Isoindolin-1-one derivatives, compositions and uses thereof

Abstract

The present application relates to isoindolin-1-one compounds of Formula I, and to compositions comprising them. More particularly, the present application relates to isoindolin-1-one compound of Formula I useful in stimulating neuritogenesis and / or providing neuroprotection, and for diseases, disorders or conditions that benefit from stimulating neuritogenesis and / or providing neuroprotection. The present application further relates to processes for preparation of compounds of Formula I.

Description

TITLE: ISOINDOLIN-1-ONE DERIVATIVES, COMPOSITIONS AND USES THEREOFRELATED APPLICATIONS

[0001] The present application claims the benefit of priority of co-pending United States provisional patent application no. 63 / 745,483 filed on January 15, 2025 the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present application relates to isoindolin-1-one derivatives to compositions comprising them, and to their use in therapy. More particularly, the present application relates to isoindolin-1-one compounds useful in stimulating neuritogenesis and / or providing neuroprotection, and for diseases, disorders or conditions that benefit from neuritogenesis and neuroprotection. The present application also relates to processes for their preparationBACKGROUND

[0003] The medical need for better therapies of all neurological diseases is enormous and encompasses neurodegenerative conditions such as Alzheimer's and Parkinson's disease as well as neuropsychiatric diseases such as treatment resistant depression. Neurodegenerative diseases, including Alzheimer’s and Parkinson’s, represent a mounting global health crisis impacting an estimated 50 million people worldwide. This burden is projected to triple to 152 million by 2050, underscoring the urgent need for effective therapeutic interventions [GBD Dementia Forecasting Collaborators, 2019], Neuropsychiatric diseases are a leading cause of disability and suicide [S. E. Hyman, 2008], The Disability Adjusted Life Year (DALY) is used to report the years lost to premature death and years lived with disability. Neuropsychiatric diseases contributed around 12% of all DALYs globally in the year 2000 [S. E. Hyman, 2008],

[0004] Neurotrophins (NTs), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), have attracted interest as therapeutics of neurological disorders, due to their roles in neuronal survival, differentiation and plasticity in both the central nervous system (CNS) and peripheral nervous system (PNS) [J. Kim, 2023] [Huang EJ, 2001], Current therapeutic approaches offer symptomatic relief rather than disease modification. There is an immediate and unmet need for curative treatments of neuropsychiatric and neurodegenerative diseases, especially therapeutics that can reverse disease progression. While NTs themselves show promise as therapeutic agents, their clinical utility is limited by poor pharmacokinetic properties, including short half-life and limited permeability across the blood-brain-barrier (BBB). However, small molecule compounds mimicking neurotrophins ormodulating neurotrophin levels represent promising drug candidates for neurodegenerative and neuropsychiatric diseases [J. Xu, 2014],

[0005] Hericium erinaceus has emerged as a rich source of neurotrophic compounds, particularly isoindolinone alkaloids. Two members of this family, isohericerinol A and / V-de(phenylethyl) isohericerin (NDPIH), have demonstrated neurotrophic and neuroprotective properties [S. H. Ryu, 2021; M. Vishwanath, 2022], NDPIH has been shown to exhibit BDNF-like effects on primary hippocampal neurons, promoting neurite outgrowth [Ramón Martínez-Mármol, 2023],

[0006] There remains a need to further investigate neurotrophic and neuroprotective properties of isoindolinone derivatives.SUMMARY

[0007] The Applicants have developed novel isoindolin-1-one compounds for stimulating neuritogenesis and / or providing neuroprotection

[0008] Accordingly, the present invention includes a compound of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:OR2R3p3awhereinR1is selected from halo, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C6-ioaryl, C1-10alkyleneC6-10aryl, C2-iOalkenyleneC6-ioaryl, C2.ioalkynyleneC6-iOaryl, C3-i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C2-i0alkenyleneC3-i2cycloalkyl, C2. ioalkynyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci-ioalkyleneC3-i2heterocycloalkyl, C2. ioalkenyleneC3.i2heterocycloalkyl, C2-i0alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci. ioalkyleneC5-i2heteroaryl, C2.ioalkenyleneC5-i2heteroaryl, C2.ioalkynyleneC5-i2heteroaryl, Ci. ioalkyleneY1R7, C2.ioalkenyleneY1R7and C2.ioalkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2.i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2. i6haloalkenyl, Z1C2.i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2.i0alkenyleneY2R8, Z1C2. i0alkynyleneY2R8, Z1C6-ioaryl, Z1Ci-iOalkyleneC6-ioaryl, Z1C2-iOalkenyleneC6-ioaryl, Z1C2. ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-i0alkyleneC3-i2cycloalkyl, Z1C2-i0alkenyleneC3- i2cycloalkyl, Z1C2-i0alkynyleneC3-i2cycloalkyl, Z1C3-i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C2-ioalkenyleneC3-i8heterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2-10alkyleneC5-12heteroaryl, Z1C2-ioalkenyleneC5- i2heteroaryl and Z1C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci.6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-i0alkyleneOCi-6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =O, C1-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3-7heterocycloalkyl ring;R2is selected from H, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C3-i2cycloalkyl, Ci-ioalkyleneC3-i2cycloalkyl, C6-10aryl, C1-10alkyleneC6-10aryl, C3-i2heterocycloalkyl, Ci-ioalkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-i0alkyleneC5- i2heteroaryl, wherein each alkyl, alkenyl, alkynyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more substituents selected from OH, halo, Ci-iOalkyl, C-Mohaloalkyl, OCi-i0alkyl and OC1. lohaloalkyl; orR1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclic ring, optionally containing one additional heteroatom selected from N, NH, N(Ci.6alkyl), O, S, S(0) and S(0)2and optionally substituted with one or more substituents selected from OH, halo, NO2, =0, Ci-isalkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, OCi-i6alkyl, 0C2. isalkenyl, 0C2-iealkynyl, OCi-iehaloalkyl, OC2-iehaloalkenyl and OC2-iehaloalkynyl, wherein each alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from OH, =0, halo, OCi-i6alkyl, OC2-i6alkenyl, OC2-i6alkynyl, OC1. ishaloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl;R3, R3aand R5are independently selected from H, halo, C1-2alkyl and Ci.2haloalkyl;R4is selected from H, Ci_4alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci.4haloalkyl, C2-iohaloalkenyl, C2. lohaloalkynyl, C6-10aryl, C-ialkyleneC6-10aryl, C3alkyleneCe6-10aryl, C2-4alkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci-4alkyleneC3-i2cycloalkyl, C2-4alkenyleneC3. i2cycloalkyl, C2-4alkynyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci-4alkyleneC3- i2heterocycloalkyl, C2-4alkenyleneC3-i2heterocycloalkyl, C2-4alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci.4alkyleneC5-i2heteroaryl, C2-4alkenyleneC5-i2heteroaryl, C2-4alkynyleneC5- i2heteroaryl, Ci.4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein eachcyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z2Ci-i6alkyl, Z2C2-i6alkenyl, Z2C2.i6alkynyl, Z2Ci-i6haloalkyl, Z2C2.i6haloalkenyl, Z2C2.i6haloalkynyl, Z2Ci.ioalkyleneY4R10, Z2C2.ioalkenyleneY4R10, Z2C2. ioalkynyleneY4R10, Z2C6-10aryl, Z2Ci-ioalkyleneC6-ioaryl, Z2C2-ioalkenyleneC6-ioaryl, Z2C2. ioalkynyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci-i0alkyleneC3-i2cycloalkyl, Z2C2-i0alkenyleneC3. i2cycloalkyl, Z2C2-i0alkynyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-i0alkyleneC3. i2heterocycloalkyl, Z2C2-i0alkenyleneC3-i8heterocycloalkyl, Z2C2-i0alkynyleneC3. i2heterocycloalkyl, Z2C5-i2heteroaryl, Z2Ci-i0alkyleneC5-i2heteroaryl, Z2C2-i0alkenyleneC5- i2heteroaryl and Z2C2-i0alkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci.6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OC1. ioalkyleneOCi.6alkyl; and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, R6is selected from C1-6alkyl and C1-6haloalkyl;Y1is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR11, NR11C(O), C(O)NR11, NR11C(O)O and OC(O)NR11;Y2is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR12, NR12C(O), C(O)NR12, NR12C(O)O and OC(O)NR12;Y3is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR13, NR13C(O), C(O)NR13, NR13C(O)O and OC(O)NR13;Y4is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR14, NR14C(O), C(O)NR14, NR14C(O)O and OC(O)NR14;Z1is selected from a direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR15, NR15C(O), C(O)NR15, NR15C(O)O and OC(O)NR15;Z2is selected from a direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR16, NR16C(O), C(O)NR16, NR16C(O)O and OC(O)NR16;R7, R8, R9and R10are independently selected from H, Ci-i6alkyl, C2.i6alkenyl, C2.i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C6-ioaryl, Ci-iOalkyleneC6-ioaryl, C2. iOalkenyleneC6-ioaryl, C2-10alkynyleneC6-10aryl, C3.i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C2-i0alkenyleneC3-i2cycloalkyl, C2-i0alkynyleneC3-i2cycloalkyl, C3.i2heterocycloalkyl, Ci.ioalkyleneC3-i2heterocycloalkyl, C2-ioalkenyleneC3-i2heterocycloalkyl, C2-ioalkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-i0alkyleneC5-i2heteroaryl, C2-ioalkenyleneC5- i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group in R7, R8, R9and R10is optionally substituted with one or more substituents selected from OH, halo, C1-16alkyl and C1-6haloalkyl;R11, R12, R13, R14, R15and R16are independently selected from H, C1-16alkyl and C1-16haloalkyl; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:i) when R2, R3, R3a, R4and R5are all H and R6is CH3, then R1is not CH2OH, C6-16alkenyl or C6-16alkenyl substituted with OH or =O;ii) when R2is CH(CH3)2, R3, R3aand R5are all H, R6is CH3, and R1is CH2OCH(CH3)2or CH2OC(O)CH3, then R4is not H or Cialkylenephenyl substituted with one or two OCH3; iii) when R2is CH3, R3, R3aand R5are all H, R6is CH(CH3)2, and R1is CH3, then R4is not H, C(CH3)3or Cialkylenephenyl substituted with one OCH3;iv) when R2, R3, R3aand R5are all H, R6is CH3, and R4is Cialkylenephenyl or Cialkylenephenyl substituted with one or two OCH3, then R1is not I, CH2OH, 3-methylbut-2-en-1-yl (Cialkyleneoctahydronaphthalenyl, Cialkylenedecahydronaphthalenyl and Cialkylenedecahydronaphtho[1,2b]oxirenyl, the latterthree of which are substituted with 3 to 5 substituents selected from OH, CH3, =0, =C and OCialkylenephenyl;v) when R2, R3, R3aand R5are all H, R6is CH3, R4is unsubstituted 3-indolyl, then R1is not (2E)-3,7-dimethyl-2,6-octadien-1-yl; andvi) when R3, R3a, R4and R5are all H, and R6is CH3, then R1and R2are not joined to form, together with the oxygen and carbon atoms therebetween, a 6 membered unsaturated ring that is disubstituted on the same carbon atom with CH3and C4-ioalkenyl or with CH3and C4.8alkenyl substituted with one =0, and the ring being optionally further substituted with one OH or one =0.

