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0168] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal. EXAMPLES

[0169] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. General

[0170] All reagents are obtained commercially and used without purification unless otherwise noted. DMSO is purified by passage under 12 psi N2through activated alumina columns. Reactions are performed using glassware that is flame-dried under reduced pressure (~1 Torr). Compounds purified by chromatography are adsorbed to the silica gel before loading. Thin layer chromatography is performed onMillipore silica gel 60 F254Silica Gel plates. Visualization of the developed chromatogram is accomplished by fluorescence quenching or by staining with ninhydrin or aqueous ceric ammonium molybdate (CAM).

[0171] Nuclear magnetic resonance (NMR) spectra are acquired on either a Bruker 400 operating at 400 and 100 MHz, a Varian 400 operating at 400 and 100 MHz, or a Varian 500 operating at 500 and 125 MHz for1H and13C, respectively, and are referenced internally according to residual solvent signals. Data for1H NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (Hz), and integration. Data for13C NMR are reported in terms of chemical shift (δ, ppm). Liquid chromatography-mass spectrometry (LC-MS) is performed using an Agilent LC-MS with Ion Trap or ELSD detector, or a Waters LC-MS with an UPLC detector. Chemistry Example A1:

[0172] Synthesis of Compound 1, 2, 3, 4, 5, 6, and 7

[0173] Scheme-1: Synthesis of Compound 1, 2, 3, 4, 5, 6, and 7:

[0174] Step-1: Synthesis of Int-2b (4,5-difluoroindoline):

[0175] To a stirred solution of commercially available 4,5-difluoro-1H-indole (Int-1b) (10 g, 65.3 mmol, 1.0 eq) in acetic acid (50 mL) was added NaBH3CN (13.5 g, 215 mmol, 3.3 eq) at 0 °C under an N2 atmosphere. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with an aqueous NaOH solution (1N in water, 50 mL) and the aqueous solution was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrousNa2SO4,filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography to get 4,5-difluoroindoline (Int-2b) (4.6 g, 45%) as an oily liquid. ESI-MS m / z:155.7 [M+H]+.

[0176] Step 2: Synthesis of Int-4a (4-(indolin-1-yl)-4-oxobutanoic acid):

[0177] To a sealed tube, indoline (Int-2a) (20 g, 168 mmol, 1.0 eq) and pyridine (200 mL) were added, followed by dihydrofuran-2,5-dione (16.8 g, 168 mmol, 1.0 eq) at room temperature. The reaction vessel was sealed, and the mixture was heated to 100 ℃ and stirred for 16 h. The reaction mixture was cooled to room temperature and an aqueous HCl solution (2M) was added until the pH = 1. The resulting precipitate was filtered, and the filter cake was washed with water and dried to afford 4-(indolin-1-yl)-4-oxobutanoic acid (Int-4a) (10 g, crude) as a light pink solid. ESI-MS m / z:220.0 [M+H]+.

[0178] Synthesis of Int-4b (4-(indolin-1-yl)-4-oxobutanoic acid):

[0179] To a sealed tube, 4,5-difluoroindoline (Int-2b) (4.6 g, 29.6 mmol, 1.0 eq) and pyridine (46 mL) were added, followed by dihydrofuran-2,5-dione (3.55 g, 35.5 mmol, 1.2 eq) at room temperature. The reaction vessel was sealed, and the mixture was heated to 100 ℃ and stirred for 16 h. The reaction mixture was cooled to room temperature and an aqueous HCl solution (2M) was added until the pH = 1. The resulting precipitate was filtered, and the filter cake was washed with water and dried to afford 4-(4,5-difluoroindolin- 1-yl)-4-oxobutanoic acid (Int-4b) (5 g, crude) as a light pink solid. ESI-MS m / z:255.9 [M+H]+.

[0180] Step 3: Synthesis of Int-5a (2,3,6,7-tetrahydroazepino[3,2,1-hi]indole-1,4-dione):

[0181] A stirred solution of 4-(indolin-1-yl)-4-oxobutanoic acid (Int-4a) (10 g, 45.6 mmol, 1.0 eq) in PPA (100 mL) was heated to 120 ℃ and stirred at that temperature for 16 h. The reaction mixture was cooled to 0 ℃ and basified with aq. NaOH solution and extracted with EtOAc. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to yield crude compound which was purified by silica gel chromatography to afford 2,3,6,7-tetrahydroazepino[3,2,1-hi]indole-1,4-dione (Int-5a) (2 g, 19%) as a colourless solid, which was carried forward without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.95 (dd, J = 1.2, 8.0 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.14 - 7.08 (m, 1H), 4.29 - 4.21 (m, 2H), 3.16 (t, J = 8.6 Hz, 2H), 2.96 - 2.91 (m, 2H), 2.88 - 2.83 (m, 2H) ppm. ESI-MS m / z: 202.3 [M+H]+.

[0182] Step 3: Synthesis of Int-5b (8,9-difluoro-2,3,6,7-tetrahydroazepino[3,2,1-hi]indole-1,4-dione):

[0183] A stirred solution of 4-(4,5-difluoroindolin-1-yl)-4-oxobutanoic acid (Int-4b) (6.8 g, 26.6 mmol, 1.0 eq) in PPA (68 mL) was heated to 120 ℃ and stirred at that temperature for 16 h. The reaction mixture was cooled to 0 ℃, basified with an aqueous NaOH solution, and extracted with EtOAc. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to yield crude compound which was purified by silica gel chromatography to afford 8,9-difluoro-2,3,6,7- tetrahydroazepino[3,2,1-hi]indole-1,4-dione (Int-5b) (900 mg, 14%) as a pale yellow solid. ESI-MS m / z:255.9 [M+H2O]+.

[0184] Step-4: Synthesis of Int-6a (2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)-one):

[0185] To a stirred solution of Int-5a (2 g, 8.64 mmol, 1.0 eq) in TFA (10 mL) at 0 ℃ was added triethylsilane (1.49 g, 12.9 mmol, 1.5 eq). The reaction mixture was heated to 60 ℃ and stirred at that temperature for 16 h. The reaction mixture was cooled to 0 ℃, basified with an aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude product. The crude material was purified by silica gel chromatography to afford 2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)-one (Int-6a) (800 mg, 43%) as a pale yellow solid. ESI-MS m / z:188.3 [M+H]+.

[0186] Step-4: Synthesis of Int-6b (8,9-difluoro-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)-one):

[0187] To a stirred solution of Int-5b (1.2 g, 5.05 mmol, 1.0 eq) in TFA (12 mL) at 0 ℃ was added triethylsilane (5.86 g, 50.4 mmol, 10 eq). The reaction mixture was heated to 60 ℃ and stirred at that temperature for 16 h. The reaction mixture was cooled to 0 ℃, basified with an aqueous NaHCO3 solutionand extracted with EtOAc. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude product. The crude material was purified by silica gel chromatography to afford 8,9-difluoro-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)-one (Int-6b) (550 mg, 49%) as an off white solid. ESI-MS m / z:223.8 [M+H]+.

[0188] Step-5: Synthesis of Int-7a (3-iodo-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)-one):

[0189] To a stirred solution of Int-6a (1.5 g, 8.01 mmol, 1.0 eq) in CH2Cl2(15 mL) at -15 ℃ were added TMEDA (2.78 g, 24.0 mmol, 3 eq) and trimethylsilyl iodide (0.32 g, 1.60 mmol, 0.2 eq). The reaction mixture was stirred at that temperature for 15 minutes and then iodine (3.04 g, 12.0 mmol, 1.5 eq) was added. The reaction mixture was allowed to warm to 0 ℃ and was stirred at that temperature for 2 h. The reaction mixture was diluted with an aqueous Na2SO3solution and brine. The quenched reaction mixture was extracted three times with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude compound. The crude material was purified by silica gel chromatography to get 3-iodo-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol- 4(1H)-one (Int-7a) (1.5 g, 60%) as a pale yellow solid. ESI-MS m / z:313.8[M+H]+.

[0190] Step-5: Synthesis of Int-7b (8,9-difluoro-3-iodo-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)- one):

[0191] To a stirred solution of Int-6b (350 mg, 1.56 mmol, 1.0 eq) in CH2Cl2 (2 mL) at -15 ℃ were added TMEDA (543 mg, 4.68 mmol, 3.0 eq) and trimethylsilyl iodide (62.4 mg, 0.31 mmol, 0.2 eq). The reaction mixture was stirred at that temperature for 15 minutes and then iodine (593 mg, 2.34 mmol, 1.5 eq) was added. The reaction mixture was allowed to warm to 0 ℃ and was stirred at that temperature for 2 h. The reaction mixture was diluted with an aqueous Na2SO3solution and brine. The quenched reaction mixture was extracted three times with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude compound. The crude material was purified by silica gel chromatography to get 8,9-difluoro-3-iodo-2,3,6,7- tetrahydroazepino[3,2,1-hi]indol-4(1H)-one (Int-7b) (400 mg, 73%) as an off white solid. ESI-MS m / z: 249.7 [M+H]+.

[0192] Step 6: Synthesis of Compound 1 (3-(dimethylamino)-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol- 4(1H)-one)

[0193] To a stirred solution of Int-7a (1.3 g, 4.15 mmol, 1.0 eq) in acetonitrile (13 mL) at 0 ℃ were added K2CO3 (1.71 g, 12.4 mmol, 3.0 eq) and dimethylamine hydrochloride (0.67 g, 8.30 mmol, 2.0 eq). The reaction mixture was heated to reflux and stirred for 12 h. The volatiles were evaporated in vacuo. The obtained crude residue was diluted with CH2Cl2, washed with brine, and extracted with additional portions of CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered and the filtrate was concentrated in vacuo to afford crude 3-(dimethylamino)-2,3,6,7-tetrahydroazepino[3,2,1- hi]indol-4(1H)-one (Compound 1) (0.8 g, crude). ESI-MS m / z: 231.1[M+H]+. The obtained crude was directly used in the next step without any purification.

[0194] Step 6: Synthesis of Compound 2 (3-(dimethylamino)-8,9-difluoro-2,3,6,7- tetrahydroazepino[3,2,1-hi]indol-4(1H)-one):

[0195] To a solution of Int-7b (350 mg, 1.00 mmol, 1.0 eq) in acetonitrile (3.5 mL) were added K2CO3(414 mg, 3.00 mmol, 3.0 eq) and dimethylamine hydrochloride (163 mg, 2.00 mmol, 2.0 eq). The reaction mixture was heated to reflux and stirred for 12 h. The volatiles were evaporated in vacuo. The obtained crude residue was diluted with CH2Cl2, washed with brine, and extracted with additional portions of CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered and the filtrate was concentrated in vacuo to afford crude product. The crude material was purified by silica gel chromatography to yield 3-(dimethylamino)-8,9-difluoro-2,3,6,7-tetrahydroazepino[3,2,1-hi]indol-4(1H)-one (Compound 2) (200 mg, 75%). ESI-MS m / z: 266.8 [M+H]+.

[0196] Step 7: Synthesis of Compound 3 (N,N-dimethyl-1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol- 3-amine):

[0197] To a stirred solution of Compound 1 (500 mg, 2.17 mmol, 1.0 eq) in THF (5 mL) at 0 ℃ was added BH3 in THF (1M solution, 149 mg, 10.8 mmol, 5.0 eq). The reaction mixture was heated to 70 °C and was stirred at that temperature for 12 h. The reaction mixture was cooled to 0 ℃ and methanol (2 mL) was added to quench the reaction. The quenched reaction mixture was then heated to 70 ℃ and stirred at that temperature for 1 h. Volatiles were evaporated in vacuo and the obtained crude residue was diluted with water and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by silica gel chromatography to yield Compound 3 (400 mg, 85%).1H NMR (400 MHz, DMSO-d6) δ = 6.88 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 6.58 - 6.47 (m, 1H), 3.26 (s, 1H), 3.20 - 3.09 (m, 2H), 2.89 - 2.78 (m, 4H), 2.61 - 2.54 (m, 2H), 2.22 (s, 6H), 1.92 - 1.84 (m, 1H), 1.75 - 1.68 (m, 1H) ppm. ESI-MS m / z: 216.9 [M+H]+.

[0198] Step 8: Synthesis of Compound 5 (N,N-dimethyl-1,2,3,4-tetrahydroazepino[3,2,1-hi]indol-3- amine)

[0199] To a stirred solution of Compound 3 (300 mg, 1.38 mmol, 1.0 eq) in toluene (3 mL) at room temperature was added 5% Ru / C (20% w / w, 60 mg, 0.5 eq) under an oxygen atmosphere. The reaction mixture was heated to 60 °C and was stirred at that temperature for 12 h. The reaction mixture was cooled to room temperature, filtered through a celite pad, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography to afford N,N-dimethyl-1-azatricyclo[6.4.1.0⁴,¹³]trideca- 2,4(13),5,7-tetraen-11-amine (Compound 5) (100 mg, 34%).1H NMR (400 MHz, DMSO-d6) δ = 7.33 - 7.26 (m, 2H), 6.88 - 6.80 (m, 2H), 6.34 (s, 1H), 4.40 - 4.28 (m, 2H), 3.18 - 3.09 (m, 1H), 3.02 - 2.91 (m, 2H), 2.25 (s, 6H), 2.15 - 1.96 (m, 2H) ppm. ESI-MS m / z:214.9 [M+H]+.

[0200] 75 mg of Compound 5 was subjected to chiral separation to get 25 mg of Compound 6 and 30 mg of Compound 7. Column : Chiralcel AY-H (250mm, 4.6mm, 5µ) Mobile Phase : Hexane / EtOH / IPA / DEA (90 / 5 / 0.1%)

[0201] Compound 6:1H NMR (400 MHz, DMSO-d6) δ = 7.33 - 7.28 (m, 2H), 6.88 - 6.80 (m, 2H), 6.34 (d, J = 3.0 Hz, 1H), 4.40 - 4.27 (m, 2H), 3.17 - 3.09 (m, 1H), 3.02 - 2.93 (m, 2H), 2.24 (s, 6H), 2.17 - 2.08 (m, 1H), 2.04 - 1.96 (m, 1H) ppm. ESI-MS m / z: 215.1 [M+H]+.

[0202] Compound 7:1H NMR (400 MHz, DMSO-d6) δ = 7.34 - 7.26 (m, 2H), 6.89 - 6.79 (m, 2H), 6.34 (d, J = 3.1 Hz, 1H), 4.40 - 4.27 (m, 2H), 3.18 - 3.09 (m, 1H), 3.01 - 2.93 (m, 2H), 2.24 (s, 6H), 2.17 - 2.08 (m, 1H), 2.06 - 1.96 (m, 1H) ppm. ESI-MS m / z: 215.1 [M+H]+.

[0203] Step 7: Synthesis of Compound 4 (8,9-difluoro-N,N-dimethyl-1,2,3,4,6,7- hexahydroazepino[3,2,1-hi]indol-3-amine)

[0204] To a stirred solution of Compound 2(0.4 g, 1.50 mmol, 1.0 eq) in THF (8 mL) at 0 ℃ was added BH3in THF (1M solution, 124 mg, 9.00 mmol, 6.0 eq). The reaction mixture was heated to 70 °C and was stirred at that temperature for 12 h. The reaction mixture was cooled to 0 ℃ and methanol (1 mL) was added to quench the reaction. The quenched reaction mixture was then heated to 70 ℃ and stirred at that temperature for 1 h. Volatiles were evaporated in vacuo and the obtained crude residue was diluted with water and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude residue was purified by silica gel chromatography to yield 8,9-difluoro-N,N-dimethyl- 1,2,3,4,6,7-hexahydroazepino[3,2,1-hi]indol-3-amine (Compound 4) (300 mg, 79%).1H NMR (400 MHz, DMSO-d6) δ = 6.87 (dd, J = 7.8, 11.4 Hz, 1H), 3.13 (d, J = 12.3 Hz, 1H), 2.98 - 2.85 (m, 3H), 2.82 - 2.74 (m, 2H), 2.67 (br s, 1H), 2.56 (s, 2H), 2.27 (br s, 6H), 1.87 (br s, 1H), 1.78 - 1.68 (m, 1H) ppm. ESI-MS m / z: 252.9 [M+H]+.

[0205] Step 8: Synthesis of Compound 8 (8,9-difluoro-N,N-dimethyl-1,2,3,4-tetrahydroazepino[3,2,1- hi]indol-3-amine):

[0206] To a stirred solution of Compound 4 (280 mg, 1.10 mmol, 1.0 eq) in THF (5 mL) at 0 ℃ was added DDQ (749 mg, 3.30 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and diluted with aqueous NaHCO3solution and extracted withmultiple portions of EtOAc. The combined organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude product. The crude material was purified by silica gel chromatography to yield Compound 8 (160 mg, 58%).1H NMR (400 MHz, DMSO-d6) δ = 7.45 (br s, 1H), 6.95 - 6.83 (m, 1H), 6.46 (br s, 1H), 4.46 - 4.37 (m, 1H), 4.34 - 4.22 (m, 1H), 3.15 - 3.05 (m, 2H), 2.94 (d, J = 6.8 Hz, 2H), 2.23 (s, 6H), 2.11 (s, 2H), 2.00 (d, J = 6.8 Hz, 1H) ppm. ESI-MS m / z: 251.1 [M+H]+. Example A2:

[0207] Synthesis of Compound 9, 10, 11, 12, 13, and 14

[0208] Scheme-2: Synthesis of Compound 9, 10, 11, 12, 13, and 14

[0209] Step 1: Synthesis of RP-1 (7-bromo-4,5-difluoro-1H-indole):

[0210] To a stirred solution of 1-bromo-4,5-difluoro-2-nitrobenzene (A) (19 g, 79.8 mmol, 1.0 eq) in THF (190 mL) at -78 °C was added a vinyl magnesium bromide solution (1M in THF, 32.2 g, 319 mmol, 4.0 eq).The reaction mixture was allowed to warm to room temperature and was stirred at that temperature for 12 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to yield crude product. The crude material was purified by silica gel chromatography to afford 7-bromo-4,5-difluoro-1H-indole (RP-1) (6.2 g, 33%) as a brown liquid. ESI-MS m / z: 231.8 [M-H]+.

[0211] Step 2: Synthesis of RP-2 (1-allyl-7-bromo-4,5-difluoro-1H-indole):

[0212] To a stirred solution of RP-1 (6.2 g, 26.7 mmol, 1.0 eq) in DMF (62 mL) at 0 ℃ was added NaH (60% in mineral oil, 1.28 g, 53.4 mmol, 2.0 eq). The reaction mixture was stirred for 20 min at that temperature and allyl bromide (3.87 g, 32 mmol, 1.2 eq) was added. The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to yield crude product. The crude material was purified by silica gel chromatography to afford 1-allyl-7-bromo-4,5-difluoro-1H-indole (RP-2) (6.5 g, 90%) as a brown liquid. ESI-MS m / z: 290.1 [M+H2O]+.