[0009] The present application also includes a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof and a pharmaceutically acceptable carrier.

[0010] The present application also includes a method of stimulating neuritogenesis in a neuronal cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of Formula I the neuronal cell.

[0011] In some embodiments, stimulating neuritogenesis is by promoting neurite elongation, promoting neurite growth and / or restoring neurite formation.

[0012] In some embodiments, stimulating neuritogenesis decreases or inhibits neurodegeneration, increases neural plasticity and / or provides neuroprotection.

[0013] In some embodiments, providing neuroprotection is by decreasing or inhibiting neurodegeneration.

[0014] The present application also includes a method of treating a disease, disorder or condition that benefits from neuritogenesis comprising administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof to a subject in need thereof.

[0015] In some embodiments, the administration of the compound stimulates neuritogenesis

[0016] In some embodiments, stimulating neuritogenesis provides neuroprotection, and the application includes a method of treating a disease, disorder or condition that benefits from neuroprotection, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, solvate and / or prodrug thereof to a subject in need thereof.

[0017] In some embodiments, the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection is a neurological disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection.

[0018] In some embodiments, the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection is a central nervous system (CNS) disorder or a peripheral nervous system disorder (PNS).

[0019] The present application further includes a process for preparing a compound of Formula I or a salt thereof, wherein R2and R3aare both H,the process comprising:reacting a compound of Formula AOH Owith a compound of Formula B, R1-Hal (B), wherein Hal is selected from F, Cl, Br and I, in the presence of a base to provide a compound of Formula COR1Osubjecting the compound of Formula C to conditions to induce a rearrangement to provide a compound of Formula Dreacting the compound of Formula D with a compound of Formula E, NH2-R4(E), in the presence of a reducing agent to provide the compound of Formula I, or a salt thereof, whereinR3is selected from H, Ci-2alkyl and Ci-2haloalkyl including embodiments thereof as defined for Formula I;R4, R5and R6are as defined for Formula I, including embodiments thereof; andR1is selected from C2-16alkenyl, C2-10alkenyleneC6-10aryl, C2-10alkenyleneC3-12cycloalkyl, C2-10alkenyleneC3-12heterocycloalkyl, C2-10alkenyleneC5-12heteroaryl and C2-10alkenyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2. i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2.ioalkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-10aryl, Z1Ci-ioalkyleneC6-ioaryl, Z1C2-ioalkenyleneC6-ioaryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-i0alkyleneC3. i2cycloalkyl, Z1C2-ioalkenyleneC3-i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci-ioalkyleneC3.i2heterocycloalkyl, Z1C2-ioalkenyleneC3. isheterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2. ioalkyleneC5-i2heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci. ehaloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-i0alkyleneOCi-6alkyl, and wherein each alkenyl and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, ON, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, and including embodiments thereof described above;provided the C2-16alkenyl or C2-10alkenylene group in R1comprises an allyl group wherein the CH2of the allyl group is covalently attached to the remaining portion of the compound of Formula I.

[0020] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The present application will be described in greater detail with reference to the attached drawings and Tables in which:

[0022] Figure 1 is a representative image of a neuron showing the analysis conducted. White circles point to the roots where outgrowth occurs. The white arrows point to the neurite extending from the neuronal body. The white triangles point to the neurite extremities

[0023] DETAILED DESCRIPTIONI. Definitions

[0024] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0025] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise

[0026] The term “compound of the application” or “compound of the present application” and the like as used herein refers to a compound of Formula I, including pharmaceutically acceptable salts, solvates and / or prodrugs thereof.

[0027] The term “composition of the application” or “composition of the present application” and the like as used herein refers to a composition comprising one or more compounds the application and at least one additional ingredient.

[0028] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present. The term “and / or” with respect to pharmaceutically acceptable salts and / or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a solvate of a salt of a compound of the application.

[0029] As used in the present application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with one compound, or two or more additional compounds.

[0030] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0031] As used herein, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”),“including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process / method steps.

[0032] As used herein, the word “consisting” and its derivatives, are intended to be close ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0033] The term “consisting essentially of”, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0034] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0035] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0036] The present application refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0037] The term “protecting group” or “PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in theart. Many conventional protecting groups are known in the art, for example as described in “Protective Groups in Organic Chemistry” McOmie, J. F. W. Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0038] The term “cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.