[0213] Step 3: Synthesis of RP-3:

[0214] To a stirred solution of RP-2 (2.0 g, 7.35 mmol, 1.0 eq) in DMF (20 mL) was added K2CO3(2.0 g, 14.7 mmol, 2.0 eq) at room temperature and the reaction was degassed under N2 atmosphere for 20 minutes. To this reaction mixture was added TBAI (4.06 g, 11 mmol, 1.5 eq) followed by Pd(OAc)2 (0.33 g, 1.47 mmol, 0.2 eq). The reaction mixture was heated at 80 ℃ and was stirred at that temperature for 3 h. The reaction mixture was cooled to room temperature, diluted with water (60 mL), filtered through a pad of celite, and the filter pad was washed with EtOAc. The combined organic phase was dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified by silica gel chromatography column to afford RP-3 (0.75 g, 53%) as a mixture of regio-isomers. ESI-MS m / z:190.2 [M+H]+.

[0215] Step 4: Synthesis of RP-4 (8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol):

[0216] To a stirred solution of RP-3 (regio-isomeric mixture, 350 mg, 1.82 mmol, 1.0 eq) in THF (6 mL) at 0 ℃ was added a solution of BH3 (1M in THF, 50.3 mg, 3.64 mmol, 2.0 eq). The reaction mixture was heated to reflux and was stirred at that temperature for 2 h. The reaction mixture was allowed to cool to room temperature, quenched with an aqueous NaOH solution (3M in water, 5 mL) and an aqueous solution of H2O2 (30% in water, 3.5 mL) was added. The reaction mixture was stirred for additional 5 h at room temperature. The reaction mixture was quenched with ice cold aqueous solution of NaCl and extracted with multiple portions of EtOAc. The combined organic layers were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude was purified by silica gel chromatography to afford RP-4 (8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol) (220 mg, 58%) as a brown liquid. ESI-MS m / z: 210.0 [M+H]+.

[0217] Step 5: Synthesis of RP-5 (8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4- methylbenzenesulfonate):

[0218] To a stirred solution of RP-4 (170 mg, 0.81 mmol, 1.0 eq) in dichloromethane (10 mL) was added triethylamine (163 mg, 1.62 mmol, 2.0 eq) at 0 ℃ and the reaction mixture was stirred for 10 mins. To the reaction mixture was added TsCl (229 mg, 1.21 mmol, 1.5 eq), followed by DMAP (9.92 mg, 0.08 mmol, 0.1 eq). The reaction mixture was warmed to room temperature and stirred at that temperature for 6 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic layers were washed with an aqueous solution of NaHCO3, dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to obtain crude product. The crude material was purified by silica gel chromatography to afford RP-5 (8,9-difluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl 4-methylbenzenesulfonate) (110 mg, 37%) as a brown liquid, which was carried forward without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.73 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 6.8, 10 Hz, 1H), 6.54 (br s, 1H), 5.35 - 5.11 (m, 1H), 4.29 (d, J = 3.4 Hz, 2H), 3.10 (s, 2H), 2.47 (s, 3H) ppm.

[0219] Step 6: Synthesis of RP-6 (5-azido-8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline):

[0220] To a stirred solution of RP-5 (110 mg, 0.28 mmol, 1.0 eq) in DMF (1.1 mL) at 0 ℃ was added NaN3(28.1 mg, 0.43 mmol, 1.5 eq). The reaction mixture was allowed to warm to room temperature, was heated to 65 ℃, and was stirred at that temperature for 2 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of diethyl ether. The combined organic layers were washed with ice cold water, followed by an aqueous solution of NaCl. The organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude 5-azido-8,9-difluoro-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinoline (RP-6) (60 mg, 83%). The crude was directly used in the next step without purification. ESI-MS m / z: 235.3 [M+H]+.

[0221] Step 7: Synthesis of Compound 9 (8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine)

[0222] To a stirred solution of crude RP-6 (60 mg, 0.24 mmol, 1.0 eq) in THF (0.6 mL) and H2O (0.3 mL) at 0 ℃ was added TPP (94.6 mg, 0.36 mmol, 1.5 eq). The reaction mixture was allowed to warm to room temperature, was heated to 80 ℃, and was stirred at that temperature for 2 h. The reaction mixture was allowed to cool at room temperature, diluted with ice cold water, and extracted with multiple portions of EtOAc. The combined organic extracts were washed with an aqueous solution of NaCl, dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 8,9-difluoro-5,6-dihydro- 4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 9) (30 mg, 56 %). ESI-MS m / z: 209.0 [M+H]+.

[0223] Step 8: Synthesis of Compound 12 (8,9-difluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine):

[0224] To a stirred solution of RP-7 (25 mg, 0.11 mmol, 1.0 eq) in a MeOH : THF mixture (1:1, 1 mL) was added a solution of formaldehyde (37% in water, 3.36 mg, 0.11 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at that temperature for 30 mins. The reaction mixture was cooled to 0 ℃ and NaCNBH3(7.03 mg, 0.11 mmol, 1.0 eq) was added portion-wise. The reaction mixture was warmed to room temperature and was stirred at that temperature for 16 h. The volatiles were removed in vacuo, the crude reaction residue was washed with water, and extracted with multiple portions of EtOAc. The combined organic extracts were washed with an aqueous solution of NaCl, the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography to afford Compound 12 (15 mg, 53%).1H NMR (400 MHz, METHANOL-d4) δ = 7.34 (d, J = 2.9 Hz, 1H), 6.98 (dd, J = 6.8, 10.8 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.58 (d, J = 4.4 Hz, 2H), 4.06 (d, J = 4.9 Hz, 1H), 3.51 - 3.40 (m, 2H), 2.93 (s, 6H) ppm. ESI-MS m / z: 237.1 [M+H]+.

[0225] Step 8+9: Synthesis of RP-8 (tert-butyl (8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-yl)carbamate):

[0226] To a stirred solution of Compound 9 (1.1 g, 5.28 mmol, 1.0 eq) in DCM (15 mL) at 0 ℃ was added triethylamine (1.46 mL, 10.5 mmol, 2.0 eq), followed by Boc2O (969 µL, 4.22 mmol, 0.8 eq), and DMAP (cat). The resulting reaction mixture was slowly warmed to room temperature and stirred at that temperature for 16 h. The reaction mixture was diluted with water and extracted with multiple portions of DCM. The combined organic phase was washed with brine, dried over Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to afford crude material. The crude compound was purified by silica gel chromatography to afford RP-8 (1.1 g, 68%) as an off white solid.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.08 (s, 1H), 6.81 (dd, J = 6.8, 10.4 Hz, 1H), 6.56 (d, J = 2.6 Hz, 1H), 4.52 (s, 2H), 4.28 - 4.21 (m, 1H), 4.14 (d, J = 9.6 Hz, 1H), 3.19 (d, J = 16.2 Hz, 1H), 2.92 (d, J = 15.4 Hz, 1H), 1.42 (br s, 9H) ppm. ESI-MS m / z: 309.2 [M+H]+.

[0227] 1.1 g of RP-8 was subjected to chiral separation to get 460 mg of RP-9 (tert-butyl (R)-(8,9-difluoro- 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate)& 450 mg of RP-10 (tert-butyl (S)-(8,9-difluoro- 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate). Column : Chiralpak-AD-H(250mm, 30mm, 5µ) Mobile Phase A : 0.1% DEA in n- Hexane Mobile Phase B : EtOH Flow rate : 36.0 mL / min

[0228] RP-9:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.08 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 6.6, 10.4 Hz, 1H), 6.56 (d, J = 2.9 Hz, 1H), 4.59 - 4.48 (m, 1H), 4.27 - 4.21 (m, 1H), 4.18 - 4.10 (m, 1H), 3.19 (d, J = 16.2 Hz, 1H), 2.96 - 2.89 (m, 1H), 1.41 (br s, 9H) ppm. ESI-MS m / z: 308.7 [M+H]+.

[0229] RP-10:1H NMR (400 MHz, CHLOROFORM-d) δ = 7.08 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 6.4, 10.8 Hz, 1H), 6.56 (d, J = 2.9 Hz, 1H), 4.53 (d, J = 10.2 Hz, 2H), 4.28 - 4.20 (m, 1H), 4.14 (2 d, J = 9.8 Hz, 1H), 3.19 (d, J = 16.2 Hz, 1H), 2.97 - 2.88 (m, 1H), 1.41 (br s, 9H) ppm. ESI-MS m / z: 308.9 [M+H]+.

[0230] Step-10: Synthesis of Compound 10 ((R)-8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine) & Compound 11 ((S)-8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine):

[0231] To a stirred solution of RP-9 (350 mg, 1.13 mmol, 1.0 eq) in DCM (15 mL) at 0 ℃ were added 2,6- lutidine (652 µL, 5.64 mmol, 5.0 eq) and TMSOTf (819 µL, 4.52 mmol, 4.0 eq). The reaction mixture slowly warmed to room temperature and was stirred at that temperature for 4 h. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted with multiple portions of DCM. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to yield crude product. The crude material was purified by silica gel chromatography to afford Compound 10 (250 mg, crude).1H NMR (400 MHz, DMSO-d6) δ: 7.47 (d, J = 2.4 Hz, 1H), 6.97 (dd, J = 6.8, 11.2 Hz, 1H), 6.51 (d, J = 2.9 Hz, 1H), 4.30 (dd, J = 3.4, 12.2 Hz, 1H), 4.09 (br s, 2H), 3.91 (dd, J = 7.2, 12.2 Hz, 1H), 3.66 - 3.59 (m, 1H), 3.10 (d, J = 3.4 Hz, 1H), 2.86 - 2.78 (m, 1H) ppm. ESI-MS m / z: 209.2 [M+H]+.

[0232] To a stirred solution of RP-10 (450 mg, 1.45 mol, 1.0 eq) in DCM (15 mL) at 0 ℃ were added 2,6- lutidine (837 µL, 7.24 mmol, 5.0 eq) and TMSOTf (1.04 mL, 5.80 mmol, 4.0 eq). The reaction mixture slowly warmed to room temperature and was stirred at that temperature for 4 h. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted with multiple portions of DCM. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated invacuo to yield crude product. The crude material was purified by silica gel chromatography to afford Compound 11 (240 mg, 80%).1H NMR (400 MHz, DMSO-d6) δ: 7.42 (d, J = 2.9 Hz, 1H), 6.91 (dd, J = 6.8, 11.2 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 4.24 (dd, J = 3.6, 12.0 Hz, 1H), 4.04 (s, 2H), 3.81 (dd, J = 7.8, 12.2 Hz, 1H), 3.52 - 3.47 (m, 1H), 3.05 (dd, J = 3.4, 16.0 Hz, 1H), 2.76 - 2.70 (m, 1H) ppm. ESI-MS m / z: 209.3 [M+H]+.

[0233] Step-11; Synthesis of Compound 13 ((R)-8,9-difluoro-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine) & Compound 14 ((S)-8,9-difluoro-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine)

[0234] To a stirred solution of Compound 10 (200 mg, 960 µmol, 1.0 eq) in THF / MeOH mixture (1:1, 10 vol) was added a solution of formaldehyde (37% in water, 233 mg, 2.88 mmol, 3.0 eq). The reaction mixture was stirred for 30 minutes, then was cooled to 0 ℃, and NaCNBH3(120 mg, 1.91 mmol, 2.0 eq) was added. The reaction mixture was warmed to room temperature and was stirred at that temperature for 12 h. The volatiles were evaporated in vacuo, the obtained crude residue was diluted with water (10 mL), and the entire mixture was extracted twice with a 10% MeOH / DCM solution. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude compound. The crude material was purified by silica gel chromatography to afford Compound 13 (120 mg, 53%).

[0235] To a stirred solution of Compound 11 (200 mg, 960 µmol, 1.0 eq) in THF / MeOH mixture (1:1, 10 vol) was added a solution of formaldehyde (37% in water, 233 mg, 2.88 mmol, 3.0 eq). The reaction mixture was stirred for 30 minutes, then was cooled to 0 ℃, and NaCNBH3(120 mg, 1.91 mmol, 2.0 eq) was added. The reaction mixture was warmed to room temperature and was stirred at that temperature for 12 h. The volatiles were evaporated in vacuo, the obtained crude residue was diluted with water (10 mL), and the entire mixture was extracted twice with a 10% MeOH / DCM solution. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crudecompound. The crude material was purified by silica gel chromatography to afford Compound 14 (105 mg, 46%). Example A3:

[0236] Synthesis of Compound 15 and Compound 16

[0237] Scheme-3: Synthesis of Compound 15 and Compound 16

[0238] Step 1: Synthesis of 1-allyl-7-bromo-1H-indole (XX-2)

[0239] Under a nitrogen atmosphere and in an ice-water bath, NaH (60% in mineral oil , 57.3 g, 1.43 mol, 2.0 eq) was added portion-wise over 25 min to a solution of 7-bromo-1H-indole (XX-1) (140 g, 715 mmol,1.0 eq) in DMF (1.1 L), while the internal temperature was kept below 5 ℃. After the resulting mixture was stirred in an ice-water bath for 30 mins, allyl bromide (130 g, 1.07 mol, 1.5 eq) was added dropwise over 25 mins into the solution above. The reaction was stirred at room temperature for an additional 30 min. The reaction was then quenched with an aqueous NH4Cl solution (2.5 L) and extracted with EtOAc (1 L x 2). The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude 1-allyl-7-bromo-1H-indole (400.5 g, crude) as a yellow-brownish oil. LC-MS (ESI+): m / z 236 (M+H)+; 1H-NMR (300 MHz, CDCl3): 7.53 (d,J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.92 (m, 1H), 6.51 (d, J = 2.7 Hz, 1H), 6.06 (m, 1H), 5.18 (m, 3H), 4.88 (d, J = 17.1 Hz, 1H).

[0240] Step 2: Synthesis of 4H-pyrrolo[3,2,1-ij]quinoline and 6H-pyrrolo[3,2,1-ij]quinoline (XX-3)

[0241] Under a nitrogen atmosphere, a mixture of crude 1-allyl-7-bromo-1H-indole (43.5 g, 77.6 mmol, 1.0 eq), K2CO3(21.5 g, 155 mmol, 2.0 eq), TBAI (14.3 g, 38.8 mmol, 0.5 eq) and Pd(OAc)2(1.74 g, 7.76 mmol, 0.1 eq) in DMF (200 mL) was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, quenched with ice-water (600 mL), and extracted with EtOAc (200 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to give crude product, a mixture of regio-isomers, as a black oil. The crude product was purified by silica gel chromatography to afford XX-3 (9.6 g, 80%) as a brown solid, a mixture of regio-isomers. LC-MS (ESI+): m / z 156 (M+H)+.

[0242] Step 3: Synthesis of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol (XX-4)

[0243] To a regio-isomeric mixture of XX-3 (9.6 g, 61.9 mmol, 1.0 eq) in THF (50 mL) in an ice-water bath was added BH3•THF (100 mL, 99.0 mmol, 1.6 eq) dropwise over 25 min. The reaction was then heated to 60 ℃ and maintained at that temperature for 2 hours. The reaction was cooled to room temperature using an ice-water bath and quenched with aqueous NaOH solution (4.95 g in 70 mL H2O, 123.7 mmol, 2.0 eq) while the reaction flask was flushed with a stream of nitrogen to blow out the waste gas generated during the quench. After quenching, H2O2 (8.3g, 123.7 mmol, 2.0 eq) was added dropwise into the solution over 15 min. The reaction was stirred at room temperature for an additional 2 h. Water (300 mL) was added, and the resulting mixture was acidified with a diluted HCl solution and extracted with EtOAc (150 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to give crude XX-4, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol (10.95 g, crude) as a dark brown solid, which was carried forward without further purification. LC-MS (ESI+): m / z 174(M+H)+; 1H-NMR (300 MHz, CDCl3) δ 7.45 (d, J = 7.8 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.97 (d, J = 6.9Hz, 1H), 6.48 (d, J = 3.0 Hz, 1H), 4.56 (s, 1H), 4.23 (m, 1H), 4.20 - 4.10 (m, 2H), 3.23 (m, 1H), 3.08 (m, 1H).

[0244] Step 4: Synthesis of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4-methylbenzenesulfonate (XX-5)

[0245] To a mixture of crude 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol (10.95 g, 61.9 mmol, 1.0 eq) in DCM (150 mL) was added triethylamine (43.8 g, 433 mmol, 7.0 eq), and DMAP (756 mg, 6.19 mmol, 0.1 eq), followed by the dropwise addition of a solution of TsCl (35.4 g, 186 mmol, 3.0 eq) in DCM (100 mL) over 30 mins. The reaction was stirred at room temperature overnight. The reaction was quenched with ice- water (1.5 L) and extracted with EtOAc (500 mL x 2). The combined organic layer was dried over anhydrous Na2SO4., the solids were filtered, and the filtrate was concentrated in vacuo to give crude material. The crude product was purified by silica gel chromatography, followed by trituration with MTBE, to afford XX-5, 5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4-methylbenzenesulfonate (7.79 g, 61%) as a white solid. LC-MS (ESI+): m / z 328 (M+H)+;1H-NMR (300 MHz, CDCl3) δ: 7.74 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.05 - 6.97 (m, 2H), 6.84 (d, J = 6.9 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 5.21 (m, 1H), 4.40 - 4.33 (m, 2H), 3.18 -3.15 (m, 2H), 2.45 (s, 3H).

[0246] Step 5: Synthesis of 5-azido-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (XX-6)

[0247] Under a nitrogen atmosphere, NaN3(26.3 g, 403 mmol, 1.5 eq) was added to a mixture of XX-5 (88 g, 269 mmol, 1.0 eq) in DMF (1.2 L). The reaction was heated to 65 ℃ and was stirred at that temperature for 3 h. The reaction was quenched with H2O (3 L) and extracted with EtOAc (1 L x 2). The combined organic layer was washed with brine (500 ml) and dried over anhydrous Na2SO4. The solids were filtered and the filtrate was concentrated in vacuo to provide XX-6, 5-azido-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (73.4 g, crude) as a dark brown oil.1H-NMR (300 MHz, CDCl3) δ: 7.46 (d, J = 7.8 Hz, 1H), 7.10 - 6.95 (m, 3H), 6.49 (d, J = 3.0 Hz, 1H), 4.40 - 4.25 (m, 2H), 4.14 (m, 1H), 3.32 (m, 1H), 3.19 (m, 1H).