[0039] The term “subject” as used herein includes all members of the animal kingdom including mammals. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.

[0040] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0041] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with an active ingredient (for example, one or more compounds of the application) to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0042] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0043] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0044] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0045] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0046] The term “solvate” as used herein means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.

[0047] The term “inert organic solvent” as used herein refers to a solvent that is generally considered as non-reactive with the functional groups that are present in the compounds to be combined together in any given reaction so that it does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and dissolve compounds that are nonsoluble in aqueous solutions.

[0048] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbonatoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-Cn2”. Thus, for example, the term “Ci-C6alkyl” (or “Ci-6alkyl”) means an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and includes, for example, any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and tert-butyl, n- and iso-propyl, ethyl and methyl. All alkyl groups are optionally fluorosubstituted, unless otherwise indicated.

[0049] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term C2-6alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond. All alkenyl groups are optionally fluorosubstituted, unless otherwise indicated

[0050] The term “alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term C2-6alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms. All alkynyl groups are optionally fluorosubstituted, unless otherwise indicated.

[0051] The term “cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated or unsaturated non-aromatic carbocyclic group containing from 3 to 20 carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix “Cni-n2”. For example, the term C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0052] The term “aryl” as used herein, whether it is used alone or as part of another group, refers to carbocyclic groups containing at least one aromatic ring and contains from 6 to 12 carbon atoms. Aryl groups are optionally fused to a cycloalkyl group.

[0053] The term “heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one non-aromatic ring containing from 3 to 12 atoms in which one or more of the atoms are a heteromoiety selected from O, S, S(O), SO2, N, NH and substituted N and the remaining atoms are C. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds). When a heterocycloalkyl group contains the prefix Cn1-n2this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heterocycloalkyl groups are optionally fused to an aryl, heteroaryl or cycloalkyl group.

[0054] The term “heteroaryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing at least one heteroaromatic ring containing 5-12 atoms in which one or more of the atoms are a heteroatom selected from O, S and N and the remaining atoms are C. When a heteroaryl group contains the prefix Cn1-n2this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteroatom as defined above. Heteroaryl groups are optionally fused to an aryl group.

[0055] All cyclic groups, including aryl, heteroaryl, heterocyclo and cycloalkyl groups, contain one (i.e. are monocyclic) or more than one ring (i.e. are polycyclic). When a cyclic group contains more than one ring, the rings may be fused, bridged or spirofused.

[0056] The term “benzofused” as used herein refers to a polycyclic group in which a benzene ring is fused with another ring.

[0057] A first ring being “fused” with a second ring means the first ring and the second ring share two adjacent atoms there between.

[0058] A first ring being “bridged” with a second ring means the first ring and the second ring share two non-adjacent atoms there between.

[0059] A first ring being “spirofused” with a second ring means the first ring and the second ring share one atom there between.

[0060] The term “haloalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “Ci.6haloalkyl” (or “Ci-C6haloalkyl”) refers to a Ci to C6linear or branched alkyl group as defined above with one or more halogen substituents.

[0061] As used herein, the term “haloalkenyl” refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “Ci-ehaloalkenyl” (or “Ci-Cehaloalkenyl”) refers to a Ci to C6linear or branched alkenyl group as defined above with one or more halogen substituents.

[0062] As used herein, the term “haloalkynyl” refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a halogen. Thus, for example, “Ci.6haloalkynyl” (or “Ci-C6haloalkynyl”) refers to a Ci to C6linear or branched alkynyl group as defined above with one or more halogen substituents.

[0063] The term “halogen” or “halo” whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0064] The term “deuteroalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a deuterium. Thus, for example, “Ci.6deuteroalkyl” refers to a Ci to C6linear or branched alkyl group as defined above with one or more deuterium substituents.

[0065] The term “fluoroalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a fluorine. Thus, for example, “Ci-efluoroalkyl” refers to a Ci to Ce linear or branched alkyl group as defined above with one or more fluorine substituents.

[0066] The term “chloroalkyl” as used herein refers to an alkyl group as defined above in which one or more of the available hydrogen atoms have been independently replaced with a chlorine. Thus, for example, “Ci-echloroalkyl” refers to a Ci to Ce linear or branched alkyl group as defined above with one or more chlorine substituents

[0067] The term "allyl group” as used herein refers to a moiety that is or comprises the structural formulawhereinindicates a point of covalent attachment to the remainder of the compound. The term “allyl group” includes substituted allyl groups.

[0068] The suffix “ene” at the end of a group (for example “alkylene” or “alkenylene”) means that the group is bivalent, that is that it is bonded to two variables each on a different end of or location on the group.

[0069] The term “optionally substituted” as used here means that the subject group is unsubstituted or substituted and the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably herein.

[0070] The term “available”, as in “available hydrogen atoms” or “available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by another atom or group.

[0071] The symbol when drawn perpendicularly across a bond indicates a point of covalent attachment of a chemical group

[0072] When a group is substituted with more than one substituent selected from a list of substituents, each of the substituents are independently selected from the listed group of substituents.

[0073] The term “substituted” as used herein unless otherwise stated means that one or more hydrogen atoms in the group are substituted or replaced with a substituent group independently selected from halo, OH, Ci-C4alkyl, OCi-C4alkyl, Ci-C4haloalkyl, OCi-C4haloalkyl, alkyleneOalkyl, alkyleneOhaloalkyl, OalkyleneOalkyl, OalkyleneOhaloalkyl, CN,NO2, NH2, NH(C1-C4alkyl), N(Ci-C4alkyl)(Ci-C4alkyl), SCi-C4alkyl, S(O)Ci-C4alkyl, SO2Ci-C4alkyl, C(O)OH, C(O)OCi-C4alkyl, C(0)NH2, C(O)NHCi-C4alkyl, C(O)N(Ci-C4alkyl)( Ci-C4alkyl), C3-C6cycloalkyl and a 3- to 6-membered heterocyclic ring including 1 to 2 ring heteromoeities selected from O, S, S(O), SO2, N, NH and NCi-C4alkyl.

[0074] The term “isoprenyl group” as used herein refers to a substituent that is orcomprises one or more isoprenyl groups, e.g., 3-methylbut-2-en-1-yl,Unless otherwise stated isoprenyl groups include substituted isoprenyl groups.

[0075] As used herein, the term “one or more” item includes a single item selected from the list as well as mixtures of two or more items selected from the list.

[0076] The term “N-de(phenylethyl) isohericerin” or “NDPIH” or“C-1” as used herein refers to a compound having the chemical name: 5-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]-2,3-dihydro-4-hydroxy-6-methoxy- 1H-lsoindol-1-one and having the chemical formula:

[0077] The term “isohericerin” or “C-2” as used herein refers to a compound having the chemical name: 5-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]-2,3-dihydro-4-hydroxy-6-methoxy-2-(2-phenylethyl)-1H-isoindol-1-one

[0078] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of a disease, disorder or condition, stabilized (i.e. not worsening) state of a disease, disorder or condition, preventing spread of a disease, disorder or condition, delay or slowing of a disease, disorder or condition progression, amelioration or palliation of a disease, disorder or condition state, diminishment of the reoccurrence of a disease, disorder or condition, inhibiting or reducing a disease, disorder or condition and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment.

[0079] “Palliating” a disease, disorder or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the disease, disorder or condition.

[0080] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection manifesting a symptom associated with a disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection.

[0081] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.

[0082] The term “administered” as used herein means administration of a therapeutically effective amount of a compound, or one or more compounds, or a composition of the application to a cell or a subject.

[0083] The term “disease, disorder or condition that benefits from neuritogenesis” as used herein refers to any disease, disorder or condition that is directly or indirectly caused by, or has as part of its etiology, neuritogenesis.

[0084] The term “stimulating neuritogenesis” as used herein means any detectable increase in neuritogenesis in a neuronal cell or in a subject in the presence of a compound of the application compared to otherwise the same conditions except in the absence of the compound of the application.

[0085] The term “neuritogenesis” as used herein refers to growth of neurites, including formation, extension and / or branching of neurites.

[0086] The term “neuroprotection” as used herein refers to the arrest and / or reverse progression of neurodegeneration.

[0087] The term “provides neuroprotection” herein means any detectable increase in neuroprotection in the presence of a compound of the application compared to otherwise the same conditions, except for in the absence in the compound of the application.

[0088] The term “neurodegeneration” as used herein means progressive loss of neurons. This includes but is not limited to immediate loss of neurons followed by subsequent loss of connecting or adjacent neurons.

[0089] The term “decreasing or inhibiting neurodegeneration” as used herein means any detectable decrease, reduction and / or inhibition in neurodegeneration in the presence of a compound of the application compared to otherwise the same conditions, except for in the absence in the compound of the application.

[0090] By “inhibiting, blocking and / or disrupting” it is meant any detectable inhibition, block and / or disruption in the presence of a compound compared to otherwise the same conditions, except for in the absence in the compound.

[0091] The term “neural plasticity” as used herein refers to the ability of neurons to change in form and function in response to alterations in their environment.

[0092] The term “increasing neural plasticity” as used herein means any detectable increase in neural plasticity in the presence of a compound of the application compared to otherwise the same conditions, except for in the absence in the compound of the application.

[0093] A “neurodegenerative disease” as used herein refers to a refers to any disease, disorder of condition marked by the gradual degeneration and / or death of neurons.

[0094] The term “central nervous system” or “CNS” as used herein means the brain and / or spinal cord.

[0095] The term “peripheral nervous system” or “PNS” as used herein means all cells and tissues which comprise the peripheral nerves.II. Compounds of the Application

[0096] Novel isoindolinone derivatives have been developed and prepared.

[0097] In some embodiments, the application includes a compound of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:OR2R3o3awhereinR1is selected from halo, C1-16alkyl, C2-16alkenyl, C2-16alkynyl, C1-16haloalkyl, C2-16haloalkenyl, C2-i6haloalkynyl, C6-ioaryl, Ci-iOalkyleneC6-ioaryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-iOaryl, C3-i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C2-ioalkenyleneC3-i2cycloalkyl, C2. ioalkynyleneC3-i2cycloalkyl, C3.i2heterocycloalkyl, Ci-ioalkyleneC3.i2heterocycloalkyl, C2-i0alkenyleneC3-i2heterocycloalkyl, C2-ioalkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, C1-ioalkyleneC5-i2heteroaryl, C2-ioalkenyleneC5-i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, C1-i0alkyleneY1R7, C2-ioalkenyleneY1R7and C2-ioalkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2.i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2. i6haloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2-ioalkenyleneY2R8, Z1C2. i0alkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2-ioalkenyleneC6-ioaryl, Z1C2. ioalkynyleneC6-ioaryl, Z1C3.i2cycloalkyl, Z1Ci-i0alkyleneC3-i2cycloalkyl, Z1C2-ioalkenyleneC3. i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3.i2heterocycloalkyl, Z1Ci-i0alkyleneC3. i2heterocycloalkyl, Z1C2-ioalkenyleneC3-i8heterocycloalkyl, Z1C2-ioalkynyleneC3. i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2-10alkyleneC5-12heteroaryl, Z1C2-ioalkenyleneC5- i2heteroaryl and Z1C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci.6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-ioalkyleneOCi-6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi-ealkyl to form a C3.7heterocycloalkyl ring;R2is selected from H, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C3.i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C6-ioaryl, Ci-ioalkyleneC6ioaryl, C3.i2heterocycloalkyl, Ci-i0alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-i0alkyleneC5- i2heteroaryl, wherein each alkyl, alkenyl, alkynyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more substituents selected from OH, halo, Ci-iOalkyl, C-Mohaloalkyl, OCi-i0alkyl and OC1. lohaloalkyl; orR1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclic ring, optionally containing one additional heteroatom selected from N, NH, N(Ci.6alkyl), O, S, S(0) and S(0)2and optionally substituted with one or more substituents selected from OH, halo, NO2, =0, C1-16alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, OCi-i6alkyl, 0C2.isalkenyl, 0C2-iealkynyl, OCi-iehaloalkyl, OC2-iehaloalkenyl and OC2-iehaloalkynyl, wherein each alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from OH, =0, halo, OCi-i6alkyl, OC2-i6alkenyl, OC2-i6alkynyl, OC1. ishaloalkyl, OC2-iehaloalkenyl and OC2-iehaloalkynyl;R3, R3aand R5are independently selected from H, halo, Ci-2alkyl and Ci-2haloalkyl;R4is selected from H, Ci_4alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci.4haloalkyl, C2-iohaloalkenyl, C2. lohaloalkynyl, C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-ioaryl, C2. ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C2.4alkenyleneC3. i2cycloalkyl, C2-4alkynyleneC3-i2cycloalkyl, C3.i2heterocycloalkyl, Ci.4alkyleneC3. i2heterocycloalkyl, C2-4alkenyleneC3-i2heterocycloalkyl, C2-4alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-4alkyleneC5-i2heteroaryl, C2-4alkenyleneC5-i2heteroaryl, C2-4alkynyleneC5-12heteroaryl, Ci.4alkyleneY3R9, C2.4alkenyleneY3R9and C2.4alkynyleneY3R9, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z2Ci-i6alkyl, Z2C2-i6alkenyl, Z2C2-i6alkynyl, Z2Ci-i6haloalkyl, Z2C2-i6haloalkenyl, Z2C2-i6haloalkynyl, Z2Ci-i0alkyleneY4R10, Z2C2-ioalkenyleneY4R10, Z2C2. ioalkynyleneY4R10, Z2C6-10aryl, Z2Ci-ioalkyleneC6-ioaryl, Z2C2-ioalkenyleneC6-ioaryl, Z2C3-ioalkynyleneC6-ioaryl, Z2C3.i2cycloalkyl, Z2Ci-i0alkyleneC3-i2cycloalkyl, Z2C2-ioalkenyleneC3. i2cycloalkyl, Z2C2-ioalkynyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-ioalkyleneC3. i2heterocycloalkyl, Z2C2-ioalkenyleneC3.i8heterocycloalkyl, Z2C2-ioalkynyleneC3. i2heterocycloalkyl, Z2C5-i2heteroaryl, Z2Ci-i0alkyleneC5-i2heteroaryl, Z2C2-ioalkenyleneC5- i2heteroaryl and Z2C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci.6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi. ioalkyleneOCi-6alkyl; and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =O, C1-4alkyl and C1-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, R6is selected from Ci.6alkyl and Ci.6haloalkyl;Y1is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR11, NR11C(O), C(O)NR11, NR11C(O)O and OC(O)NR11;Y2is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR12, NR12C(O), C(O)NR12, NR12C(O)O and OC(O)NR12;Y3is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR13, NR13C(O), C(O)NR13, NR13C(O)O and OC(O)NR13;Y4is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR14, NR14C(O), C(O)NR14, NR14C(O)O and OC(O)NR14;Z1is selected from a direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR15, NR15C(O), C(O)NR15, NR15C(O)O and OC(O)NR15;Z2is selected from a direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR16, NR16C(O), C(O)NR16, NR16C(O)O and OC(O)NR16;R7, R8, R9and R10are independently selected from H, Ci-i6alkyl, C2.i6alkenyl, C2.i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C6-ioaryl, Ci-iOalkyleneC6-ioaryl, C2. ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci-ioalkyleneC3-i2cycloalkyl, C2-i0alkenyleneC3-i2cycloalkyl, C2-i0alkynyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci. ioalkyleneC3.i2heterocycloalkyl, C2-i0alkenyleneC3-i2heterocycloalkyl, C2-i0alkynyleneC3- i2heterocycloalkyl, C5-i2heteroaryl, C1-10alkyleneC5-i2heteroaryl, C2-ioalkenyleneC5-i2heteroaryl, C2-i0alkynyleneC5-i2heteroaryl, wherein each cyclic group in R7, R8, R9and R10is optionally substituted with one or more substituents selected from OH, halo, C1-16alkyl and C1-6haloalkyl;R11, R12, R13, R14, R15and R16are independently selected from H, Ci-i6alkyl and Ci. i6haloalkyl; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:i) when R2, R3, R3a, R4and R5are all H and R6is CH3, then R1is not CH2OH, C6-i6alkenyl or C6-i6alkenyl substituted with OH or =0;ii) when R2is CH(CH3)2, R3, R3aand R5are all H, R6is CH3, and R1is CH2OCH(CH3)2or CH2OC(O)CH3, then R4is not H or Cialkylenephenyl substituted with one or two OCH3; iii) when R2is CH3, R3, R3aand R5are all H, R6is CH(CH3)2, and R1is CH3, then R4is not H, C(CH3)3or Cialkylenephenyl substituted with one OCH3;iv) when R2, R3, R3aand R5are all H, R6is CH3, and R4is Cialkylenephenyl or Cialkylenephenyl substituted with one or two OCH3, then R1is not I, CH2OH, 3-methylbut-2-en-1-ylCialkyleneoctahydronaphthalenyl, Cialkylenedecahydronaphthalenyland Cialkylenedecahydronaphtho[1,2b]oxirenyl, the latter three of which are substituted with 3 to 5 substituents selected from OH, CH3, =0, =C and OCialkylenephenyl;v) when R2, R3, R3aand R5are all H, R6is CH3, R4is unsubstituted 3-indolyl, then R1is not (2E)-3,7-dimethyl-2,6-octadien-1-yl; andvi) when R3, R3a, R4and R5are all H, and R6is CH3, then R1and R2are not joined to form, together with the oxygen and carbon atoms therebetween, a 6 membered unsaturated ring that is disubstituted on the same carbon atom with CH3and C4-ioalkenyl or with CH3and C4.8alkenyl substituted with one =0, and the ring being optionally further substituted with one OH or one =0.