[0248] Step 6: Synthesis of XX-7 tert-butyl (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate

[0249] To a solution of the intermediate XX-6 (7.02 g, 25.7 mmol, 1.0 eq) and Boc2O (8.41 g, 38.5 mmol, 1.5 eq) in MeOH (150 mL) was added Pd / C (0.7 g, 10 wt%). The suspension was stirred at room temperature under a hydrogen atmosphere overnight. The suspension was filtered through a pad of Celite. The filter cake was washed with MeOH (10 mL). The combined filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography to give XX-7, tert-butyl (5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)carbamate (4.48 g, 64%) LC-MS (ESI+): m / z 295 (M+Na)+;1H-NMR (300 MHz, CDCl3) δ: 7.50 (d, J = 6.0 Hz, 1H), 7.10 - 6.90 (m, 3H), 6.48 (d, J = 3.0 Hz, 1H), 4.65 (m, 1H), 4.54 (m, 1H), 4.23 (m, 1H), 4.18 (m, 1H), 3.25 (m, 1H), 2.97 (m, 1H), 1.40 (s, 9H).

[0250] Step 7: Synthesis of XX-8 tert-butyl (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)- carbamate

[0251] Under a nitrogen atmosphere, NaH (853 mg, 21.3 mmol, 2.0 eq) was added portion-wise over 2 minutes to a solution of XX-7 (2.91 g, 10.66 mmol, 1.0 eq) in DMF (40 mL) in an ice-water bath. The reaction mixture was stirred in an ice-water bath for an additional 10 mins. MeI (4.54 g, 32 mmol, 3.0 eq) was added to the reaction dropwise over 1 minute. The reaction was then stirred at room temperature for 20 mins. The reaction was quenched with an aqueous NH4Cl solution (200 mL) and extracted with EtOAc (80 mL x 2). The combined organic layer was washed with water (100 mL) and dried with anhydrous Na2SO4. The solids were filtered, and the filtrate was concentrated in vacuo to afford XX-8, tert-butyl (5,6-dihydro- 4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)-carbamate (3.06 g, 100%) as an off-white solid. LC-MS (ESI+): m / z 287 (M+H)+;1H-NMR (300 MHz, DMSO-d6) δ :7.40-7.35 (m, 2H), 7.01-6.85 (m, 2H), 6.40 (d, J = 3.0 Hz, 1H), 4.50 (m, 1H), 4.30-4.18 (m, 2H), 3.28 (m, 1H), 2.95 (m, 1H), 2.81 (s, 3H), 1.43 (s, 9H).

[0252] Step 8: Synthesis of XX-9 N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine

[0253] Under a nitrogen atmosphere, to a suspension of LAH (1.01 g, 26.7 mmol, 2.5 eq) in THF (50 mL) at 10 ℃ was added intermediate XX-8 (3.06 g, 10.7 mmol, 1.0 eq) portion wise over 3 mins. After addition, the suspension was warmed to 70 ℃ and maintained at that temperature for 2 h. The reaction was quenched with ice-cold water (1 mL), followed by an aqueous NaOH solution (1 mL, 15 wt%) and ice-cold water (3 mL). The resulting mixture was stirred at room temperature for 30 min. The suspension was filtered, andthe filter cake was washed with THF (20 mL). The combined filtrate was concentrated in vacuo to give XX-9 (2.42, crude), as an oil which was carried forward without further purification. LC-MS (ESI+): m / z 201 (M+H)+;1H-NMR (300 MHz, CDCl3) δ: 7.43 (d, J = 7.8 Hz, 1H), 7.10 - 6.90 (m, 3H), 6.48 (d, J = 3.0 Hz, 1H), 4.35 (m, 1H), 4.10 (m, 1H), 3.18 - 3.02 (m, 3H), 2.46 (s, 6H).

[0254] Step 9: Synthesis of Compound 15, 1-bromo-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine

[0255] Under a nitrogen atmosphere, to a solution of XX-9 (37.5 g, 187 mmol, 1.0 eq) in DMF (800 mL) at 0 ℃ was added NBS (33.3 g, 187 mmol,1.0 eq) portion-wise over 10 min while stirring. The reaction mixture was stirred at the same condition for 1 h. The reaction mixture was diluted with ice-cold water and extracted with EtOAc (1.5 L x 2). The combined organic layer was washed with aqueous NaHCO3solution (500 ml), dried over anhydrous Na2SO4. The solids were filtered and the filtrate was concentrated in vacuo to give crude product. The crude material was purified by silica gel chromatography to afford Compound 15 (35.5 g, 65%). HPLC purity was 98.7%. LC-MS (ESI+): m / z 279 (M+H)+;1H-NMR (300 MHz, CDCl3) δ: 7.50 (s, 1H), 7.17 (d, J = 7.8 Hz,1H), 7.03 (m, 1H), 6.96 (d, J = 7.8 Hz, 1H), 4.33 (m, 1H), 4.04 (m, 1H), 3.13-2.97 (m, 3H), 2.31 (s, 6H). Example A4:

[0256] Synthesis of Compound 16 (1-(3-methoxyphenyl)-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine)

[0257] To a stirred solution of Compound 15 (70 mg , 0.25 mmol, 1.0 eq) in 1,4 dioxane (0.7 mL) were added sodium hydroxide (16.9 mg, 0.42 mmol, 2.0 eq) in water (0.14 mL) followed by (3- methoxyphenyl)boronic acid (75.9 mg, 0.50 mmol, 2.0 eq) at room temperature and the reaction mixture was degassed under a N2atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate trimer (16.8 mg, 0.02 mmol, 0.1 eq) followed by tri-tert-butylphosphonium tetrafluoroborate (14.5 mg, 0.05 mmol, 0.2 eq) at room temperature. The reaction mixture was heated to 80 ℃ and stirred at thattemperature for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, the solids were filtered and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to get 1-(3-methoxyphenyl)-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine (Compound 16) (10 mg, 13%).1H NMR (400 MHz, DMSO-d6) δ: 7.70 - 7.62 (m, 2H), 7.32 - 7.22 (m, 2H), 7.17 (s, 1H), 7.03 - 6.97 (m, 1H), 6.92 (d, J = 6.8 Hz, 1H), 6.76 (d, J = 6.8 Hz, 1H), 4.39 - 4.32 (m, 1H), 4.10 - 4.04 (m, 1H), 3.79 (s, 3H), 3.11 - 2.97 (m, 3H), 2.32 (s, 6H) ppm. ESI-MS m / z: 307.4 [M+H]+. Example A5:

[0258] Synthesis of Compound 17, 18, 19, 20, and 21:

[0259] To a stirred solution of Compound 15 (350 mg, 1.25 mmol, 1 eq) in 1,4 dioxane: water (4:1, 13 mL) were added sodium hydroxide (84.8 mg, 2.12 mmol, 1.7 eq) followed by (3-cyanophenyl)boronic acid (220 mg, 1.50 mmol, 1.2 eq) at room temperature and the reaction mixture was degassed under a N2atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate trimer (84.1 mg, 0.12 mmol, 0.1 eq) followed by tri-tert-butylphosphonium tetrafluoroborate (72.5 mg, 0.25 mmol, 0.2 eq) at room temperature. The reaction mixture was heated to 80 ℃ and stirred at that temperature for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, the solids were filtered an the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 3- (5-(dimethylamino)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (Compound 17) (230 mg, 65%).1H NMR (400 MHz, DMSO-d6) δ = 8.05 (s, 1H), 8.01 - 8.02 (m, 1H), 7.87 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.60 (s, 2H), 7.06 - 7.02 (m, 1H), 6.95 (d, 1H), 4.35 (d, J = 2.8 Hz, 1H), 4.13 - 4.11 (m, 1H), 3.10 - 3.01 (m, 3H), 2.32 (br s, 6H) ppm. ESI-MS m / z: 302.3 [M+H]+.

[0260] Racemic Compound 17 (200 mg) was subjected to chiral separation to get 56 mg of Compound 18 with chiral HPLC purity 99% and 50 mg of Compound 19 with chiral HPLC purity 92%; this was re- purified by chiral column to get 40 mg of Compound 19 with chiral HPLC purity 98% . Column : Chiralpak IG (250mm, 30mm, 5µ) Mobile Phase A : 0.1% DEA in n- Hexane Mobile Phase B : EtOH: IPA ( 1:1) Flow rate : 36.0 mL / min

[0261] Step 1: Synthesis of Compound 20 ((R)-1-bromo-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine) and Compound 21 ((S)-1-bromo-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine):

[0262] 4.5 g of Compound 15 was subjected to chiral separation to get each 2 g of Compound 20 & Compound 21. Column : Chiralpak AD-H (250mm, 4.6mm, 5µ) Mobile Phase : Hexane / MeOH / IPA / DEA (90 / 5 / 5 / 0 / 1)

[0263] Compound 20:1H NMR (400 MHz, CHLOROFORM-d) δ: 7.35 (d, J = 7.9 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.97 (d, J = 7.0 Hz, 1H), 4.34 - 4.27 (m, 1H), 4.00 (t, J = 10.6 Hz, 1H), 3.21 - 2.98 (m, 3H), 2.45 (s, 6H) ppm. ESI-MS m / z: 280.9 [M+H]+.

[0264] Compound 21:1H NMR (400 MHz, CHLOROFORM-d) δ: 7.35 (d, J = 7.9 Hz, 1H), 7.12 - 7.07 (m, 2H), 6.97 (d, J = 7.0 Hz, 1H), 4.33 - 4.28 (m, 1H), 4.03 - 3.96 (m, 1H), 3.20 - 3.10 (m, 2H), 3.06 - 2.98 (m, 1H), 2.45 (s, 6H) ppm. ESI-MS m / z: 281.0 [M+H]+. Example A6:

[0265] Synthesis of Compound 22 ((S)-1-(2-fluorophenyl)-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0266] To a stirred solution of Compound 21 (1 g, 3.58 mmol, 1.0 eq) in 1,4 dioxane: water (4:1, 25 mL) were added sodium hydroxide (243 mg, 6.08 mmol, 1.7 eq), followed by (2-fluorophenyl)boronic acid (1 g, 7.16, 2.0 eq) at room temperature and the reaction mixture was degassed under a N2atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate trimer (160 mg, 0.716 mmol, 0.2 eq) followed by tri-tert-butyl-phosphonium tetrafluoroborate (207 mg, 0.71 mmol, 0.2 eq) at room temperature. The reaction mixture was stirred at 80 °C for 8 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, the solids were filtered and the filtrate was concentrated in vacuo to obtain crudematerial. The crude product was purified by silica gel chromatography to afford (S)-1-(2-fluorophenyl)-N,N- dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 22) (550 mg, 52%).1H NMR (400 MHz, DMSO-d6) δ = 7.75 (br s, 1H), 7.66 (br s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 6.6 Hz, 3H), 7.07 - 6.98 (m, 1H), 6.96 (d, J = 6.6 Hz, 1H), 4.43 (d, J = 12.0 Hz, 1H), 4.12 (dd, J = 8.1, 11.4 Hz, 1H), 3.11 (t, J = 9.5 Hz, 1H), 3.07 - 2.96 (m, 2H), 2.35 (s, 6H) ppm. ESI-MS m / z: 295.1 [M+H]+. Example A7:

[0267] Synthesis of Compound 23 (1-((dimethylamino)methyl)-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine)

[0268] Scheme-4: Synthetic scheme for the Synthesis of Compound 23:

[0269] Step 1: Synthesis of B-1 (5-(dimethylamino)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1- carbaldehyde):

[0270] To a stirred solution of phosphorus oxychloride (182 mg, 1.19 mmol, 1.2 eq) in DMF (0.5 mL) was added XX-9 (200 mg, 0.99 mmol, 1 eq) in DMF (1.5 mL) at 0 ℃ and the resulting reaction mixture was stirred for 30 mins at same temperature and subsequently poured into ice. The resulting reaction mixture was basified with concentrated aqueous NaOH solution and was stirred at room temperature for 1 h. The reaction mixture was extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford 5- (dimethylamino)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbaldehyde (B-1) (125 mg, 55%) as a pale yellow gummy, which was carried forward without further purification. ESI-MS m / z: 229.0 [M+H]+.

[0271] Step 2: Synthesis of Compound 23:

[0272] To a stirred solution of B-1 (70 mg, 0.35 mmol, 1.0 eq) in MeOH (5 mL) were added dimethylamine hydrochloride (74 mg, 0.91 mmol, 3.0 eq) followed by 3Å molecular sieves at 0 ℃. The reaction mixture was stirred at room temperature for 1 h. To this was added NaCNBH3 (192 mg, 3.06 mmol, 10 eq) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the obtained crude residue was diluted with CH2Cl2. The organic phase was washed with saturated aqueous solution of NaCl and extracted with CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by RP prep HPLC purification to afford Compound 23 (5.6 mg).1H NMR (400 MHz, DMSO-d6) δ = 7.35 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 6.92 - 6.81 (m, 2H), 4.33 - 4.27(m, 1H), 4.02 - 3.90 (m, 1H), 3.50 (s, 2H), 3.10 - 2.90 (m, 3H), 2.33 (s, 6H), 2.14 (s, 6H) ppm. ESI-MS m / z: 256.0 [M-H]+. Example A8:

[0273] Synthesis of Compound 24 and Compound 25

[0274] Scheme-5: Synthetic route for Compound 24 and Compound 25

[0275] Step 1: Synthesis of YY-0 and its enantiomers YY-0-1 and YY-0-2

[0276] Racemate YY-0 (5.9 g) was submitted for chiral HPLC purification to afford: Column : ChiralPak IK (250mm, 4.6mm, 5µ) Mobile Phase A : n-Hexane: IPA (90:10)

[0277] YY-0-1: 2.3 g as a pale yellow solid. ESI-MS m / z: 273.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.39 - 7.27 (m, 2H), 7.19 - 7.04 (m, 1H), 6.96 - 6.89 (m, 1H), 6.88 - 6.83 (m, 1H), 6.37 (d, J = 2.9 Hz, 1H), 4.35 (dd, J = 3.8, 11.6 Hz, 1H), 4.02 (d, J = 2.4 Hz, 1H), 3.91 - 3.81 (m, 1H), 3.14 - 3.05 (m, 1H), 2.97 - 2.89 (m, 1H), 1.41 (s, 9H) ppm.

[0278] YY-0-2: 1.8 g as a pale yellow solid. ESI-MS m / z: 273.3 [M+H]+.1H NMR (400 MHz, CHLOROFORM-d) δ: 7.48 (d, J = 7.8 Hz, 1H), 7.13 - 7.00 (m, 2H), 6.95 (d, J = 7.2 Hz, 1H), 6.48 (d, J = 2.9 Hz, 1H), 4.66 - 4.49 (m, 2H), 4.30 - 4.23 (m, 1H), 4.17 (d, J = 9.8 Hz, 1H), 3.26 (dd, J = 3.4, 16.2 Hz, 1H), 2.98 (dd, J = 4.2, 15.8 Hz, 1H), 1.40 (s, 9H) ppm.

[0279] Step 2: Synthesis of tert-butyl (1-bromo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)- carbamates (YY-1 and YY-2)

[0280] To a stirred solution of YY-0-1 (2.1 g, 7.71 mmol, 1.0 eq) in DMF (20 mL) was added NBS (1.37 g, 7.71 mmol, 1.0 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with ice cold water (2 X 50 mL) and an aqueous solution of NaCl. The organic layers were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford tert-butyl (R)-(1-bromo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (YY-1) (2.1 g, crude) as a pale brown solid, which was carried forward without further purification. ESI-Ms m / z: 350.9 [M+H]+.

[0281] To a stirred solution of YY-0-2 (1.7 g, 6.24 mmol, 1.0 eq) in DMF (20 mL) was added NBS (1.11 g, 6.24 mmol, 1.0 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with ice cold water (2 X 50 mL) and an aqueous solution of NaCl. The organic layers were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford tert-butyl (S)-(1-bromo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (YY-2) (1.7 g, crude) as a pale brown solid, which was carried forward without further purification. ESI-MS m / z: 350.8 [M+H]+.

[0282] Step 3: Synthesis of tert-butyl -(1-(2-fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamates (YY-3 and YY-4)

[0283] In a sealed tube, YY-1 (100 mg, 0.28 mmol, 1.0 eq) in dioxane:water (4:1, 5 mL) was added, followed by NaOH (20 mg, 0.48 mmol, 1.7 eq), tri-tert-butylphosphonium tetrafluoroborate (16.4 mg, 0.05 mmol, 0.2 eq) and (2-fluorophenyl)boronic acid (79.4 mg, 0.56 mmol, 2.0 eq) at room temperature. The resulting reaction mixture was degassed under a N2atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate (12.7 mg, 0.05 mmol, 0.2 eq) at room temperature. The reaction mixture was heated to 80 ℃ and was stirred at that temperature for 8 h. The reaction mixture was filtered through a celite bed, diluted with water, and extracted with multiple portions of EtOAc. The combined organic layer was washed with a saturated aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (R)-(1-(2-fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate (YY-3) (40 mg, 38%) as a pale yellow solid. ESI-MS m / z: 368.3 [M+H]+.

[0284] In a sealed tube, YY-2 (1.7 g, 5.97 mmol, 1.0 eq) in dioxane:water (4:1, 30 mL) was added, followed by NaOH (328 mg, 8.21 mmol, 1.7 eq), tri-tert-butylphosphonium tetrafluoroborate (280 mg, 0.96 mmol, 0.2 eq) and (2-fluorophenyl)boronic acid (1.35 g, 9.66 mmol, 2.0 eq) at room temperature. The resulting reaction mixture was degassed under a N2 atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate (216 mg, 0.96 mmol, 0.2 eq) at room temperature. The reaction mixture was heated to 80 ℃ and was stirred at that temperature for 8 h. The reaction mixture was filtered through a celite bed, diluted with water, and extracted with multiple portions of EtOAc. The combined organic layer was washed with a saturated aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (S)-(1-(2-fluorophenyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate (YY-4) (1.1 g, 63%) as a pale yellow solid. ESI-MS m / z: 95.14 %; 368.3 [M+H]+.

[0285] Step 4: Synthesis of Compound 25 ((S)-1-(2-fluorophenyl)-N-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine) & Compound 24 ((R)-1-(2-fluorophenyl)-N-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0286] To a stirred solution of YY-3 (1.0 g, 3.0 mmol, 1.0 eq) in DCM (10 mL) was added 2M LAH in THF (6.0 mL, 12.0 mmol, 4.0 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with aqueous Na2SO4 solution (5 mL) and the obtained solids were filtered-off and extracted with DCM (10 mL). The combined organic extracts were washed with an aqueous NaCl solution (30 mL). The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography, followed by RP Prep HPLC to afford Compound 24 (247 mg, 32%).