[0098] In some embodiments, R1is selected from F, Cl, Br, I, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, C1-16haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C6-10aryl, Ci-ioalkyleneCe-iOaryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3.i2cycloalkyl, Ci-ioalkyleneC3. i2cycloalkyl, C2-ioalkenyleneC3.i2cycloalkyl, C2-ioalkynyleneC3.i2cycloalkyl, C3-i2heterocycloalkyl, Ci-i0alkyleneC3-i2heterocycloalkyl, C2-ioalkenyleneC3.i2heterocycloalkyl, C2-ioalkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-i0alkyleneC5-i2heteroaryl, C2. ioalkenyleneC5-i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, Ci-ioalkyleneY1R7, C2. i0alkenyleneY1R7and C2-ioalkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2- i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2-ioalkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-i0aryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2-ioalkenyleneC6-ioaryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3. i2cycloalkyl, Z1Ci-ioalkyleneC3.i2cycloalkyl, Z1C2-ioalkenyleneC3.i2cycloalkyl, Z1C2-ioalkynyleneC3.i2cycloalkyl, Z1C3.i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C2-ioalkenyleneC3-i8heterocycloalkyl, Z1C2-ioalkynyleneC3.i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2-10alkyleneC5-12heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2. ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, F, Cl, Br, NO2, C1-i6alkyl, Ci.6haloalkyl, Ci.6alkyleneOCi.6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OC1. ioalkyleneOCi.6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1is selected from F, Cl, Br, Ci-i6alkyl, C2-i6alkenyl, C2.isalkynyl, Ci-iehaloalkyl, C2-iehaloalkenyl, C2-iehaloalkynyl, C6-10aryl, C-i-ioalkyleneC6-10aryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci-i0alkyleneC3. i2cycloalkyl, C2-ioalkenyleneC3-i2cycloalkyl, C2-ioalkynyleneC3-i2cycloalkyl, C3. i2heterocycloalkyl, Ci-ioalkyleneC3.i2heterocycloalkyl, C2-ioalkenyleneC3.i2heterocycloalkyl, C2-ioalkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-i0alkyleneC5-i2heteroaryl, C2. i0alkenyleneC5-i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, C1-10alkyleneY1R7, C2. i0alkenyleneY1R7and C2-ioalkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2.i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2.i6haloalkenyl, Z1C2. i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2-ioalkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-i0aryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2-ioalkenyleneC6-ioaryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3. i2cycloalkyl, Z1Ci-i0alkyleneC3-i2cycloalkyl, Z1C2-ioalkenyleneC3-i2cycloalkyl, Z1C2. ioalkynyleneC3.i2cycloalkyl, Z1C3.i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C2-ioalkenyleneC3-i8heterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5. i2heteroaryl, Z1C2-10alkyleneC5-12heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2. ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, F, Cl, Br, NO2, Ci. i6alkyl, Ci.6haloalkyl, Ci.6alkyleneOCi.6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OC1. ioalkyleneOCi.6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi-ealkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0099] In some embodiments, R1is selected from F, Cl, Br, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C6-ioaryl, Ci.ioalkyleneC6-ioaryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3.i2cycloalkyl, Ci-ioalkyleneC3. i2cycloalkyl, C2-ioalkenyleneC3.i2cycloalkyl, C2-ioalkynyleneC3.i2cycloalkyl, C3. i2heterocycloalkyl, Ci.ioalkyleneC3.i2heterocycloalkyl, C2-ioalkenyleneC3.i2heterocycloalkyl, C2-ioalkynyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci-ioalkyleneC5-i2heteroaryl, C2. ioalkenyleneC5-i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, Ci-ioalkyleneY1R7, C2-i0alkenyleneY1R7and C2-ioalkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2.i6haloalkynyl, Z1C6-ioaryl, Z1Ci-ioalkyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-ioalkyleneC3-i2cycloalkyl, Z1C3-i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl and Z1C2-10alkyleneC5-12heteroaryl, wherein each cyclic group comprised in the latter 8 groups is optionally substituted with one or more substituents selected from OH, F, Cl, Br, NO2, Ci-i6alkyl, Ci.6haloalkyl, Ci.6alkyleneOCi.6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OC1. ioalkyleneOCi.6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0100] In some embodiments, R1is selected from F, Cl, Br, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C6-ioaryl, Ci.ioalkyleneC6-iOaryl, C2-ioalkenyleneC6-ioaryl, C3-i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C2. ioalkenyleneC3.i2cycloalkyl, C3-i2heterocycloalkyl, Ci.ioalkyleneC3.i2heterocycloalkyl, C2. ioalkenyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-ioalkyleneC5-i2heteroaryl, C2-ioalkenyleneC5-i2heteroaryl, C1-10alkyleneY1R7, C2-ioalkenyleneY1R7and C2. i0alkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2-i6haloalkynyl, Z1C6-ioaryl, Z1Ci-ioalkyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-i0alkyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci.ioalkyleneC3.i2heterocycloalkyl, Z1C5-i2heteroaryl and Z1C2. ioalkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 8 groups is optionally substituted with one or more substituents selected from OH, F, Cl, Br, NO2, C1-i6alkyl, Ci.6haloalkyl, Ci.6alkyleneOCi.6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OC1. ioalkyleneOCi.6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0101] In some embodiments, R1is selected from F, Cl, Br, C1-16alkyl, C2.i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2.i6haloalkynyl, C6-ioaryl, Ci-i0alkyleneC6-i0aryl, C2-ioalkenyleneC6-ioaryl, C3-i2cycloalkyl, Ci-ioalkyleneC3-i2cycloalkyl, C2. ioalkenyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci-ioalkyleneC3.i2heterocycloalkyl, C2. ioalkenyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci-i0alkyleneC5-i2heteroaryl and C2. ioalkenyleneC5-i2heteroaryl, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci. i6alkyl, Z1C2-i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2.i6haloalkenyl, Z1C2.i6haloalkynyl, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C3.i2cycloalkyl, Z1Ci-i0alkyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci-i0alkyleneC3.i2heterocycloalkyl, Z1C5-i2heteroaryl and Z1C2. ioalkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 8 groups is optionally substituted with one or more substituents selected from OH, F, Cl, Br, NO2, Ci. i6alkyl, Ci.6haloalkyl, Ci.6alkyleneOCi.6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OCi. ioalkyleneOCi.6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0102] In some embodiments, R1is selected from F, Cl, Br, C1-16alkyl, C2.i6alkenyl, C2.i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C6-ioaryl, Ci.ioalkyleneC6-iOaryl, C2-ioalkenyleneC6-ioaryl, C3.i2cycloalkyl, Ci-i0alkyleneC3.i2cycloalkyl, C2. ioalkenyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci-i0alkyleneC3.i2heterocycloalkyl, C2. ioalkenyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci-ioalkyleneC5-i2heteroaryl and C2. ioalkenyleneC5-i2heteroaryl, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci. i6alkyl, Z1C2.i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2.i6haloalkenyl and Z1C2. i6haloalkynyl, and wherein each alkyl, alkenyl, alkynyl, alkylene and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0103] In some embodiments, R1is selected from F, Cl, Br, C1-16alkyl, C2.i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl and C2.i6haloalkynyl, each of which is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3-7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0104] In some embodiments, R1is selected from F, Cl, Br, l, Ci-i6alkyl, C2.i6alkenyl, C2.i6alkynyl, Ci-i6fluoroalkyl, Ci-i6chloroalkyl, C2.i6fluoroalkenyl, C2.i6chloroalkenyl, C2-i6fluoroalkynyl and C2.i6chloroalkynyl, each of which is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1is selected from F, Cl, Br, Ci-i6alkyl, C2.i6alkenyl, C2.i6alkynyl, Ci. lefluoroalkyl, Ci-i6chloroalkyl, C2.i6fluoroalkenyl, C2.i6chloroalkenyl, C2.i6fluoroalkynyl and C2. lechloroalkynyl, each of which is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl orwith C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0105] In some embodiments, R1is selected from F, Cl, Br, I and Ci-i6alkyl and Ci-i6alkyl optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl orwith C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1is selected from F, Cl, Br, I and Ci-i6alkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0106] In some embodiments, R1is selected from F, Cl, Br, I, Ci-i6alkyl, Ci-i6fluoroalkyl and Ci-i6chloroalkyl. In some embodiments, R1is selected from F, Cl, Br, Ci-ioalkyl, Ci-i0fluoroalkyl and Ci-i0chloroalkyl. In exemplary embodiments, R1isselected from F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCl2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3, CH2CH(CD3)2, CH2CH2CH(CH3)CH2CH2CH2CH(CH3)2, and CH2CH2CH(CH3)CH2CH2CH2CH(CH3)CH2CH2CH2CH(CH3)2. In some embodiments, R1is selected from F, Cl, Br, I, Ci-ealkyl, Ci-efluoroalkyl and C1-echloroalkyl. In some embodiments, R1is selected from F, Cl, Br, I, Ci-4alkyl, C1-4fluoroalkyl and Ci-4chloroalkyl. In some embodiments, R1is selected from F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCl2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3 and CH2CH(CD3)2. In some embodiments, R1is selected from F, Cl, Br, I, Ci-3alkyl, Ci-3fluoroalkyl and Ci-3chloroalkyl. In some embodiments, R1is selected from F, Cl, Br, CH3, CH2CH3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCl2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2 and CH(CD3)2, In some embodiments, R1is selected from F, Cl, Br, I, Ci-2alkyl, Ci-2fluoroalkyl and C1-2Chloroalkyl. In some embodiments, R1is selected from F, Cl, Br, I, CH3, CH2CH3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCI3, CCI2H, CCIH2, CH2CCl2H, CH2CCI3, CH2CCIH2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, and CH2CDH2. In some embodiments, R1is selected from F, Cl, Br, I, CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, R1is selected from CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2.

[0107] In some embodiments, R1is selected from F, Cl, I and Br. In some embodiments, R1is selected from F, Cl and Br.

[0108] In some embodiments, R1is selected from Ci-i6alkyl and C2-i6alkenyl, each of which is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independentlyreplaced with a fluorine atom and / or a deuterium. In some embodiments, R1is selected from Ci-i6alkyl and C2-i6alkenyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0109] In some embodiments, R1is Ci-i6alkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In exemplary embodiments, R1is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3, CH2CH(CD3)2, CH2CH2CH(CH3)CH2CH2CH2CH(CH3)2, and CH2CH2CH(CH3)CH2CH2CH2CH(CH3)CH2CH2CH2CH(CH3)2In exemplary embodiments, R1is selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3, CH2CH(CD3)2, CH2CH2CH(CH3)CH2CH2CH2CH(CH3)2, and CH2CH2CH(CH3)CH2CH2CH2CH(CH3)CH2CH2CH2CH(CH3)2

[0110] In some embodiments, R1is C2.i6alkenyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1is C3.i6alkenyl and the C3.i6alkenyl is or comprises an allyl group wherein the methylene group (CH2) of the allyl group is covalently attached to the remaining portion of the compound of Formula I.

[0111] In some embodiments, R1is C5-i6alkenyl and the C5-i6alkenyl is or comprisesan isoprenyl groupIn some embodiments, R1is C5-i6alkenyl and the C5. isalkenyl is isoprenyl, farnesyl or geranyl. In some embodiments, R1is C2-16alkenyl and the C5-i6alkenyl is farnesyl.

[0112] In some embodiments, R1is selected from C6-ioaryl, Ci.ioalkyleneC6-10aryl, C2. ioalkenyleneC6-ioaryl, C3.i2cycloalkyl, Ci-i0alkyleneC3.i2cycloalkyl, C2.i0alkenyleneC3. i2cycloalkyl, C3.i2heterocycloalkyl, Ci-ioalkyleneC3.i2heterocycloalkyl, C2.ioalkenyleneC3. i2heterocycloalkyl, C5-i2heteroaryl, Ci-ioalkyleneC5-i2heteroaryl and C2.ioalkenyleneC5. i2heteroaryl, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2.i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2.i6haloalkenyl and Z1C2.i6haloalkynyl, and wherein each alkyl, alkenyl, alkynyl, alkylene and alkenylene group comprised in R1, including in any ofthe optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0113] In some embodiments, R1is selected from Ci-ioalkyleneC6-10aryl, C2. ioalkenyleneC6-ioaryl, Ci-i0alkyleneC3.i2cycloalkyl, C2.i0alkenyleneC3.i2cycloalkyl, Ci. ioalkyleneC3.i2heterocycloalkyl, C2.i0alkenyleneC3.i2heterocycloalkyl, Ci-ioalkyleneC5-i2heteroaryl and C2-ioalkenyleneC5-i2heteroaryl, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-ioalkyl, Z1C2.i0alkenyl, Z1C2.i0alkynyl, Z1Ci-iofluoroalkyl, Z1C1-10chloroalkyl, Z1C2-10fluoroalkenyl, Z1C2.iochloroalkenyl, Z1C2-10fluoroalkynyl and Z1C2.iochloroalkynyl and wherein each alkyl, alkenyl, alkynyl, alkylene and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0114] In some embodiments, each C2.ioalkenylene in R1independently is or comprise an allyl group wherein the methylene (CH2) of the allyl group is covalently attached to the remaining portion of the compound of Formula I. In some embodiments, each C2.iOalkenylene in R1independently comprises an isoprenyl group

[0115] In some embodiments, each C3.i2cycloalkyl in R1is independently selected from a monocyclic or a bicyclic C3.i2cycloalkyl. In some embodiments, the bicyclic C3. i2cycloalkyl is a spirocyclic C3.i2cycloalkyl, bridged C3.i2cycloalkyl or fused C3.i2cycloalkyl.