[0287] To a stirred solution of YY-4 (1.1 g, 3.00 mmol, 1.0 eq) in DCM (30 mL) was added 2M LAH in THF (6.0 mL, 12 mmol, 4.0 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with aqueous Na2SO4 solution (5 mL) and the obtained solids were filtered-off and extracted with DCM (10 mL). The combined organic extracts were washed with an aqueous NaCl solution (30 mL). The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography, followed by RP Prep HPLC to afford Compound 25 (295 mg, 35%). Example A9:

[0288] Synthesis of Compound 26, Compound 27, and Compound 28

[0289] Scheme-6: Synthetic scheme for various analogues obtained from YY-0

[0290] Step-1: Synthesis of ZZ-1 (N-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine):

[0291] To a stirred solution of YY-0 (500 mg, 1.83 mmol, 1.0 eq) in THF (10 mL) was added 2M LAH solution (2.28 mL, 4.57 mmol, 2.5 eq) at 0 ℃ and the reaction mixture was heated to 70 ℃ and stirred at that temperature for 4 h. The reaction mixture was quenched with aqueous Na2SO4 solution and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by silica gel chromatography to afford N-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine (ZZ-1) (300 mg, 88%) as a pale yellow gummy. ESI-MS m / z: 187.0 [M+H]+.

[0292] Step-2: Synthesis of Compound 26 (N-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine):

[0293] To a stirred solution of ZZ-1 (80 mg, 0.42 mmol, 1.0 eq) in MeOH (5 ml) were added 2-(tetrahydro- 2H-pyran-4-yl)acetaldehyde (82.4 mg, 0.64 mmol, 1.5 eq) and acetic acid (cat). The resulting reaction mixture was stirred at room temperature for 30 mins. To this was added NaCNBH3(67.2 mg, 1.07 mmol, 2.5 eq) at 0 ℃ and the reaction mixture was allowed to warm to room temperature and was stirred for 12 h. The volatiles were evaporated in vacuo, and the obtained crude residue was diluted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3solution and extracted with multiple portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by RP prep HPLC purification to afford N-methyl-N-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine (Compound 26) (20 mg, 6%).1H NMR (400 MHz, DMSO-d6) δ = 7.33 - 7.27 (m, 2H), 6.92 - 6.87 (m, 1H), 6.86 - 6.83 (m, 1H), 6.34 (d, J = 2.9 Hz, 1H), 4.29 (dd, J = 4.0, 12.0 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.80 (dd, J = 3.4, 10.8 Hz, 2H), 3.26 - 3.21 (m, 3H), 3.03 - 2.99 (m, 2H), 2.62 - 2.58 (m, 2H), 2.32 (s, 3H), 1.60 - 1.53 (m, 3H), 1.40 - 1.34 (m, 2H), 1.18 - 1.09 (m, 2H) ppm. ESI-MS m / z: 299.5 [M+H]+.

[0294] Step-2: Synthesis of Compound 27 (N-methyl-N-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0295] To a solution of ZZ-1 (100 mg, 0.53 mmol, 1.0 eq) in EtOH (1 mL) was added a solution of tetrahydro-4H-pyran-4-one (64.3 mg, 0.64 mmol, 1.2 eq) and Ti[OCH(CH3)2]4 (152 mg, 0.53 mmol, 1.0 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 2 h. To this was added NaCNBH3(33.6 mg, 0.53 mmol, 1.0 eq) at 0 ℃ and the reaction mixture was allowed to room temperature and was stirred for 16 h. The volatiles were evaporated in vacuo, and the obtained crude residue was diluted with CH2Cl2. The organic phase was washed with water and extracted with multiple portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by silica gel chromatography to afford Compound 27 (15 mg, 10%).1H NMR (400 MHz, DMSO-d6) δ = 7.32 - 7.26 (m, 2H), 6.92 - 6.83 (m, 2H), 6.35 (d, J = 3.1 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.12 - 4.00 (m, 1H), 3.87 (dd, J = 3.6, 11.2 Hz, 2H), 3.45 - 4.36 (m, 2H), 3.27 (d, J = 2.0 Hz, 1H), 3.15 - 3.06 (m, 1H), 2.99 - 2.92 (m, 1H), 2.90 - 2.80 (m, 1H), 2.34 (s, 3H), 1.67 (br s, 2H), 1.59 - 1.47 (m, 2H) ppm. ESI-MS m / z: 271.4 [M+H]+.

[0296] Step 2: Synthesis of ZZ-2 (tert-butyl 3-((5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)(methyl)amino)pyrrolidine-1-carboxylate):

[0297] To a solution of ZZ-1 (100 mg, 0.53 mmol, 1.0 eq) in EtOH (1 mL) were added tert-butyl 3- oxopyrrolidine-1-carboxylate (99.2 mg, 0.53 mmol, 1.0 eq) and Ti(Oi-Pr)4(0.16 mL, 0.53 mmol, 1.0 eq) at room temperature and the reaction mixture was stirred at that temperature for 12 h. The reaction mixture was cooled to 0 ℃ and NaBH4(30.4 mg, 0.80 mmol, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 12 h. The volatiles were evaporated in vacuo, and the obtained crude residue was diluted with CH2Cl2, washed with water, and extracted with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to get crude compound. The crude product was purified by silica gel chromatography to afford tert-butyl3-((5,6-dihydro- 4H-pyrrolo[3,2,1-ij]quinolin-5yl)(methyl)amino)pyrrolidine-1-carboxylate (ZZ-2) (50 mg, 26%) as a pale yellow gummy solid. ESI-MS m / z: 354.0 [M-H]+.

[0298] Step-3: Synthesis of Compound 28 (N-methyl-N-(1-methylpyrrolidin-3-yl)-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0299] To a stirred solution of ZZ-2 (50 mg, 0.14 mmol, 1.0 eq) in THF (1 mL) was added an LAH solution in THF (2M, 0.21 mL, 0.42 mmol, 3.0 eq) at 0 ℃. The reaction mixture was heated to reflux and stirred at that temperature for 4 h. The reaction mixture was quenched with an aqueous Na2SO4 solution (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by silica gel chromatography, followed by RP prep HPLC purification to yield Compound 28 (8 mg, 21%).1H NMR (400 MHz, DMSO-d6) δ = 7.33 - 7.25 (m, 2H), 6.93 - 6.81 (m, 2H), 6.35 (d, J = 3.0 Hz, 1H), 4.26 (dd, J = 3.6, 11.8 Hz, 1H), 4.04 (t, J = 10.9 Hz, 1H), 3.52 - 3.45 (m, 1H), 3.27 (br s, 1H), 3.12 - 3.03 (m, 1H), 2.98 - 2.91 (m, 1H), 2.61 (d, J = 8.8 Hz, 1H), 2.46 - 2.37 (m, 3H), 2.30 (d, J = 1.4 Hz, 3H), 2.21 (d, J = 0.9 Hz, 3H), 1.94 - 1.84 (m, 1H), 1.76 - 1.66 (m, 1H) ppm. ESI-Ms m / z: 370.4 [M+H]+. Example A10:

[0300] Synthesis of Compound 29 and Compound 30

[0301] Scheme-7: Synthetic scheme for Compound 29 and Compound 30:

[0302] Step-1: Synthesis of AA-2 (7-bromo-5-methyl-1H-indole):

[0303] To a stirred solution of 2-bromo-4-methyl-1-nitrobenzene (AA-1) (25 g, 115 mmol, 1.0 eq) in THF (250 mL) at -40 ℃ was added a vinyl magnesium bromide solution (1M, 61.3 g, 460 mmol, 4.0 eq). The resulting mixture was warmed to room temperature and stirred at that temperature for 2 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with multiple portions of EtOAc. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 7- bromo-5-methyl-1H-indole (AA-2) (11 g, 46%), which was carried forward without further purification.1H NMR (400 MHz, DMSO-d6) δ: 11.14 (br s, 1H), 7.33 (s, 2H), 7.14 (s, 1H), 6.45 (br s, 1H), 2.36 (s, 3H) ppm.

[0304] Step 2: Synthesis of AA-3 (1-allyl-7-bromo-5-methyl-1H-indole):

[0305] To a stirred solution of AA-2 (10 g, 47.6 mmol, 1.0 eq) in DMF (100 mL) at 0 ℃ was added sodium hydride (3.8 g, 95.2 mmol, 2.0 eq) and the reaction mixture was stirred for 20 min. To the reaction mixture was added allyl bromide (8.64 g, 71.4 mmol, 1.5 eq) at 0 ℃. The reaction mixture was allowed to warm to room temperature and was stirred at that temperature for 16 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic layers were washed with an aqueous solution of NaCl. The organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 1-allyl-7-bromo-5-methyl-1H-indole (AA-3) (7.5 g, 63%) as a pale- yellow liquid. ESI-MS m / z: 251.3 [M+H]+.

[0306] Step 3: Synthesis of regio-isomeric mixture of AA-4a and AA-4b:

[0307] To a stirred solution of AA-3 (7.5 g, 29.9 mmol, 1.0 eq) in DMF (75 mL) was added K2CO3(8.25 g, 59.8 mmol, 2.0 eq), followed by TBAI (cat.) at room temperature and the reaction mixture was degassed under a N2atmosphere for 20 minutes. To this reaction mixture was added Pd(OAc)2(667 mg, 2.98 mmol, 0.1 eq) at same temperature. The reaction mixture was heated to 80 ℃ and was stirred at that temperature for 3 h. The reaction mixture was diluted with water and extracted with multiple portions of EtOAc. The combined organic phase were dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford to afford a mixture of regio-isomers of 8-methyl-4H-pyrrolo[3,2,1-ij]quinoline (AA-4a) and 8-methyl-6H-pyrrolo[3,2,1-ij]quinoline (AA-4b) (5.2 g, 51%). ESI-MS m / z: 170.3 [M+H]+.

[0308] Step 4: Synthesis of AA-5 (8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol):

[0309] To a stirred solution of regio-isomeric mixture AA-4a and AA-4b (5.2 g, 31.4 mmol, 1.0 eq) in THF (60 mL) was added a solution of BH3 in THF (1M, 893 mg, 62.7 mmol, 2.0 eq) at 0 ℃. The reaction mixturewas heated to reflux and stirred at that temperature for 2 h. The reaction mixture was allowed to cool to room temperature, quenched with aqueous NaOH (3M, 46.5 mL), and a solution of H2O2(30% in water, 31 mL) was added. The resulting reaction mixture was stirred at room temperature for an additional 4 h. The reaction mixture was quenched with 6N HCl (until pH = 2) and extracted multiple portions of DCM. The combined organic layers were washed sequentially with a saturated aqueous NaHCO3solution and brine and dried over anhydrous Na2SO4. The solids were filtered, and the filtrated was concentrated in vacuo to afford 8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol (AA-5) (3.1 g, 53%), which was carried forward without further purification. ESI-MS m / z: 188.1 [M+H]+.

[0310] Step 5: Synthesis of AA-6 (8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4-

[0311] To a solution of AA-5 (3.5 g, 18.6 mmol, 1.0 eq) in DCM (40 mL) at 0 ℃ was added triethylamine (5.63 g, 55.8 mmol, 3.0 eq), TsCl (4.25 g, 22.3 mmol, 1.2 eq) and DMAP (113 mg, 0.93 mmol, 0.1 eq). The reaction mixture was allowed to warm to room temperature and was stirred at that temperature for 6 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic extracts were washed with an aqueous solution of NaHCO3, dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 8-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl 4-methylbenzenesulfonate (AA-6) (3.6 g, 57%), which was carried forward without further purification.1H NMR (400 MHz, DMSO- d6) δ: 7.79 (d, J = 8.3 Hz, 1H), 7.51 - 7.47 (m, 1H), 6.78 - 6.68 (m, 1H), 6.65 (s, 1H), 5.76 (s, 1H), 4.06 - 4.00 (m, 1H), 3.21 (d, J = 17 Hz, 2H), 2.98 - 2.89 (m, 2H), 2.34 (s, 3H) ppm.

[0312] Step 6: Synthesis of AA-7 (5-azido-8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline):

[0313] To a stirred solution of AA-6 (3.6 g, 10.5 mmol, 1.0 eq) in DMF (36 mL) was added NaN3 (1.36 g, 21.0 mmol, 2 eq) at room temperature and the resulting reaction mixture was heated to 65 ℃ and was stirred at that temperature for 3 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous solution of NaCl, dried overanhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford 5-azido-8- methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (AA-7) (2.8 g, crude). The crude material was directly used in next step without further purification. ESI-MS m / z: 213.1 [M+H]+.

[0314] Step 7: Synthesis of AA-8 (tert-butyl (8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate:

[0315] To a stirred solution of AA-7 (2.8 g, 13.1 mmol, 1.0 eq) in MeOH (28 mL) were added 10% Pd / C (2.8 g, w / w) and Boc anhydride (3.42 g, 15.7 mmol, 1.2 eq) at room temperature. The reaction mixture was stirred for 16 h under an H2atmosphere (50 psi). The reaction mixture was filtered through a pad of celite, washed with MeOH, and concentrated in vacuo to afford crude product. The crude material was purified by silica gel chromatography to afford tert-butyl (8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate (AA-8) (2.3 g, 61%) as a brown liquid.1H NMR (400 MHz, DMSO-d6) δ = 7.28 - 7.23 (m, 1H), 7.12 (s, 1H), 6.38 (d, J = 2.9 Hz, 1H), 6.26 (d, J = 2.9 Hz, 1H), 5.75 (s, 1H), 4.36 - 3.97 (m, 2H), 3.87 - 3.79 (m, 1H), 3.04 (d, J = 12.2 Hz, 2H), 2.41 (s, 3H), 1.41 (s, 9H) ppm.

[0316] Step 8: Synthesis of AA-9 (tert-butyl (1-bromo-8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)carbamate):

[0317] To a stirred solution of AA-8 (230 mg, 0.80 mmol, 1.0 eq) in DMF (3 mL) at 0 ℃ was added NaHCO3 (134 mg, 1.60 mmol, 2.0 eq), followed by an NBS (142 mg, 0.80 mmol, 1.0 eq) solution in DMF (1 mL). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ice cold water, filtered, and dried in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (1-bromo-8-methyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)carbamate (AA-9) (160 mg, 55%) as a pale yellow gummy solid. ESI-MS m / z: 364.8 [M+H]+.

[0318] Step 9: Synthesis of AA-10 (tert-butyl (1-(2-fluorophenyl)-8-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate):

[0319] In a sealed tube, to a solution of AA-9 (160 mg, 0.43 mmol, 1.0 eq) in dioxane:water (4:1, 5 mL) were added NaOH (29.7 mg, 0.74 mmol, 1.7 eq), (2-fluorophenyl)boronic acid (122 mg, 0.87 mmol, 2.0 eq) and tri-tert-butylphosphonium tetrafluoroborate (25 mg, 0.08 mmol, 0.2 eq) at room temperature and the resulting reaction mixture was degassed under an N2 atmosphere for 20 minutes. To the reaction mixture was added palladium(II) acetate (19.6 mg, 0.08 mmol, 0.2 eq) and the reaction mixture was heated to 80 ℃ and was stirred at that temperature for 8 h. The reaction mixture was diluted with water and extracted with multiple portions of EtOAc. The combined organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (1-(2-fluorophenyl)-8-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (AA-10) (110 mg, 66%) as a pale yellow gummy solid. ESI-MS m / z: 381.0 [M+H]+.

[0320] Step 10: Synthesis of Compound 29 (1-(2-fluorophenyl)-N,8-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine) and Compound 30 (N-ethyl-1-(2-fluorophenyl)-N,8-dimethyl-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine):

[0321] To a stirred solution of AA-10 (110 mg, 0.28 mmol, 1.0 eq) in DCM (5 mL) at 0 ℃ was added an LAH solution in THF (2M, 0.86 mL, 1.73 mmol, 6.0 eq). The reaction mixture was heated to 50 ℃ and stirred at that temperature for 5 h. The reaction mixture was quenched with an aqueous Na2SO4solution and extracted with multiple portions of EtOAc. The combined organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by silica gel chromatography to afford Compound 29 (30 mg, 36%) and Compound 30 (10 mg, 11%).

[0322] Compound 29: ESI-MS m / z: 295.7 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ: 7.68 – 7.63 (m, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.30 (br s, 1H), 7.14 – 7.10 (m, 2H), 7.08 – 7.03 (m, 1H), 6.73 (br s, 1H),4.35 – 4.31 (m, 1H), 3.95 (dd, J = 7.2, 12 Hz, 1H), 3.26 – 3.21 (m, 1H), 3.15 (dd, J = 4.2, 16 Hz, 1H), 2.84 (dd, J = 7.8, 16 Hz, 1H), 2.43 (s, 3H), 2.33 (s, 3H).

[0323] Compound 30:1H NMR (400 MHz, DMSO-d6) δ = 7.77 - 7.70 (m, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.34 - 7.24 (m, 4H), 6.79 (s, 1H), 4.36 (dd, J = 4.2, 12.2 Hz, 1H), 4.08 (dd, J = 10.0, 11.8 Hz, 1H), 3.27 - 3.21 (m, 1H), 3.04 - 2.99 (m, 2H), 2.69 - 2.62 (m, 2H), 2.41 - 2.37 (m, 3H), 2.33 (s, 3H), 1.03 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m / z: 323.7 [M+H]+. Example A11:

[0324] Synthesis of Compound 32, Compound 33, Compound 34, and Compound 35

[0325] Scheme 8: Synthetic route for Compound 32, Compound 33, Compound 34, and Compound 35:

[0326] Step 1: Synthesis of BB-2 (7-bromo-5-fluoro-1H-indole):

[0327] To a stirred solution of 2-bromo-4-fluoro-1-nitrobenze (BB-1) (25 g, 113 mmol, 1.0 eq) in THF (250 mL) at -40 ℃ was added a vinyl magnesium bromide solution in THF (1M, 452 mL, 452 mmol, 4.0 eq)and the resulting reaction mixture was warmed to room temperature and stirred at that temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 7-bromo-5-fluoro-1H-indole (BB-2) (11 g, 45%) as a pale-yellow liquid. ESI-MS m / z: 215.7 [M+2]+.

[0328] Step 2: Synthesis of BB-3 (1-allyl-7-bromo-5-fluoro-1H-indole):

[0329] To a stirred solution of 7-bromo-5-fluoro-1H-indole (BB-2) (11g, 51.3 mmol, 1.0 eq) in DMF (110 mL) at 0 ℃ was added sodium hydride (2.44 g, 102 mmol, 2.0 eq) and the reaction mixture was stirred for 20 min. To this reaction mixture was added allyl bromide (5.35 mL, 61.5 mmol, 1.2 eq) at 0 ℃. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic extracts were washed with an aqueous solution of NaCl (100 mL). The organic phase was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 1-allyl-7-bromo-5-fluoro-1H-indole (BB-3) (10.5 g, 80%) as a pale- yellow liquid. ESI-MS m / z: 255.7 [M+H]+.

[0330] Step 3: Synthesis of regio-isomeric mixture of BB-4a and BB-4b

[0331] To a stirred solution of 1-allyl-7-bromo-5-fluoro-indole (BB-3) (10.5 g, 41.3 mmol, 1.0 eq) in DMF (100 mL) was added K2CO3(11.4 g, 82.6 mmol, 2.0 eq), followed by TBAI (7.60 g, 20.6 mmol, 0.5 eq) at room temperature and the reaction mixture was degassed under an N2 atmosphere for 20 minutes. To this reaction mixture was added Pd(OAc)2(0.925 g, 4.13 mmol, 0.1 eq) at room temperature. The reaction mixture was heated to 80 ℃ and was stirred at that temperature for 3 h. The reaction mixture was diluted with water and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford to afford a mixture of regio isomers 8-fluoro-4H-pyrrolo[3,2,1-ij]quinoline (BB-4a) & 8-fluoro-6H-pyrrolo[3,2,1- ij]quinoline (BB-4b) (3.5 g, 48%) as a colourless liquid. ESI-MS m / z: 171.9 [M+H]+.

[0332] Step 4: Synthesis of BB-5 (8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol)

[0333] To a stirred solution of regio-isomeric mixture BB-4a & BB-4b (6 g, 34.6 mmol, 1.0 eq) in THF (60 mL) at 0 ℃ was added a BH3solution in THF (1M, 70 mL, 69.2 mmol, 2.0 eq). The reaction mixture was heated to reflux and was stirred at that temperature for 2 h. The reaction mixture was allowed to cool at room temperature, quenched with an aqueous NaOH solution (3M in water, 80 mL), and a solution of H2O2(30% in water, 59 mL) was added. The resulting reaction mixture was stirred at room temperature for an additional 4 h. The reaction mixture was quenched with a 6N HCl solution until pH = 2 and was extracted with multiple portions of DCM. The combined organic extracts were washed with a saturated NaHCO3solution, brine, and dried over anhydrous Na2SO4. The solids were removed by filtration and the filtrate was concentrated in vacuo to afford 8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol (BB-5) (4.5 g, crude) as a pale yellow gummy. ESI-MS m / z: 192.2 [M+H]+.

[0334] Step 5: Synthesis of BB-6 (8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4- methylbenzenesulfonate):

[0335] To a stirred solution of BB-5 (4.5 g, 23.5 mmol, 1.0 eq) in DCM (40 mL) at 0 ℃ was added Et3N (8.25 mL, 58.7 mmol, 2.5 eq), followed by 4-dimethylaminopyridine (287 mg, 2.35 mmol, 0.1 eq) and TsCl (5.37 g, 28.2 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with multiple portions of DCM. The combined organic extracts were dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4-methylbenzenesulfonate (BB-6) (4.5 g, 55%) as a pale yellow gummy solid. ESI-MS m / z: 346.2 [M+H]+.

[0336] Step 6: Synthesis of BB-7 (5-azido-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline)

[0337] To a stirred solution of BB-6 (4.5 g, 13 mmol, 1.0 eq) in DMF (40 mL) was added NaN3 (1.69 g, 26 mmol, 2.0 eq) at room temperature and the resulting reaction mixture was heated to 70 ℃ and was stirred at that temperature for 4 h. The reaction mixture was diluted with ice cold water and extracted with multiple portions of EtOAc. The combined organic extracts were washed with ice cold water followed by an aqueous solution of NaCl. The organic phase was dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to afford 5-azido-8-fluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinoline (BB-7) (2.5 g, crude) as a pale brown gummy. ESI-MS m / z: 217.2 [M+H]+.

[0338] Step 7: Synthesis of BB-8 (tert-butyl (8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate):

[0339] To a stirred solution of BB-7 (2.5 g, 11.5 mmol, 1.0 eq) in MeOH (20 mL) were added 10% Pd / C (2.4 g, 23.0 mmol, 2.0 eq) and Boc2O (3.94 mL, 17.2 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 16 h under an H2 atmosphere (50 psi). The reaction mixture was filtered through a pad of celite, washed with MeOH (20 mL) and concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (8-fluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (BB-8) (1.5 g, 45%) as a pale yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.15 - 7.08 (m, 2H), 6.78 - 6.70 (m, 1H), 6.44 (d, J = 2.9 Hz, 1H), 4.64 - 4.51 (m, 2H), 4.28 - 4.22 (m, 1H), 4.18 - 4.10 (m, 1H), 3.24 (dd, J = 3.6, 16.6 Hz, 1H), 2.96 (dd, J = 4.6, 16.4 Hz, 1H), 1.41 (s, 9H) ppm. ESI-MS m / z: 292.8 [M+H]+.

[0340] Step 8: Chiral Separation of BB-8 into BB-8a (tert-butyl (R)-(8-fluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate) and BB-8b (tert-butyl (S)-(8-fluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate)

[0341] g of BB-8 was used in the chiral separation to get 420 mg of BB-8a & 400 mg of BB-8b. Column : Chiralpak-AD-H(250mmX4.6mm, 5µ) Mobile Phase A : 0.1% DEA in n- Hexane Mobile Phase B : EtOH Flow rate : 36.0 mL / min

[0342] BB-8a:1H NMR (400 MHz, CHLOROFORM-d) δ: 7.15 - 7.09 (m, 2H), 6.78 - 6.69 (m, 1H), 6.44 (d, J = 3.2 Hz, 1H), 4.63 - 4.53 (m, 1H), 4.30 - 4.21 (m, 1H), 4.19 - 4.11 (m, 1H), 3.49 (d, J = 5.4 Hz, 1H), 3.24 (dd, J = 3.4, 16 Hz, 1H), 2.97 (dd, J = 4.4, 16 Hz, 1H), 1.47 - 1.39 (m, 9H) ppm.

[0343] BB-8b:1H NMR (400 MHz, CHLOROFORM-d) δ: 7.15 - 7.09 (m, 2H), 6.75 (d, J = 9.2 Hz, 1H), 6.44 (d, J = 3.1 Hz, 1H), 4.54 (br s, 2H), 4.29 - 4.21 (m, 1H), 4.16 (s, 1H), 3.24 (dd, J = 3.8, 16 Hz, 1H), 2.97 (dd, J = 4.6, 16 Hz, 1H), 1.41 (s, 9H) ppm.

[0344] Step 9a: Synthesis of BB-9a (tert-butyl (R)-(8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-yl)(methyl)carbamate):

[0345] To a stirred solution of BB-8a (110 mg, 0.37 mmol, 1.0 eq) in DMF (2 mL) at 0 °C was added NaH (13.6 mg, 0.56 mmol, 1.5 eq) and the reaction mixture was stirred for 30 min. To this was added MeI (107 mg, 0.75 mmol, 2.0 eq) at 0 °C. The reaction mixture was warmed to room temperature and stirred at that temperature for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous NaCl solution. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude tert-butyl (R)-(8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (BB-9a) (110 mg, crude) as a yellow liquid, which was carried forward without further purification. ESI-MS m / z: 305.3 [M+H]+.

[0346] Step 9b: Synthesis of BB-9b (tert-butyl (S)-(8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-yl)(methyl)carbamate)

[0347] To a stirred solution of BB-8b (250 mg, 0.86 mmol, 1.0 eq) in DMF (5 mL) at 0 ℃ was added NaH (30 mg, 1.29 mmol, 1.5 eq) and the reaction mixture was stirred for 30 min. To this was added MeI (1.07 mL, 1.72 mmol, 2.0 eq) at 0 °C. The reaction mixture was warmed to room temperature and stirred at that temperature for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous NaCl solution. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude tert-butyl (S)-(8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (BB-9b) (250 mg, crude) as a pale yellow solid. The crude was directly used to next step without purification. Esi-MS m / z: 305.3 [M+H]+.

[0348] Step 10a: Synthesis of BB-10a ((R)-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine):

[0349] To a stirred solution of BB-9a (110 mg, 0.36 mmol, 1.0 eq) in DCM (2 mL) at 0 °C was added an LAH solution (2.0 M in THF, 41 mg, 1.08 mmol, 3.0 eq). The reaction mixture was heated to 50 °C and was stirred at that temperature for 4 h. The reaction mixture was diluted with an aqueous Na2SO4solution and DCM. The obtained solids were filtered and washed with additional portions of DCM. The combined organic phase was washed with an aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography column to afford (R)-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine (BB-10a) (70 mg, 89%) as a colourless liquid. ESI-MS m / z: 218.9 [M+H]+.

[0350] Step 10b: Synthesis of BB-10b ((S)-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine):

[0351] To a stirred solution of BB-9b (250 mg, 0.82 mmol, 1.0 eq) in DCM (5 mL) at 0 °C was added an LAH solution (2.0 M in THF, 1.03 mL, 2.46 mmol, 3.0 eq). The reaction mixture was heated to 50 °C and was stirred at that temperature for 4 h. The reaction mixture was diluted with an aqueous Na2SO4solution and DCM. The obtained solids were filtered and washed with additional portions of DCM. The combined organic phase was washed with an aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography column to afford (S)-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine (BB-10b) (170 mg, 95 %) as a pale yellow gummy. ESI-MS m / z: 219.2 [M+H]+.

[0352] Step 11a: Synthesis of Compound 32 ((R)-1-bromo-8-fluoro-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0353] To a stirred solution of BB-10a (70 mg, 0.32 mmol, 1.0 eq) in DMF (1 mL) at 0°C was added N- bromosuccinimide (57 mg, 0.32 mmol, 1.0 eq) in DMF (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with a saturated aqueous NaHCO3solution and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous NaCl solution (20 mL), dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude (R)-1-bromo-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine Compound 32 (70 mg, crude) which was carried forward without further purification. ESI-MS m / z: 299.1 [M+2]+.

[0354] Step 11b: Synthesis of Compound 33 ((S)-1-bromo-8-fluoro-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0355] To a stirred solution of BB-10b (170 mg, 0.77 mmol, 1.0 eq) in DMF (5 mL) at 0 °C was added N- bromosuccinimide (138 mg, 0.77 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with a saturated aqueous NaHCO3solution and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous NaCl solution (20 mL), dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude (S)-1-bromo-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine Compound 33 (170 mg, 74%), which was carried forward without further purification. ESI-MS m / z: 299.1 [M+2]+.

[0356] Step 12a: Synthesis of BB-12a ((R)-8-fluoro-N,N-dimethyl-1-(prop-1-en-2-yl)-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0357] To a stirred solution of Compound 32 (70 mg , 0.23 mmol, 1.0 eq) in 1,4 dioxane (1.6 mL) and water (0.4 mL) were added sodium hydroxide (16 mg, 0.40 mmol, 1.7 eq) and 4,4,5,5-tetramethyl-2-(prop- 1-en-2-yl)-1,3,2-dioxaborolane (79 mg, 0.47 mmol, 2.0 eq) at room temperature, and the reaction was degassed under an N2 atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate (16 mg, 0.02 mmol, 0.1 eq), followed by tri-tert-butylphosphonium tetrafluoroborate (14 mg, 0.04 mmol, 0.2 eq) at room temperature. The reaction mixture was heated to 80 ℃ and was stirred that temperature for 12 h. The reaction mixture was filtered through a celite pad, diluted with water, and extracted with multiple portions of EtOAc. The combined organic extracts were dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford (R)-8-fluoro-N,N-dimethyl-1-(prop-1-en-2-yl)-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine (BB-12a) (80 mg, crude) as a pale yellow liquid, which was carried forward without further purification. ESI-MS m / z: 258.8 [M+H]+.

[0358] Step 12b: Synthesis of BB-12b ((S)-8-fluoro-N,N-dimethyl-1-(prop-1-en-2-yl)-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0359] To a stirred solution of Compound 33 (170 mg , 0.57 mmol, 1.0 eq) in 1,4 dioxane (10 mL) and water (3.0 mL) were added sodium hydroxide (40 mg, 0.97 mmol, 1.7 eq) and 4,4,5,5-tetramethyl-2-(prop- 1-en-2-yl)-1,3,2-dioxaborolane (191 mg, 1.14 mmol, 2.0 eq) at room temperature, and the reaction was degassed under an N2atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate (40 mg, 0.05 mmol, 0.1 eq), followed by tri-tert-butylphosphonium tetrafluoroborate (33 mg, 0.11 mmol, 0.2 eq) at room temperature. The reaction mixture was heated to 80 ℃ and was stirred that temperature for 12 h. The reaction mixture was filtered through a celite pad, diluted with water, and extracted with multipleportions of DCM. The combined organic extracts were dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude (S)-8-fluoro-N,N-dimethyl-1-(prop-1-en-2-yl)-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (BB-12b) (200 mg, crude) as a pale yellow gummy. The crude was directly used to next step without purification. ESI-MS m / z: 277.3 [M+H2O]+

[0360] Step 13a: Synthesis of Compound 34 ((R)-8-fluoro-1-isopropyl-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0361] To a stirred solution of BB-12a (80 mg, 0.30 mmol, 1.0 eq) in methanol (10 vol) was added 10% Pd / C (80 mg, 0.72 mmol, 2.4 eq) at room temperature. The reaction mixture was stirred at room temperature for 4 h in a steel bomb under an H2(60 psi) atmosphere. The reaction mixture was filtered through a celite pad, washed with methanol, and the filtrate was concentrated in vacuo to afford crude compound. The crude product was purified by silica gel chromatography to obtain (R)-8-fluoro-1-isopropyl-N,N-dimethyl-5,6- dihydro-4H-pyrrolo-[3,2,1-ij]quinolin-5-amine (Compound 34) (10 mg, 100%).1H NMR (400 MHz, DMSO-d6) δ: 7.12 - 7.10 (m, 1H), 7.07 (dd, J = 2.2, 10.6 Hz, 1H), 6.72 (dd, J = 2.0, 9.9 Hz, 1H), 4.25 (d, J = 12.0 Hz, 1H), 3.99 - 3.93 (m, 1H), 3.09 - 2.92 (m, 4H), 2.31 (s, 6H), 1.27 (dd, J = 0.6, 6.8 Hz, 6H) ppm. ESI-MS m / z: 261.2 [M+H]+.

[0362] Step 13b: Synthesis of Compound 35 ((S)-8-fluoro-1-isopropyl-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine):

[0363] To a stirred solution of BB-12b (200 mg, 0.77 mmol, 1.0 eq) in methanol (10 vol) was added 10% Pd / C (163 mg, 1.54 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 4 h in a steel bomb under an H2 (70 psi) atmosphere. The reaction mixture was filtered through a celite pad, washed with methanol (20 mL), and the filtrate was concentrated in vacuo to afford crude material. The crude product was purified by silica gel chromatography to afford (S)-8-fluoro-1- isopropyl-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 35) (15 mg, 7%).1H NMR (400 MHz, METHANOL-d4) δ: 7.04 (dd, J = 1.7, 10.3 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.71 (d, J =10.1 Hz, 1H), 4.38 (dd, J = 2.9, 12.3 Hz, 1H), 4.17 - 4.09 (m, 1H), 3.34 (d, J = 4.3 Hz, 2H), 3.24 (br s, 1H), 3.09 - 3.05 (m, 1H), 2.58 (br s, 6H), 1.32 (d, J = 6.9 Hz, 6H) ppm. ESI-MS m / z: 261.0 [M+H]+. Example A12:

[0364] Synthesis of Compound 36 and Compound 37:

[0365] Scheme-9: Synthetic route for Compound 36 and Compound 37:

[0366] Step 1: Synthesis of CC-1& CC-2:

[0367] To a stirred solution of BB-8a (60 mg, 0.15 mmol, 1.0 eq) in DCM (10 vol) at 0 ℃ was added an LAH solution in THF (2M, 1.03 mL, 2.06 mmol, 4.0 eq). The reaction mixture was heated to 50 ℃ and was stirred at that temperature for 3 h. The reaction mixture was diluted with an aqueous Na2SO4solution and EtOAc. The formed solids were filtered and washed with multiple portions of EtOAc. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford (R)-8-fluoro-N- methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (CC-1) (60 mg, 57%) as a pale yellow gummy. ESI-MS m / z: 204.9 [M+H]+.

[0368] In similar fashion, BB-8b was used in the same reaction to obtain (S)-8-fluoro-N-methyl-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (CC-2) (61 mg, 58%) as a pale yellow gummy. ESI-MS m / z: 204.8 [M+H]+.

[0369] Step 2: Synthesis of Compound 37 and Compound 37:

[0370] To a solution of CC-1 (60 mg, 0.29 mmol, 1.0 eq) in MeOH (3 mL) and THF (3 mL) was added 2- (tetrahydro-2H-pyran-4-yl)acetaldehyde (44.9 mg, 0.35 mmol, 1.2 eq) at room temperature and the reaction mixture was stirred for 1 h. To this mixture was added sodium cyanoborohydride (36.8 mg, 0.58 mmol, 2eq) at 0 ℃ and the resulting reaction mixture was warmed to room temperature and stirred at that temperature for 12 h. The volatiles were evaporated in vacuo and obtained crude residue was diluted with water and extracted multiple portions of DCM. The combined organic extracts were dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford (R)-8-fluoro-N-methyl-N-(2-(tetrahydro-2H-pyran-4- yl)ethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 36) (60 mg, 65%).1H NMR (400 MHz, DMSO-d6) δ: 7.36 (d, J = 2.9 Hz, 1H), 7.06 (dd, J = 2.4, 10.4 Hz, 1H), 6.78 - 6.73 (m, 1H), 6.34 (d, J = 3.0 Hz, 1H), 4.28 (dd, J = 4.4, 11.8 Hz, 1H), 4.04 (dd, J = 9.8, 11.8 Hz, 1H), 3.83 - 3.77 (m, 2H), 3.25 - 3.18 (m, 3H), 3.05 - 3.00 (m, 2H), 2.60 - 2.56 (m, 2H), 2.31 (s, 2H), 1.59 - 1.48 (m, 3H), 1.40 - 1.32 (m, 2H), 1.26 - 1.21 (m, 1H), 1.21 - 1.08 (m, 2H) ppm. ESI-MS m / z: 317.0 [M+H]+.