[0116] In some embodiments, each C3.i2cycloalkyl in R1is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent-1 -enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclooctanyl, bicyclononanyl, bicycloundecanyl, bicycloheptanyl such as norbornyl, bicyclohexanyl, bicyclopentanyl, adamantanyl, spirodecanyl, spirococtanyl, spirocheptanyl and spiropentanyl. In some embodiments, each C3.i2cycloalkyl in R1is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent-1 -enyl, 1 -cyclopent- 2-enyl, 1-cyclopent-3-enyl and cyclo hexyl.

[0117] In some embodiments, each C6-10aryl in R1is independently selected from a monocyclic or a bicyclic C6-ioaryl. In some embodiments, each C6-ioaryl in R1is independently selected from phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, dihydroindenyl and indenyl. In some embodiments, each C6-10aryl in R1is phenyl.

[0118] In some embodiments, each Cs-ioheteroaryl in R1is independently selected from a monocyclic or a bicyclic C5-i2heteroaryl. In some embodiments, each C5-i2heteroaryl in R1is independently selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, diazolyl, triazolyl (including 1,2,3 triazolyl, and 1,2,4 triazolyl) thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, adeninyl, guaninyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzodioxolyl, benzimidazolyl, azaindolyl, purinyl, isobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoisothiazolyl, benzoxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, pyridoyrimidinyl, pyridopyrazinyl, pyridopyrazinyl, pteridinyl, quinuclidinyl, azaadamantanyl, carbazolyl, dibenzofuranyl, acridinyl, phenazinyl, phenoxazinyl, phenothiazinyl and phenoxathiinyl.

[0119] In some embodiments, each C3-i2heterocycloalkyl in R1is independently selected from a monocyclic or a bicyclic C3-i2heterocycloalkyl. In some embodiments, the bicyclic C3-i2heterocycloalkyl is a spirocyclic C3.i2heterocycloalkyl, bridged C3. i2heterocycloalkyl or fused C3-i2heterocycloalkyl.

[0120] In some embodiments, each C3-i2heterocycloalkyl in R1is independently selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide, dioxanyl, indolinyl, 3H-indolyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, chromenyl, chromenonyl, benzoxazinyl, quinolinonyl, azaspiroundecanyl, diazaspiroundecanyl, azaspirodecanyl, diazaspirodecanyl, azaspirononanyl, diazaspirononanyl, azaspirooctanyl, diazaspirooctanyl, azaspiroheptanyl, diazaspiroheptanyl, diazaspirooctanyl, azaspirohexanyl, diazaspirohexanyl, azaspiropentanyl and diazaspiropentanyl.

[0121] In some embodiments, each C3-i2heterocycloalkyl in R1is independently selected from aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and thiomorpholinyl.

[0122] In an exemplary embodiment, R1is selected from C2-ioalkenylenephenyl, C2-iOalkenyleneaziridinyl, C2-ioalkenylene azetidinyl, C2-ioalkenyleneoxetanyl, C2. ioalkenylenetetrahydrofuranyl, C2-ioalkenylenetetrahydrothiophenyl and C2-i0alkenylenepyrrolidinyl, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z1Ci.6alkyl, Z1Ci. sfluoralkyl and Z1Ci-iochloroalkyl, and wherein each alkyl and alkenylene group comprised in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0123] In some embodiments, Z1is selected from NR15C(O)O and OC(O)NR15In some embodiments, Z1is selected from direct bond, C(O), C(O)O, OC(O), S, S(O)2, NR15, NR15C(O) and C(O)NR15. In some embodiments, Z1is selected from a direct bond, O, C(O), C(O)O, S, S(O), S(O)2and NR15. In some embodiments, Z1is selected from a direct bond and C(O)O. In some embodiments, Z1is C(O)O. In some embodiments, Z1is a direct bond.

[0124] In some embodiments, R1is selected from C1-10alkyleneY1R7, C2. i0alkenyleneY1R7and C2-ioalkynyleneY1R7, and optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1is selected from C1-10alkyleneY1R7, C2-ioalkenyleneY1R7and C2. i0alkynyleneY1R7, wherein each alkylene, alkenylene and alkynylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl. In some embodiments, R4is selected from C1-i0alkyleneY1R7, C2-ioalkenyleneY1R7and C2-ioalkynyleneY1R7.

[0125] In some embodiments, Y1is selected from C(O)O, OC(O), NR11C(O) and C(O)NR11. In some embodiments, Y1is selected from O, S, C(O), S(O), S(O)2, NR11, NR11C(O), C(O)NR11, NR11C(O)O and OC(O)NR11. In some embodiments, Y1is selected from O, S, C(O), S(O), S(O)2, NR11, NR11C(O)O and OC(O)NR11.

[0126] In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, unless otherwise stated, is optionally substituted with one to four substituents selected from OH, F, Cl, Br, Ci-4alkyl and Ci-4haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, unless otherwise stated, is optionally substituted with one to four selected from OH, F, Cl, Br, Ci_4alkyl Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, unless otherwise stated, is optionally substituted with one to four substituents selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCl3, CCl2H, CClH2, CH2CCl2H, CH2CCl3, CH2CClH2, CH(CCl3)2, C(CCl3)3, CH2CH(CCl3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3, and CH2CH(CD3)2. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, unless otherwise stated, is optionally substituted with one to four substituents selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, C(CCI3)3, CD3, CD2H, CDH2, CH2CD2H, CH2CD3, CH2CDH2and C(CD3)3. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one to four substituents selected from OH, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CD3, CDH2and CHD2.

[0127] In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring selected from aziridinyl, diazirinyl,oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide and dioxanyl.

[0128] In an exemplary embodiment, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is further optionally disubstituted on the same carbon atom with C2.6alkylene interrupted with one to three of O, S, SO2, N, NH, or NCi.6alkyl to form a C3. 7heterocycloalkyl ring selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl and azetidinyl.

[0129] In some embodiments, Y2is selected from C(O)O, OC(O), NR12C(O)O and OC(O)NR12. In some embodiments, Y2is selected from O, S, C(O), S(O), S(O)2, NR12, NR12C(O), C(O)NR12, NR12C(O)O and OC(O)NR12. In some embodiments, Y2is selected from O, S, C(O), S(O), S(O)2, NR12, NR12C(O)O and OC(O)NR12.