[0371] In similar fashion, CC-2 was used in the same reaction to obtain (S)-8-fluoro-N-methyl-N-(2- (tetrahydro-2H-pyran-4-yl)ethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 37) (60 mg, 65%).1H NMR (400 MHz, DMSO-d6) δ: 7.36 (d, J = 3.0 Hz, 1H), 7.06 (dd, J = 2.2, 10.6 Hz, 1H), 6.78 - 6.73 (m, 1H), 6.34 (d, J = 3.0 Hz, 1H), 4.28 (dd, J = 3.8, 11.8 Hz, 1H), 4.08 - 4.00 (m, 1H), 3.80 (dd, J = 3.4, 11.2 Hz, 2H), 3.28 - 3.20 (m, 4H), 3.05 - 3.00 (m, 2H), 2.62 - 2.55 (m, 2H), 2.42 - 2.36 (m, 1H), 2.31 (s, 3H), 1.58 - 1.52 (m, 2H), 1.39 - 1.34 (m, 2H), 1.19 - 1.11 (m, 2H) ppm. ESI-MS m / z: 317.0 [M+H]+. Example A13:

[0372] Synthesis of Compound 31, Compound 38, Compound 39, and Compound 40

[0373] Scheme-10: Synthetic route for Compound 31, Compound 38, Compound 39, and Compound 40

[0374] Step 1: Synthesis of BB-9 (tert-butyl (8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)(methyl)carbamate):

[0375] To a stirred solution of BB-8 (1.2 g, 0.41 mmol, 1.0 eq) in DMF (12 mL) at ℃ was added NaH (286 mg, 8.26 mmol, 2.0 eq) and the reaction mixture was stirred for 15 min. To this mixture was added MeI (0.76 mL, 12.3 mmol, 3.0 eq) at 0 ℃, and resulting reaction mixture was warmed to room temperature and stirred at that temperature for 2 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with multiple portions of EtOAc. The combined organic extracts were washed with water, brine, and dried over Na2SO4. The solids were filtered and the filtrate was concentrated in vacuo to afford tert- butyl (8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (BB-9) (1.2 g, crude) as a pale yellow solid, which was carried forward without further purification. ESI-MS m / z: 307.2 [M+3]+.

[0376] Step 2: Synthesis of BB-10 (8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine):

[0377] To a stirred solution of crude BB-8 (1.2 g, 3.94 mmol, 1.0 eq) in DCM (20 mL) at 0 ℃ was added an LAH solution in THF, (2 M, 17.8 mL, 15.7 mmol, 4.0 eq). The reaction mixture was heated to 50 ℃ and was stirred at that temperature for 3 h. The reaction mixture was quenched with an aqueous Na2SO4 solution, the obtained solids were filtered, and the solids were washed with multiple portions of EtOAc. The combined organic phase was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 8- fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (BB-10) (650 mg, 76%) as a pale yellow gummy.1H NMR (400 MHz, DMSO-d6) δ = 7.35 (d, J = 2.4 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.75 (d, J = 9.8 Hz, 1H), 6.34 (d, J = 2.9 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.03 (dd, J = 8.6, 12.0 Hz, 1H), 3.10 - 2.98 (m, 3H), 2.32 (s, 6H) ppm. ESI-MS m / z: 219.1 [M+H]+.

[0378] Step 3: Synthesis of Compound 31:

[0379] To a stirred solution of BB-10 (150 mg, 0.68 mmol, 1.0 eq) in DMF (2 mL) at 0 ℃ was added N- bromosuccinimide (122 mg, 0.68 mmol, 1.0 eq) in DMF (2 mL). The reaction mixture was warmed to room temperature and stirred at that temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with an aqueous NaCl solution, dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product (1-bromo-8-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine) (Compound 31) (150 mg, crude). ESI-MS m / z: 298.7 [M+H]+.

[0380] Step 2: Synthesis of Compound 38, Compound 39, and Compound 40:

[0381] To a stirred solution of crude Compound 31 (150 mg, 0.50 mmol, 1.0 eq) in 1,4 dioxane (1.2 mL) and water (0.3 mL) were added sodium hydroxide (34.2 mg, 0.85 mmol, 1.7 eq) and (3-cyanophenyl)boronic acid (146 mg, 1.00 mmol, 2.0 eq) at room temperature and the reaction was degassed under an N2 atmosphere for 20 minutes. To this reaction mixture was added Pd(dppf)Cl2•DCM (41 mg, 0.05 mmol, 0.1 eq) at room temperature. The reaction mixture was heated to 80 ℃ and was stirred at that temperature for 16 h. The reaction mixture was filtered through a celite pad, diluted with water, and extracted with multiple portions of EtOAc. The combined organic phase was washed with an aqueous NaCl solution (20 mL), dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by Prep HPLC to afford 3-(5-(dimethylamino)-8-fluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (Compound 38) (30 mg, 19%).

[0382] 30 mg of Compound 38 was subjected to chiral purification to get 4.5 mg of Compound 39 & 7 mg of Compound 40. Each sample was triturated with n-pentane and lyophilized to get 2.8 mg of (S)-3-(5- (dimethylamino)-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (Compound 40) & 2.4 mg of (R)-3-(5-(dimethylamino)-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)benzonitrile (Compound 39).

[0383] Compound 39:1H NMR (400 MHz, METHANOL-d4) δ: 7.99 - 7.93 (m, 2H), 7.68 (s, 1H), 7.64 - 7.48 (m, 2H), 7.36 (dd, J = 2.2, 10.4 Hz, 1H), 6.86 - 6.81 (m, 1H), 4.53 - 4.44 (m, 1H), 4.20 - 4.12 (m, 1H), 3.23 - 3.07 (m, 3H), 2.48 (s, 6H) ppm. ESI-MS m / z: 320.2 [M+H]+.

[0384] Compound 40:1H NMR (400 MHz, METHANOL-d4) δ: 8.00 - 7.93 (m, 2H), 7.69 (s, 1H), 7.63 - 7.49 (m, 2H), 7.36 (dd, J = 2.0, 10.5 Hz, 1H), 6.86 - 6.80 (m, 1H), 4.51 - 4.45 (m, 1H), 4.16 (dd, J = 8.8, 12.1 Hz, 1H), 3.22 - 3.09 (m, 3H), 2.47 (s, 6H) ppm. ESI-MS m / z:320.3 [M+H]+. Example A14:

[0385] Synthesis of Compound 41, Compound 42, Compound 43, and Compound 44

[0386] Scheme-11: Synthetic scheme for Compound 41, Compound 42, Compound 43, and Compound 44:

[0388] To a stirred solution of DD-1 (200 g, 840 mmol, 1.0 eq) in THF (2 L) at -40 ℃ was added a vinyl magnesium bromide solution (1M, 2.52 L, 2.52 mol, 3.0 eq). The resulting reaction mixture was warmed to room temperature and stirred at that temperature for 2 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with multiple portions of EtOAc. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 7-bromo-4,5-difluoro-1H-indole (DD-2) (90 g, 46%) as an off white solid, which was carried forward without further purification.1H NMR (400 MHz, DMSO- d6) δ: 11.74 (br s, 1H), 7.58 - 7.37 (m, 2H), 6.70 (br s, 1H) ppm.

[0389] Step 1: Synthesis of 7-bromo-4-fluoro-1H-indole (EE-2):

[0390] To a stirred solution of EE-1 (50 g, 227 mmol, 1.0 eq) in THF (500 mL) at -75 ℃ was added a vinyl magnesium bromide solution (1M, 681 mL, 681 mmol, 3.0 eq). The resulting reaction mixture was warmed to room temperature and stirred at that temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (2 X 250 mL). The combined organic layers were washed with ice cold water, followed by an aqueous solution of NaCl. The organic layers were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 7- bromo-4-fluoro-1H-indole (EE-2) (18 g, 37%) as a pale-yellow oily liquid, which was carried forward without further purification.1H NMR (400 MHz, DMSO- d6) δ: 11.63 (br s, 1H), 7.43 (d, J = 2.9 Hz, 1H), 7.26 (dd, J = 4.0, 8.2 Hz, 1H), 6.77 (dd, J = 8.4, 10 Hz, 1H), 6.61 (d, J = 2.9 Hz, 1H) ppm.

[0391] Step 2: Synthesis of 7-bromo-4,5-difluoroindoline (DD-3):

[0392] To a stirred solution of DD-2 (10 g, 51.0 mmol, 1.0 eq) in TFA (50 mL) at 0 ℃ was added triethylsilane (17.7 g, 153 mmol, 3.0 eq). The resulting reaction mixture was warmed to room temperature and stirred at that temperature for 4 h. The reaction mixture was concentrated, quenched with an aqueous NaHCO3solution, and extracted with multiple portions of EtOAc. The combined organic phase was washed with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude compound. The crude product was purified by silica gel chromatography to afford 7-bromo-4,5-difluoroindoline (DD-3) (19 g, 47%) as a pale-yellow oily liquid,which was carried forward without further purification.1H NMR (400 MHz, DMSO- d6) δ: 7.28 (dd, J = 7.8, 9.8 Hz, 1H), 5.70 (br s, 1H), 3.54 (t, J = 8.4 Hz, 2H), 3.13 (t, J = 8.8 Hz, 2H) ppm.

[0393] Step 2: Synthesis of 7-bromo-4-fluoroindoline (EE-3):

[0394] To a stirred solution of EE-3 (18 g, 84.0 mmol, 1.0 eq) in TFA (90 mL) at 0 ℃ was added triethylsilane (40.2 mL, 252 mmol, 3.0 eq). The resulting reaction mixture was warmed to room temperature and stirred at that temperature for 3 h. The reaction mixture was concentrated, quenched with an aqueous NaHCO3 solution, and extracted with multiple portions of EtOAc. The combined organic phase was washed with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude compound. The crude product was purified by silica gel chromatography to afford 7-bromo-4-fluoroindoline (EE-3) (15 g, 83%) as an oily liquid. ESI-MS m / z: 319.7 [M+Na]+.

[0395] Step 3: Synthesis of DD-4 ((E)-1-(7-bromo-4,5-difluoroindolin-1-yl)but-2-en-1-one):

[0396] To a stirred solution of 7-bromo-4,5-difluoroindoline (DD-3) (40 g, 170 mmol, 1.0 eq) in DCM (400 mL) at 0 ℃ was added Et3N (71.1 mL, 510 mmol, 3.0 eq) and 2-butenoyl chloride (48.1 mL, 425 mmol, 2.5 eq). The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 X 200 mL). The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude DD-4 (70 g, crude), which was carried forward without further purification. ESI-MS m / z: 303.6 [M+H]+.

[0397] Step 3: Synthesis of (E)-1-(7-bromo-4-fluoroindolin-1-yl)but-2-en-1-one (EE-4):

[0398] To a stirred solution of 7-bromo-4-fluoroindoline (EE-3) (15 g, 69.4 mmol, 1.0 eq) in DCM (150 mL) at 0 ℃ was added Et3N (29.1 mL, 208 mmol, 3.0 eq) and 2-butenoyl chloride (20.5 g, 173 mmol, 2.5eq). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-cold water, basified with an aqueous NaHCO3solution, and extracted with EtOAc (3 x 200 mL). The combined extracts were washed brine (300 mL), dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford EE-4 (16 g, 81 %) as a pale-yellow oily liquid. ESI m / z 286.0 [M+3]+.

[0399] Step 4: Synthesis of 8,9-difluoro-6-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (DD- 5):

[0400] In a sealed tube, to a solution of DD-4 (17 g, 56.2 mmol, 1.0 eq) in ACN (170 mL) were added Et3N (15.5 mL, 112 mmol, 2 eq) and triphenylphosphine (5.87 g, 22.4 mmol, 0.4 eq) at room temperature and the reaction mixture was degassed under an N2 atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate (1.26 g, 5.62 mmol, 0.1 eq), and the reaction mixture was heated to 80 ℃ and stirred at that temperature for 12 h. The reaction mixture was washed with water, basified with an aqueous NaHCO3 solution, and extracted with multiple portions of EtOAc. The combined extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 8,9-difluoro-6-methyl-1,2- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (DD-5) (8 g, 65%) as a brown solid. ESI-MS n / z: 222.0 [M+H]+.

[0401] Step 4: Synthesis of 9-fluoro-6-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (EE-5):

[0402] In a sealed tube, to a solution of EE-4 (16 g, 56.3 mmol, 1.0 eq) in ACN (160 mL) was added Et3N (15.6 mL, 112 mmol, 3.0 eq), followed by triphenylphosphine (5.90 g, 22.5 mmol, 0.4 eq) at room temperature and the reaction mixture was degassed under an N2atmosphere for 20 minutes. To this reaction mixture was added palladium(II) acetate (1.26 g, 5.63 mmol, 0.1 eq), and the reaction mixture was heated to 80 ℃ and stirred at that temperature for 12 h. The reaction mixture was washed with water and extracted with multiple portions of EtOAc. The combined extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford EE-5 (12 g, 30%) as a brown solid. ESI-MS m / z: 203.9 [M+H]+.

[0403] Step 5: Synthesis of DD-6 (8,9-difluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinolin-5-ol):

[0404] To a stirred solution of DD-5 (8.0 g, 36.1 mmol, 1.0 eq) in THF (80 mL) at 0 ℃ was added a BH3 solution in THF (2M, 54 mL, 108 mmol, 3.0 eq). The reaction mixture was heated to reflux and was stirred at that temperature for 2 h. The reaction mixture was basified using an aqueous solution of 2N NaOH (80 mL), then H2O2 (120 mL) was added dropwise at -5 ℃. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with multiple portions of EtOAc. The combined extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford 8,9-difluoro-6-methyl-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (DD-6) (10 g, crude) as a pale brown solid. ESI-MS m / z: 225.8 [M+H]+.The crude was directly used for next step without any purification.

[0405] Step 5: Synthesis of EE-6 (9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-ol):

[0406] To a stirred solution of EE-5 (12 g, 59.0 mmol, 1.0 eq) in THF (120 mL) at 0 ℃ was added a BH3solution in THF (1M, 177 mL, 177 mmol, 3.0 eq). The reaction mixture was heated to reflux and was stirred at that temperature for 2 h. The reaction mixture was basified using an aqueous solution of 2N NaOH (120 mL) and 30% H2O2 (180 mL) was added dropwise at -5 ℃. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-5-ol (EE-6) (6.0 g, 86%) as a pale brown liquid. ESI-MS m / z: 208.3 [M+H]+.

[0407] Step 6: Synthesis of DD-7 (8,9-difluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl 4-methylbenzenesulfonate):

[0408] To a stirred solution of crude DD-6 (500 mg, 2.21 mmol, 1.0 eq) in pyridine (2.5 mL) at 0 ℃ was added p-toluenesulfonyl chloride (631 mg, 3.31 mmol, 1.5 eq), followed by DMAP (26.9 mg, 0.22 mmol, 0.1 eq). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with multiple portions of EtOAc. The combined organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 8,9-difluoro-6-methyl-1,2,5,6- tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl 4-methylbenzenesulfonate (DD-7) (300 mg, 36%) as a colourless sticky liquid. ESI-MS m / z: 379.8 [M+H]+.

[0409] Step 6: Synthesis of EE-7 (9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-yl 4-methylbenzenesulfonate)

[0410] To a stirred solution of EE-6 (3.0 g, 14.4 mmol, 1.0 eq) in DCM (30 mL) at 0 ℃ was added Et3N (6.06 mL, 43.2 mmol, 3.0 eq) and 4-dimethylaminopyridine (175 mg, 1.44 mmol, 0.1 eq), followed by TsCl (3.27 g, 17.2 mmol, 0.2 eq). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with water and extracted with multiple portions of DCM. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 5- azido-9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (EE-7) (3.75 g, 72%) as an off white solid. ESI-MS m / z: 361.8 [M+H]+.

[0411] Step 7: Synthesis of DD-8 (5-azido-8,9-difluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinoline):

[0412] To a stirred solution of DD-7 (9.5 g, 25.0 mmol, 1.0 eq) in DMF (95 mL) was added sodium azide (6.50 g, 100 mmol, 4.0 eq) at room temperature and the resulting reaction mixture was heated to 70 ℃ and stirred at that temperate for 16 h. The reaction mixture was diluted with ice-cold water and extracted with multiple portions of EtOAc. The combined extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford crude 5-azido-8,9-difluoro-6-methyl-1,2,5,6- tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (DD-8) (7 g, crude) as a brown gummy solid. The crude was directly used for next step without any purification. ESI-MS m / z: 249.9 [M-H]+.

[0413] Step 7: Synthesis of EE-8 (5-azido-9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinoline):

[0414] To a stirred solution of EE-7 (7.5 g, 20.7 mmol, 1.0 eq) in DMF (75 mL) was added sodium azide (4.03 g, 62.1 mmol, 3.0 eq) at room temperature. The reaction mixture was heated to 70 ℃ and stirred at that temperature for 16 h. The reaction mixture was washed with water and extracted with multiple portions of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford 5-azido-9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinoline (EE-8) (2 g, 42 %) as an oily liquid. ESI-MS m / z: 232.8 [M+H].

[0415] Step 8: Synthesis of DD-9 (tert-butyl (8,9-difluoro-6-methyl-1,2,5,6-tetrahydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate):

[0416] To an autoclave containing a solution of DD-8 (12 g, 47.9 mmol, 1.0 eq) in MeOH (120 mL) was added 10% Pd / C (5.09 g, 47.9 mmol, 1.0 eq) and di-tert-butyl dicarbonate (15.6 mg, 71.8 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 16 h under an H2 atmosphere (70 psi). The reaction mixture was filtered through a pad of celite, washed with MeOH, and concentrated in vacuo to obtain crude material. The crude was purified by silica gel chromatography to afford tert-butyl(8,9-difluoro-6-methyl- 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (DD-9) (6 g, 39%) as a pale yellow gummy solid, which was carried forward without further purification.1H NMR (400 MHz, DMSO- d6) δ: 6.72 (d, J = 7.5 Hz, 1H), 5.76 (s, 1H), 3.94 (d, J = 4.0 Hz, 1H), 3.40 - 3.36 (m, 1H), 3.27 - 3.25 (m, 1H), 2.96 (d, J = 7.8 Hz, 4H), 2.87 - 2.81 (m, 1H), 1.39 (s, 9H), 1.08 - 0.99 (m, 3H) ppm. ESI-MS m / z: 324.5 [M+H]+.

[0417] Step 8: Synthesis of EE-9 (tert-butyl (9-fluoro-6-methyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)carbamate):

[0418] To an autoclave containing a solution of EE-8 (2 g, 8.61 mmol, 1.0 eq) in MeOH (20 mL) was added 10% Pd / C (2.0 g, 18.7 mmol, 2.1 eq) and di-tert-butyl dicarbonate (2.81 g, 12.9 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 16 h under an H2 atmosphere (70 psi). The reaction mixture was filtered through a pad of celite, washed with MeOH, and concentrated in vacuo to obtain crude material. The crude was purified by silica gel chromatography to afford tert-butyl (9-fluoro-6-methyl- 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (EE-9) (2.3 g, 87%) as an off white solid. ESI-MS m / z: 306.9 [M+H]+.

[0419] Step 9: Synthesis and chiral separation of (tert-butyl (8,9-difluoro-6-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate) (DD-10) into tert-butyl ((5R)-8,9-difluoro-6-methyl-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (DD-10a) and tert-butyl ((5S)-8,9-difluoro-6- methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (DD-10b):

[0420] To a stirred solution of DD-9 (3.0 g, 9.28 mmol, 1.0 eq) in THF (30 mL) at 0 ℃ was added DDQ (3.14 g, 13.92 mmol, 1.5 eq) and the resulting reaction mixture was warmed to room temperature and was stirred at that temperature for 2 h. The reaction mixture was quenched with an aqueous NaHCO3 solution and extracted with multiple portions of EtOAc. The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (8,9-difluoro-6- methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (DD-10) (1.2 g, 81%) as a sticky liquid. ESI-MS m / z: 322.8 [M+H]+.

[0421] 2.5 g of DD-10 was subjected to chiral separation to get 1g of each DD-10a & DD-10b Column : Chiralpak-IC (250*4.6mm, 5µ) Mobile Phase A : 0.1% IPA in n- Hexane Mobile Phase B : DCM: IPA (50:50) Flow rate : 36.0 mL / min

[0422] DD-10a:1H NMR (400 MHz, DMSO- d6) δ: 7.44 (s, 1H), 7.02 - 6.81 (m, 2H), 6.50 (br s, 1H), 4.23 (d, J = 10 Hz, 1H), 4.17 - 4.00 (m, 2H), 1.38 (br s, 9H), 1.27 - 1.17 (m, 3H) ppm.

[0423] DD-10B:1H NMR (400 MHz, DMSO- d6) δ: 7.43 (br s, 1H), 6.97 (dd, J = 7.0, 11 Hz, 1H), 6.90 (d, J = 5.8 Hz, 1H), 6.50 (d, J = 2.1 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 4.16 - 4.02 (m, 2H), 1.38 (s, 9H), 1.22 (d, J = 6.6 Hz, 3H) ppm.

[0424] Step 9: Synthesis of tert-butyl (9-fluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate (EE-10) and chiral separation into tert-butyl ((5R)-9-fluoro-6-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (EE-10a) and tert-butyl ((5S)-9-fluoro-6-methyl-5,6-dihydro- 4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (EE-10b)

[0425] To a stirred solution of EE-9 (2.3 g, 7.50 mmol, 1.0 eq) in THF (25 mL) at 0 ℃ was added DDQ (2.54 g, 11.2 mmol, 1.5 eq) and the resulting reaction mixture was warmed to room temperature and stirred at that temperature for 2 h. The reaction mixture was quenched with an aqueous NaHCO3 solution and extracted with multiple portions of EtOAc. The combined organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford tert-butyl (9-fluoro-6-methyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate (EE-10) (1 g, 44%) as a pale-yellow solid. ESI-MS m / z: 305.2 [M+H]+.

[0426] 1 g of EE-10 was subjected to chiral separation to get 313 mg of EE-10a & 228 mg of EE-10b. Column : Chiralpak AY-H (250mm, 4.6mm, 5µ) Mobile Phase : Hexane / EtOH (90 / 10)

[0427] EE-10a:1H NMR (400 MHz, DMSO- d6) δ: 7.35 - 7.31 (m, 1H), 6.89 - 6.77 (m, 2H), 6.67 (dd, J = 8.4, 11 Hz, 1H), 6.43 - 6.38 (m, 1H), 4.20 (d, J = 8.8 Hz, 1H), 4.12 - 4.00 (m, 2H), 1.36 (s, 9H), 1.17 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m / z: 304.8 [M+H].

[0428] EE-10b:1H NMR (400 MHz, DMSO- d6) δ: 7.36 (br s, 1H), 6.92 - 6.79 (m, 2H), 6.76 - 6.65 (m, 1H), 6.44 (d, J = 1.8 Hz, 1H), 4.23 (d, J = 9.4 Hz, 1H), 4.15 - 4.00 (m, 2H), 1.39 (br s, 9H), 1.20 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m / z: 304.8 [M+H].

[0429] Step 10: Synthesis of tert-butyl ((5R)-8,9-difluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)(methyl)carbamate (DD-11a):

[0430] To a stirred solution of DD-10a (1.0 g, 3.24 mmol, 1.0 eq) in DMF (10 mL) at 0 ℃ was added NaH (214 mg, 6.20 mmol, 2.0 eq) and the reaction mixture was stirred for 10 min. To this reaction mixture was added MeI (0.57 mL, 9.30 mmol, 3.0 eq) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with multiple portions of EtOAc. The combined organic layer was washed with water, brine, and then dried over Na2SO4. The solids were filtered and the filtrate was concentrated in vacuo to afford crude tert-butyl ((5R)- 8,9-difluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (DD-11a) (1 g, crude) as a pale yellow solid. The crude was directly used to the next step without purification. Esi-MS m / z: 336.9 [M+H]+.

[0431] Step 10: Synthesis of tert-butyl ((5S)-8,9-difluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)(methyl)carbamate (DD-11b):

[0432] In a similar fashion, DD-10b (1 g) was treated with NaH / MeI to get crude tert-butyl ((5S)-8,9- difluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (DD-11b) (1 g, crude) as a pale yellow solid. The crude was directly used to the next step without purification. Esi-MS m / z: 337.0 [M+H]+.

[0433] Step 10: Synthesis of tert-butyl ((5R)-9-fluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)(methyl)carbamate (EE-11a):

[0434] To a stirred solution of EE-10a (220 mg, 0.72 mmol, 1.0 eq) in DMF (3 mL) at 0 ℃ was added NaH (50 mg, 1.44 mmol, 2.0 eq) and the reaction mixture was stirred for 10 min. To this reaction mixture was added MeI (0.13 mL, 2.16 mmol, 3.0 eq) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted with multiple portions of EtOAc. The combined organic layer was washed with water, brine, and dried over Na2SO4. The solids were filtered and the filtrate was concentrated in vacuo to afford crude tert-butyl ((5R)- 9-fluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (EE-11a) (250 mg, crude) as a pale yellow solid. The crude was directly used to next step without purification. ESI-MS m / z: 319.7 [M+H]+.

[0435] Step 10: Synthesis of tert-butyl ((5S)-9-fluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)(methyl)carbamate (EE-11b):

[0436] In a similar fashion, EE-10b (310 mg) was treated with NaH / MeI to get crude tert-butyl ((5S)-9- fluoro-6-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate (EE-11b) (310 mg, crude) as a pale yellow solid. The crude was directly used to the next step without purification. ESI-MS m / z: 319.7 [M+H]+.

[0437] Step 11: Synthesis for (5R)-8,9-difluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine (Compound 41):

[0438] To a stirred solution of DD-11a (900 mg, 2.67 mmol, 1.0 eq) in DCM (10 mL) at 0 ℃ was added an LAH solution in THF (2M, 3.33 mL, 6.67 mmol, 2.5 eq) and the resulting reaction mixture was warmed to room temperature and stirred at that temperature for 4 h. The reaction mixture was diluted with an aqueous Na2SO4 solution, and the obtained solids were filtered and washed with multiple portions of DCM. The combined organic layer was washed with an aqueous NaCl solution. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford (5R)-8,9-difluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 41) (480 mg, 72%).1H NMR (400 MHz, DMSO-d6) δ: 7.44 (br s, 1H), 6.98 (dd, J = 6.8, 11.2 Hz, 1H), 6.51 (s, 1H), 4.49 (dd, J = 3.6, 12.0 Hz, 1H), 3.89 (t, J = 11.2 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.29 (s, 3H), 2.60 - 2.54 (m, 1H), 2.28 (s, 9H), 1.14 (d, J = 6.6 Hz, 3H) ppm. ESI-MS m / z: 251.0 [M+H]+.

[0439] Step 11: Synthesis for (5S)-8,9-difluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine (Compound 42):

[0440] In a similar fashion to Compound 41, DD-11b (900 mg) was treated with 2M LAH in THF / DCM to get (5S)-8,9-difluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 42) (450 mg, 67%).1H NMR (400 MHz, DMSO-d6) δ: 7.44 (s, 1H), 6.98 (dd, J = 6.8, 11.4 Hz, 1H), 6.51 (br s, 1H), 4.49 (dd, J = 3.6, 12.0 Hz, 1H), 3.89 (t, J = 11.2 Hz, 1H), 3.45 - 3.34 (m, 1H), 3.29 (s, 3H), 2.60 - 2.54 (m, 1H), 2.28 (s, 9H), 1.14 (d, J = 6.6 Hz, 3H) ppm. ESI-MS m / z: 251.0 [M+H]+.

[0441] Step 11: Synthesis of (5R)-9-fluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-amine (Compound 43):

[0442] To a solution of EE-11a (250 mg, 0.78 mmol, 1.0 eq) in DCM (2.5 mL) at 0 ℃ was added an LAH solution in THF (2M, 1.57 mL, 3.14 mmol, 4.0 eq) and the resulting reaction mixture was warmed to room temperature and stirred at that temperature for 4 h. The reaction mixture was diluted with an aqueous Na2SO4 solution, and the obtained solids were filtered and washed with DCM. The combined organic layer was washed with an aqueous NaCl solution. The organic layer was dried over Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to obtain crude material. The crude product was purified by silica gel chromatography to afford (5R)-9-fluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine (Compound 43) (130 mg, 71%).1H NMR (500 MHz, DMSO-d6) δ: 7.37 (d, J = 3.1 Hz, 1H), 6.87 (dd, J = 4.4, 7.8 Hz, 1H), 6.69 (dd, J = 7.8, 11.2 Hz, 1H), 6.44 (d, J = 3.1 Hz, 1H), 4.50 (dd, J = 4.4, 12.2 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.44 - 3.37 (m, 1H), 3.32 (s, 3H), 2.54 (td, J = 4.4, 9.9 Hz, 1H), 2.29 (s, 6H), 1.12 (d, J = 7.0 Hz, 3H) ppm. ESI-MS m / z:233.1 [M+H]+.

[0443] Step 11: Synthesis of (5S)-9-fluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin- 5-amine (Compound 44):

[0444] In a similar fashion to Compound 43, EE-11b (160 mg) was treated with 2M LAH in THF / DCM to get (5S)-9-fluoro-N,N,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 44) (80 mg, 69%).1H NMR (400 MHz, DMSO-d6) δ = 7.37 (d, J = 2.9 Hz, 1H), 6.90 - 6.84 (m, 1H), 6.69 (dd, J = 7.8, 11.2 Hz, 1H), 6.44 (d, J = 3.1 Hz, 1H), 4.50 (dd, J = 4.2, 12.2 Hz, 1H), 3.93 - 3.79 (m, 2H), 3.42 - 3.36 (m, 1H), 3.32 (s, 3H), 2.29 (s, 9H), 1.12 (d, J = 7.0 Hz, 3H) ppm. ESI-MS m / z: 233.1 [M+H]+. Example A15:

[0445] Scheme-12: Synthesis of 1-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine; Compound 111

[0446] Step-1: Synthesis of Compound GG-7: tert-butyl (1-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)carbamate):

[0447] To a solution of Compound GG-6a (200 mg, 0.73 mmol, 1.0 eq) in DMF (2 mL) at 0 ℃ was added N-fluorobenzenesulfonimide (277 mg, 0.88 mmol, 1.2 eq). The reaction mixture was warmed to roomtemperature and stirred at that temperature for 2 hours. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with an aqueous solution of NaCl (15 mL), the organic layer was dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (20% EtOAc / Heptane) to afford tert-butyl (1-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)carbamate), Compound GG-7, (70 mg, 33% yield) as a white solid. ESI-MS m / z: 290.8 [M+H]+.

[0448] Step-2: Synthesis of Compound GG-8: tert-butyl (1-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)(methyl)carbamate):

[0449] To a solution of Compound GG-7 (30 mg, 0.10 mmol, 1.0 eq) in DMF (10 vol) at 0 ℃ was added NaH (4.94 mg, 0.20 mmol, 2.0 eq). The reaction mixture was stirred for 10 minutes at 0 ℃ and then MeI (29.2 mg, 0.20 mmol, 2.0 eq) was added. The reaction mixture was warmed to room temperature and stirred at that temperature for 2 hours. The reaction mixture was diluted with ice cold water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with an aqueous solution of NaCl (10 mL), the organic layer was dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo to afford tert-butyl (1-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- yl)(methyl)carbamate), Compound GG-8 (30 mg, crude) as a pale yellow film. This was carried forward without further purification. ESI-MS m / z: 204.9 [M-100]+.

[0450] Step-3: Synthesis of Compound 111: 1-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine:

[0451] To a stirred solution of Compound GG-8 (30 mg, 0.10 mmol, 1.0 eq) in DCM (10 vol) at 0 ℃ was added a LiAlH4solution (2M in THF, 0.19 mL, 0.39 mmol, 4.0 eq). The reaction mixture was heated to reflux and stirred at that temperature for 2 hours. The reaction mixture was cooled to 0 ℃, quenched with a saturated aqueous NH4Cl solution (5 mL), and extracted with DCM (2 x 10 mL). The combined organic layers were washed with an aqueous solution of NaCl, the organic layer was dried over anhydrous Na2SO4,the solids were filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (40% EtOAc / Heptane) to afford 1-fluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-amine, Compound 111 (12 mg, 56% yield). ESI-MS m / z: 219.8 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ: 7.22 - 7.18 (m, 1H), 6.95 - 6.92 (m, 1H), 6.89 - 6.81 (m, 2H), 4.21 (ddd, J = 1.4, 4.2, 11.8 Hz, 1H), 3.88 (dd, J = 9.0, 11.8 Hz, 1H), 3.14 - 3.07 (m, 1H), 3.06 - 2.99 (m, 1H), 2.95 - 2.88 (m, 1H), 2.36 - 2.34 (m, 6H). Example A16:

[0452] Scheme-13 Synthesis of 1,8-difluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amin; Compound 106

[0453] Step-1: Synthesis of Compound GG-14: (tert-butyl(1,8,9-trifluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]qui nolin-5-yl)carbamate):

[0454] To a solution of Compound GG-6c (500 mg, 1.72 mmol, 1.0 eq) in DMF (10 vol) at 0 ℃ was added N-fluorobenzenesulfonimide (812 mg, 2.58 mmol, 1.5 eq). The resulting reaction mixture was warmed to room temperature and stirred at that temperature for 6 hours. The reaction mixture was diluted with ice cold water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (20% EtOAc / Heptane) to afford (tert-butyl(1,8,9-trifluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]qui nolin-5-yl)carbamate), Compound GG-14 (100 mg, 18% yield) as an off-white solid. ESI-MS m / z: 309.2 [M+H]+.

[0455] Step-2: Synthesis of Compound GG-15: tert-butyl (1,8-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-5-yl)(methyl)carbamate):

[0456] To a solution of Compound GG-14 (100 mg, 0.32 mmol, 1.0 eq) in DMF (10 vol) at 0 ℃ was added NaH (15.3 mg, 0.64 mmol, 2.0 eq) and the mixture was stirred at 0 ℃ for 10 minutes. MeI (0.041 mL, 0.64 mmol, 2.0 eq) was added at 0 ℃ and the reaction mixture was warmed to room temperature and stirred at that temperature for 30 minutes. The reaction mixture was diluted with ice cold water (2 mL) and extracted with ethyl acetate (2 x 3 mL). The combined organic layers were washed with an aqueous NaCl solution (3 mL), dried over anhydrous Na2SO4, the solids were removed by filtration, and the filtrate was concentrated in vacuo. The crude residue was triturated with diethyl ether (2 x 5 mL) to provide tert-butyl (1,8-difluoro- 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)(methyl)carbamate), Compound GG-15 (30 mg, 29% yield) as a yellow solid. ESI-MS m / z: 323.2 [M+H]+.

[0457] Step-3: Synthesis of 1,8-difluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine; Compound 106:

[0458] To a solution of Compound GG-15 (30 mg, 0.09 mmol 1.0 eq) in DCM (10 vol) at 0 ℃ was added a LiAlH4 solution (2M in THF, 0.18 mL, 0.36 mmol, 4.0 eq). The resulting reaction mixture was heated to reflux and was stirred at that temperature for 2 hours. The reaction mixture was cooled to 0 ℃ and quenched with a saturated aqueous NH4Cl solution (5 mL). The formed solids were filtered off and washed with multiple portions of ethyl acetate. The combined organic extracts were washed with an aqueous solution of NaCl (10 mL), the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography (3% MeOH / DCM) to afford 1,8-difluoro-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine, Compound 106 (3 mg, 10% yield). ESI-MS m / z: 236.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.40 (d, J = 2.9 Hz, 1H), 7.08 (dd, J = 1.8, 9.6 Hz, 1H), 6.85 - 6.80 (m, 1H), 4.23 - 4.18 (m, 1H), 4.01 - 3.94 (m, 1H), 3.11 - 3.00 (m, 3H), 2.30 (s, 6H). Example A17:

[0459] Synthesis of 1,8-difluoro-N-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine; Compound 90:

[0460] To a solution of Compound GG-14 (30 mg, 0.10 mol 1.0 eq) in DCM (10 vol) at 0 ℃ was added a LiAlH4solution (2M in THF, 0.19 mL, 0.38 mmol, 4.0 eq). The resulting reaction mixture was heated to reflux and was stirred at that temperature for 2 hours. The reaction mixture was cooled to 0 ℃ and quenched with a saturated aqueous NH4Cl solution (5 mL). The formed solids were filtered off and washed with multiple portions of ethyl acetate. The combined organic extracts were washed with an aqueous solution of NaCl (10 mL), the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography (3% MeOH / DCM) to afford 1,8-difluoro-N-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine, Compound 90 (9 mg, 42% yield). ESI-MS m / z: 222.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.40 (d, J = 2.8 Hz, 1H), 7.07 (dd, J = 2.1, 9.9 Hz, 1H), 6.82 - 6.78 (m, 1H), 4.21 (dd, J = 3.2, 11.9 Hz, 1H), 3.77 (dd, J = 7.3, 11.9 Hz, 1H), 3.16 - 3.11 (m, 2H), 2.76 (dd, J = 8.6, 17.2 Hz, 1H), 2.37 (s, 3H). Example A18:

[0461] Scheme-14 Synthesis of 1-chloro-8-fluoro-5-(pyrrolidin-1-yl)-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinoline; Compound 105

[0462] Step-1: Synthesis of Compound GG-16: (tert-butyl (1-chloro-8-fluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate):

[0463] To a solution of Compound GG-6c (350 mg, 1.20 mmol, 1.0 eq) in DCM (3.5 mL) at 0 ℃ was added N-chlorosuccinimide (194 mg, 1.44 mmol, 1.2 eq), portion wise over a period of 10 minutes. The reaction mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and the crude residue was purified by silica gel chromatography (20% EtOAc / Heptane) to afford (tert-butyl (1- chloro-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate), Compound GG-16 (200 mg, 51% yield) as an off white solid. ESI-MS m / z: 268.1 [M-56] -.

[0464] Step-2: Synthesis of 1-chloro-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine; Compound 112:

[0465] To a solution of GG-16 (200 mg, 0.61 mmol, 1.0 eq) in DCM (6.6 mL) at 0 ℃ was added TFA (1 mL). The resulting mixture was warmed to room temperature and stirred at that temperature for 2 hours. Volatiles were removed in vacuo and the crude reaction residue was diluted with DCM (10 mL) and washed with a saturated NaHCO3solution (10 mL). The combined organic layers were washed with an aqueous NaCl solution (10 mL), the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude reaction residue was purified by silica gel chromatography (2% MeOH / DCM) to afford 1-chloro-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine, Compound 112 (120 mg, 88% yield). ESI-MS m / z: 224.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.57 (s, 1H), 7.02 - 6.98 (m, 1H), 6.84 (br d, J = 10.3 Hz, 1H), 4.19 (dd, J = 3.7, 11.8 Hz, 1H), 3.73 (dd, J = 8.0, 11.9 Hz, 1H), 3.43 - 3.37 (m, 1H), 3.06 (dd, J = 3.9, 16.0 Hz, 1H), 2.73 (dd, J = 8.8, 16.2 Hz, 1H), 2.04 - 1.88 (m, 2H).

[0466] Step-3: Synthesis of succinaldehyde as a reagent and synthesis of 1-chloro-8-fluoro-5- (pyrrolidin-1-yl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline; Compound 105:

[0467] To a 1M aqueous HCl solution (5 mL) at 0 ℃ was added 2,5-dimethoxytetrahydrofuran (500 mg, 4.99 mmol, 1.0 eq). The resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to give succinaldehyde (220 mg, crude) which was used immediately in the next step without further characterization or purification.

[0468] To a solution of Compound 112 (100 mg, 0.44 mmol, 1.0 eq) in a 1:1 ratio of THF: MeOH (10 vol) at room temperature was added succinaldehyde (75.6 mg, 0.88 mmol, 2.0 eq) and the reaction mixture was stirred for 30 min. The reaction mixture was then cooled to 0 ℃, and NaCNBH3 (88 mg, 0.88 mmol, 2.0 eq) was added. The resulting reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for 12 hours. Volatiles were removed in vacuo and the crude reaction residue was washed with water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with an aqueous solution of NaCl (10 mL), the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (1-2% MeOH / DCM) to afford 1-chloro-8-fluoro-5-(pyrrolidin-1-yl)-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinoline, Compound 105 (18 mg, 15% yield). ESI-MS m / z: 279.14 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.56 - 7.54 (m, 1H), 7.01 (dd, J = 2.1, 9.8 Hz, 1H), 6.88 - 6.83 (m, 1H), 4.38 - 4.33 (m, 1H), 4.03 (dd, J = 7.4, 12.3 Hz, 1H), 3.23 - 3.16 (m, 1H), 3.03 - 2.93 (m, 1H), 2.91 - 2.85 (m, 1H), 2.66 - 2.61 (m, 4H), 1.67 (br s, 4H). Example A19:

[0469] Scheme-15 Synthesis of 1-cyclobutyl-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine; Compound 102

[0470] Step-1: Synthesis of Compound HH-1; (1-(5-(dimethylamino)-5,6-dihydro-4H-pyrrolo[3,2,1- ij]quinolin-1-yl)cyclobutan-1-ol):

[0471] To a solution of Compound 15 (150 mg, 0.53 mmol, 1.0 eq) in THF (1.5 mL) at –78 ℃ was added an n-BuLi solution, (2 M in THF, 1.07 mL, 2.15, 4.0 eq) and the reaction mixture was stirred at –78 ℃ for 30 minutes. Cyclobutanone, Compound HH-0 (74 mg, 1.06 mmol, 2.0 eq) was added at –78 ℃ and the resulting mixture was warmed to room temperature and stirred at that temperature for 1 hour. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with saturated aqueous NaCl solution (5 mL), the layers were separated, the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (20% EtOAc / Hexane) to afford (1-(5-(dimethylamino)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)cyclobutan- 1-ol), Compound HH-1 (100 mg, 69% yield) as a colorless film. ESI-MS m / z: 271.30 [M+H]+.

[0472] Step-2: Synthesis of 1-cyclobutyl-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5- amine; Compound 102:

[0473] To a solution of Compound HH-1 (70 mg, 0.25 mmol, 1.0 eq.) in TFA (0.05 mL, 0.77, 3.0 eq) at 0 ℃ was added triethylsilane (0.4 mL, 2.5 mmol, 10 eq). The resulting mixture was warmed to roomtemperature and stirred at that temperature for 12 hours. The volatiles were evaporated in vacuo to give a residue. The residue was treated with a NaHCO3solution (40 mL) at 0 ℃ and was stirred for 20 minutes at that temperature. Ethyl acetate (30 mL) was added, and the layers were separated. The aqueous phase was extracted with additional portions of EtOAc (2 x 30 mL). The combined organic layers were washed with an aqueous solution of NaCl (100 mL), the organic layer was dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase HPLC (details below) to give 1-cyclobutyl-N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine, Compound 102 (8 mg, 13% yield). ESI-MS m / z: 255.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ: 7.31 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.89 - 6.81 (m, 2H), 4.30 - 4.25 (m, 1H), 3.98 - 3.92 (m, 1H), 3.68 - 3.59 (m, 1H), 3.07 - 2.94 (m, 3H), 2.40 - 2.32 (m, 8H), 2.22 - 2.11 (m, 2H), 2.06 - 1.96 (m, 1H), 1.92 - 1.85 (m, 1H). Reverse Phase Prep HPLC conditions:Example A20:

[0474] Scheme-16 Synthesis of 1-cyclopropyl-8,9-difluoro-N,N-dimethyl-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 113), (R)-1-cyclopropyl-8,9-difluoro-N,N-dimethyl-5,6- dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 114), and (S)-1-cyclopropyl-8,9-difluoro- N,N-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-amine (Compound 101)

[0475] Step-1: Synthesis of Compound JJ-1 (tert-butyl (1-bromo-8,9-difluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate):

[0476] To a solution of Compound RP-8 (500 mg, 1.62 mmol, 1.0 eq) in DMF (10 vol) at 0 ℃ was added N-bromosuccinimide (288 mg, 1.62 mmol 1.0 eq). The reaction mixture was warmed to room temperature and stirred at that temperature for 1 hour. The reaction mixture was diluted with ice-water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with an aqueous NaCl solution (5 mL), dried over anhydrous Na2SO4, the solids were filtered, and the filtrate was concentrated in vacuo to afford (tert-butyl (1-bromo-8,9-difluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate), Compound JJ-1 (0.5 g, 80% yield) as a brown solid. ESI-MS m / z: 387.8 [M+H]+.

[0477] Step-2: Synthesis of Compound JJ-2: tert-butyl (1-cyclopropyl-8,9-difluoro-5,6-dihydro-4H- pyrrolo[3,2,1-ij]quinolin-5-yl)carbamate):

[0478] To a solution of Compound JJ-1 (300 mg, 0.77 mmol, 1.0 eq) in a toluene:water mixture (40:1, 10 vol) at room temperature was added cyclopropylboronic acid, Compound JJ-0 (397 mg, 4.62 mmol 6.0 eq), followed by K3PO4 (0.48 g, 2.31 mmol, 3.0 eq). The reaction mixture was degassed under an N2 atmosphere for 10 minutes. Pd(OAc)2 (90 mg, 0.30 mmol 0.4 eq) was added, followed by RuPhos (140 mg, 0.30 mmol, 0.4 eq), and tricyclohexylphosphine tetrafluoroborate (113 mg, 0.30 mmol, and 0.40 eq). The reaction mixture was degassed under an N2 atmosphere for 10 minutes. The reaction mixture was heated to 120 ℃ and stirred at that temperature for 6 hours. The reaction mixture was cooled to room temperature and filtered through a Celite® pad. The filtrate was washed with a saturated NaCl solution (5 mL), dried ...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof:Formula (I) wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C1-C6alkyl(cycloalkyl), C1-C6alkyl(heterocycloalkyl), C1-C6alkyl(aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, cycloalkyl, and C1-C3alkyl(cycloalkyl), wherein each alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy and each cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C6cycloalkyl or oxo, or R7aand R7bare taken together to form a C3-C6 cycloalkyl or oxo, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy; R8is hydrogen, C1-C6alkyl, or -L-R8a; L is a bond, C1-C6alkylene, or C1-C6heteroalkylene; R8ais -ORb, -SRb, -NRcRd, -SeRb, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2NRcRd, -C(=O)Rb, - C(=O)ORb, -OC(=O)Rb, -OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, - NRbC(=O)NRcRd, -C(=O)NRcRd, -P(=O)(ORc)(ORd), -P(=O)RcRd, cycloalkyl, or heterocycloalkyl,wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; R9is hydrogen or C1-C6alkyl; or R8and R9are taken together to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, and =O; R10is hydrogen or C1-C3alkyl; each Rais independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, aryl, C1- C3alkyl(phenyl), C3-C6cycloalkyl, 5- to 6- membered heteroaryl, C1-C3alkyl(5- to 6- membered heteroaryl), or 4- to 6- membered heterocycloalkyl, wherein each alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O; each Rbis independently hydrogen or C1-C6alkyl; each Rcand Rdis independently hydrogen or C1-C6alkyl; or Rcand Rdare taken together to form a 4- to 6- membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O; m is 1 or 2; and n is 1 or 2; wherein: (a) at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen; (b) R8is -L-R8a; (c) R2is not hydrogen; (d) at least one of R6a, R6b, R7a, R7b, and R10is not hydrogen; (e) n is 2; or (f) m is 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, halogen, -CN, -NO2, -ORa, -SRa, -NRcRd, -S(=O)Rb, -S(=O)2Rb, -S(=O)2NRcRd, -NRbS(=O)2Rb, -NRbS(=O)2NRcRd, -C(=O)Rb, -C(=O)ORb, -OC(=O)Rb, - OC(=O)ORb, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, - P(=O)(ORc)(ORd), -P(=O)RcRd, C6-C10aryl, 5-10 membered heteroaryl, C3-C7cycloalkyl, 3- to 10- membered heterocycloalkyl, C1-C6alkyl(C3-C7cycloalkyl), C1-C6alkyl(3- to 10- membered heterocycloalkyl), C1-C6alkyl(C6-C10aryl), or C1-C6alkyl(heteroaryl), wherein each of the alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is optionally substituted with one ormore substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, halogen, C6- C10aryl, or C3-C7cycloalkyl, wherein each of the alkyl, heteroalkyl, aryl, and cycloalkyl is optionally substituted with one or more substituents selected from halogen, C1-C3alkyl, C1-C3alkoxy, halogen, - OH, and -CN.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R1, R2, R3, R4, and R5is independently hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R1is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R1is hydrogen.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R1is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R2is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R2is hydrogen.

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R2is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, phenyl, cyclopropyl, or cyclobutyl, wherein each of the alkyl, heteroalkyl, phenyl, cyclopropyl, and cyclobutyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R3is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R3is hydrogen.

13. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R3is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R4is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R4is hydrogen.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R4is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R5is hydrogen, C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1- C3alkyl, C1-C3alkoxy, -F, -Cl, -Br, and -CN.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R5is hydrogen.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R5is C1-C6alkyl, C1-C6heteroalkyl, -F, -Cl, -Br, or phenyl, wherein each of the alkyl, heteroalkyl, and phenyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1- C3alkoxy, -F, -Cl, -Br, and -CN.

20. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein:

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: at least one of R1and R2is not hydrogen, and at least one of R3, R4, and R5is not hydrogen.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein:R2is not hydrogen.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R6a, R6b, R7a, R7bis independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, -CN, -NO2, -ORb, -SRb, -NRcRd, C3-C6cycloalkyl, and C1-C3alkyl(C3-C6cycloalkyl), wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a C3-C4cycloalkyl, or R7aand R7bare taken together to form a C3- C4 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy.

24. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R6a, R6b, R7a, R7bis independently hydrogen, -ORb, or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy.

25. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R6a, R6b, R7a, R7bis independently hydrogen or C1-C6alkyl optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy; or R6aand R6bare taken together to form a cyclopropyl, or R7aand R7bare taken together to form a cyclopropyl, wherein the cyclopropyl is optionally substituted with one or more substituents selected from C1-C3alkyl, halogen, -OH, -CN, and C1-C3alkoxy.

26. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R6a, R6b, R7a, R7bis independently hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

27. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: each R6a, R6b, R7a, R7bis independently hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

28. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6ais hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

29. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6ais hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, - OH, -CN, and C1-C3alkoxy.

30. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6ais hydrogen.

31. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6ais -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

32. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6ais -OH.

33. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6ais -CH3.

34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6bis hydrogen, -OH, or -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

35. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6bis hydrogen or -CH3optionally substituted with one or more substituents selected from halogen, - OH, -CN, and C1-C3alkoxy.

36. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6bis hydrogen.

37. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6bis -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

38. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6bis -OH.

39. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R6bis -CH3.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7ais hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

41. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7ais hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, - OH, -CN, and C1-C3alkoxy.

42. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7ais hydrogen.

43. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7ais -CH3optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

44. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7ais -OH.

45. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7ais -CH3.

46. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7bis hydrogen, -OH, or -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

47. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7bis hydrogen or -CH3 optionally substituted with one or more substituents selected from halogen, - OH, -CN, and C1-C3alkoxy.

48. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7bis hydrogen.

49. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7bis -CH3 optionally substituted with one or more substituents selected from halogen, -OH, -CN, and C1-C3alkoxy.

50. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7bis -OH.

51. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R7bis -CH3.

52. The compound of any one of claims 1 to 25, wherein R6aand R6bare taken together to form a cyclopropyl.

53. The compound of any one of claims 1 to 25, wherein R7aand R7bare taken together to form a cyclopropyl.

54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: at least one of R6a, R6b, R7a, R7b, and R10is not hydrogen.

55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8is hydrogen or C1-C6alkyl.

56. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8is hydrogen or C1-C3alkyl.

57. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8is -CH3.

58. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8is hydrogen.

59. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8is C1-C3alkyl.

60. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8is -L-R8a.

61. The compound of claim 60, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: L is a bond.

62. The compound of claim 60, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: L is C1-C6alkylene, or C1-C6heteroalkylene.

63. The compound of claim 60, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: L is C1-C6alkylene.

64. The compound of claim 60, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: L is ethylene.

65. The compound of any one of claims 60 to 64, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8ais -NRcRd, -OC(=O)NRcRd, -NRbC(=O)Rb, -NRbC(=O)ORb, -NRbC(=O)NRcRd, -C(=O)NRcRd, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

66. The compound of any one of claims 60 to 64, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8ais heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

67. The compound of any one of claims 60 to 64, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8ais 4- to 6- membered heterocycloalkyl optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, halogen, -OH, -CN, and =O.

68. The compound of any one of claims 60 to 64, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R8ais pyrrolidinyl or tetrahydropyranyl, wherein each of the pyrrolidinyl and tetrahydropyranyl is optionally substituted with one or more substituents selected from C1-C3alkyl, C1-C3haloalkyl, C1- C3alkoxy, halogen, -OH, -CN, and =O.

69. The compound of claim 61, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein:.

70. The compound of any one of claims 62 to 68, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein:

71. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R9is hydrogen or C1-C3alkyl.

72. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R9is hydrogen.

73. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R9is -CH3.

74. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R9is -CH2CH3.

75. The compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R10is hydrogen.

76. The compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: R10is -CH3.

77. The compound of any one of claims 1 to 76, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: m is 1 or 2.

78. The compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: m is 1.

79. The compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein:m is 2.

80. The compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: n is 1 or 2.

81. The compound of any one of claims 1 to 80, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: n is 1.

82. The compound of any one of claims 1 to 80, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein: n is 2.

83. A compound, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, selected from:, , , , ,,84. The compound of claim 83, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein the compound is:,85. The compound of claim 83, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, wherein the compound is:.

86. The compound of claim 83, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof wherein the compound is:

87. The compound of claim 83, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof wherein the compound is:

88. The compound of claim 83, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof wherein the compound is: ,, , , ,89. The compound of any one of claims 1 to 88 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof, for use as medicine.

90. A pharmaceutical composition comprising the compound of any one of claims 1 to 88, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof.

91. The pharmaceutical composition of claim 90, further comprising at least one pharmaceutically acceptable excipient.

92. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 88, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, individual enantiomer, or isotopically enriched form thereof.

93. The method of claim 92, wherein the disease or disorder is a disease or disorder of the brain.

94. The method of claim 92, wherein the disease or disorder is a neurodegenerative, a neuropsychiatric, or substance use disease or disorder.

95. The method of claim 92, wherein the disease or disorder is a neurological disease or disorder.

96. The method of claim 92, wherein the disease or disorder is a brain injury.

97. The method of claim 92 or 93, wherein the disease or disorder is an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, or a factitious disorder.

98. The method of claim 92 or 93, wherein the disease or disorder is a psychotic disorder.

99. The method of claim 97 or 98, wherein the psychotic disorder is selected from schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, delusional disorder, shared psychotic disorder, substance-induced psychotic disorder, paraphrenia, psychotic depression, bipolar disorder, schizotypal personality disorder, paranoid personality disorder, schizoid personality disorder, borderline personality disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and dissociative disorders, or psychosis associated with a neurodegenerative disorders.

100. The method of claim 99, wherein the neurodegenerative disorder is selected from Huntington’s disease, Alzheimer’s disease, Lewy body dementia, and Parkinson’s disease.

101. The method of claim 98 or 99, wherein the psychotic disorder is schizophrenia or bipolar disorder.

102. The method of any one of claims 92 to 101, wherein the method further comprises administering to the subject a therapeutically effective amount of an additional therapeutic agent.

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