[0130] In exemplary embodiments, R1is selected from F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H,CH2CCI3, CH2CCIH2, C(CCl3)3CH2CH(CCl3)2,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0131] In exemplary embodiments, R1is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2,C(CCl3)3CH2CH(CCl3)2,,available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0132] In some embodiments, R2is selected from H, Ci-i6alkyl, C2-i6alkenyl, C2. i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C3-i2cycloalkyl, Ci.6alkyleneC3. i2cycloalkyl, C6-ioaryl, Ci.6alkyleneC6-ioaryl, C3.i2heterocycloalkyl, Ci.6alkyleneC3. i2heterocycloalkyl, C5-i2heteroaryl and Ci-6alkyleneC5-i2heteroaryl, wherein each alkyl, alkenyl, alkynyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more substituents selected from OH, halo, Ci-ioalkyl, C-Mohaloalkyl, OCi-i0alkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is selected from H, C1-16alkyl, C2.i6alkenyl, C1-16haloalkyl, C2. i6haloalkenyl, C3.i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C6-ioaryl, Ci-4alkyleneC6-ioaryl, C3. i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci.4alkyleneC5. i2heteroaryl, wherein each alkyl, alkenyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one to four substituents selected from OH, halo, Ci.6alkyl, OCi-i0alkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0133] In some embodiments, R2is selected from H, Ci-i6alkyl, C2.i6alkenyl, Ci. lehaloalkyl and C2.i6haloalkenyl, wherein each alkyl and alkenyl group in R2is independently and optionally substituted with one to four substituents selected from OH, halo, Ci.6alkyl, Ci. ehaloalkyl, OCi-i0alkyl and OCi-iohaloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is selected from H, Ci-i6alkyl, C2.i6alkenyl, Ci-i6haloalkyl and C2.i6haloalkenyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0134] In some embodiments, R2is selected from H, C-Moalkyl and Ci-i0haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is selected from H, Ci.6alkyl and Ci. ehaloalkyl. In some embodiments, R2is selected from H, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl. In some embodiments, R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H,CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCl3, CCl2H, CClH2, CH2CCl2H, CH2CCl3, CH2CClH2, CH(CCl3)2, C(CCl3)3, CH2CH(CCl3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3and CH2CH(CD3)2. In some embodiments, R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, C(CF3)3and CH2CH(CF3)2. In some embodiments, R2is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and C(CH3)3.

[0135] In some embodiments, R2is H.

[0136] In some embodiments, R2is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and C(CH3)3.

[0137] In some embodiments, R2is selected from C2-iealkenyl and C2-i6haloalkenyl, wherein each alkenyl is independently and optionally substituted with one to four substituents selected from OH, halo, Ci.6alkyl, Ci.6haloalkyl, OCi-i0alkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is C2-i6alkenyl, optionally substituted with one to four substituents selected from OH, halo, Ci.6alkyl, Ci.6haloalkyl, OCi-i0alkyl and OC1. lohaloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is C2-i6alkenyl.

[0138] In some embodiments, R2is C5-i6alkenyl and the C2-i6alkenyl is or comprisesan isoprenyl groupIn some embodiments, R2is C5-i6alkenyl and the C5. i6alkenyl is isoprenyl, farnesyl or geranyl. In some embodiments, R2is C5-i6alkenyl and the C2-i6alkenyl is farnesyl

[0139] In some embodiments, R2is selected from C3.i2cycloalkyl, Ci.4alkyleneC3. i2cycloalkyl, C6-ioaryl, Ci-4alkyleneC6-ioaryl, C3.i2heterocycloalkyl, Ci.4alkyleneC3. i2heterocycloalkyl, C5-i2heteroaryl and Ci.4alkyleneC5-i2heteroaryl, wherein each alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more substituents selected from OH, halo, Ci.6alkyl, Ci.6haloalkyl, OCi-ioalkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is selected from C3.i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C6-ioaryl, Ci.4alkyleneC6-ioaryl, C3.i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci.4alkyleneC5. i2heteroaryl, wherein each alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more substituents selected from OH, halo Ci_4alkyl, Ci.4haloalkyl, OCi-i0alkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0140] In some embodiments, each C3-i2cycloalkyl in R2is independently selected from a monocyclic or a bicyclic C3-i2cycloalkyl. In some embodiments, the bicyclic C3. i2cycloalkyl is a spirocyclic C3.i2cycloalkyl, bridged C3.i2cycloalkyl or fused C3.i2cycloalkyl. In some embodiments, each C3.i2cycloalkyl in R2is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclooctanyl, bicyclononanyl, bicycloundecanyl, bicycloheptanyl such as norbornyl, bicyclohexanyl, bicyclopentanyl, adamantanyl, spirodecanyl, spirococtanyl, spirocheptanyl and spiropentanyl. In some embodiments, each C3.i2cycloalkyl in R2is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl and cyclohexyl.

[0141] In some embodiments, each C6-ioaryl in R2is independently selected from a monocyclic or a bicyclic C6-ioaryl. In some embodiments, each C6-ioaryl in R2is independently selected from phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, dihydroindenyl and indenyl. In some embodiments, each C6-ioaryl in R2is phenyl.

[0142] In some embodiments, each C5-i2heteroaryl in R2is independently selected from a monocyclic or a bicyclic C5-i2heteroaryl. In some embodiments, each C5-i2heteroaryl in R2is independently selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, diazolyl, triazolyl (including 1,2,3 triazolyl, and 1,2,4 triazolyl) thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, adeninyl, guaninyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzodioxolyl, benzimidazolyl, azaindolyl, purinyl, isobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoisothiazolyl, benzoxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, pyridoyrimidinyl, pyridopyrazinyl, pyridopyrazinyl, pteridinyl, quinuclidinyl, azaadamantanyl, carbazolyl, dibenzofuranyl, acridinyl, phenazinyl, phenoxazinyl, phenothiazinyl and phenoxathiinyl.

[0143] In some embodiments, each C3.i2heterocycloalkyl in R2is independently selected from a monocyclic or a bicyclic C3.i2heterocycloalkyl. In some embodiments, the bicyclic C3.i2heterocycloalkyl is a spirocyclic C3.i2heterocycloalkyl, bridged C3. i2heterocycloalkyl or fused C3.i2heterocycloalkyl.

[0144] In some embodiments, each C3.i2heterocycloalkyl in R2is independently selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl),tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide, dioxanyl, indolinyl, 3H-indolyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, chromenyl, chromenonyl, benzoxazinyl, quinolinonyl, azaspiroundecanyl, diazaspiroundecanyl, azaspirodecanyl, diazaspirodecanyl, azaspirononanyl, diazaspirononanyl, azaspirooctanyl, diazaspirooctanyl, azaspiroheptanyl, diazaspiroheptanyl, diazaspirooctanyl, azaspirohexanyl, diazaspirohexanyl, azaspiropentanyl and diazaspiropentanyl.

[0145] In some embodiments, each C3-i2heterocycloalkyl in R2is independently selected from aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and thiomorpholinyl.

[0146] In some embodiments, R2is Ci.4alkylenephenyl, optionally substituted with one to four substituents selected from OH, halo, Ci-4alkyl, Ci.4haloalkyl, OCi-ioalkyl and OC1. lohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is Ci.4alkylenephenyl. In some embodiments, R2is Ci.2alkylenephenyl.

[0147] In some embodiments, R2is tetrahydropyranyl optionally substituted with one to four substituents selected from OH, halo, Ci_4alkyl, Ci.4haloalkyl, OCi-i0alkyl and OCi. lohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R2is tetrahydropyranyl optionally substituted with one to four OH.

[0148] In some embodiments, each alkyl, alkenyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one to four substituents selected from OH, F, Cl, Br, Ci-4alkyl, Ci.4haloalkyl, OCi-ioalkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, each alkyl, alkenyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one to four substituents selected from OH, F, Cl, Br, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, OCi.4alkyl, OCi.4fluoroalkyl and OCi.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, each alkyl, alkenyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one to foursubstituents selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCl3, CCl2H, CClH2, CH2CCl2H, CH2CCl3, CH2CClH2, CH(CCl3)2, C(CCl3)3, CH2CH(CCl3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3, CH2CH(CD3)2, OCH3, OCH2CH3, OCH2CH2CH3, OCH(CH3)2, OC(CH3)3, CH2CH(CH3)2, OCF3, OCFH2, OCHF2, OCH2CF2H, OCH2CF3, OCH2CFH2, OCH(CF3)2, OC(CF3)3, OCH2CH(CF3)2, OCCl3, OCCl2H, OCClH2, OCH2CCl2H, OCH2CCl3, OCH2CClH2, OCH(CCl3)2, OC(CCl3)3, OCH2CH(CCl3)2, OCD3, OCD2H, OCDH2, OCH2CD2H, OCH2CDH2, OCH2CD3, OCH(CD3)2, OCH2CDH2, OCH(CD3)2, OC(CD3)3and OCH2CH(CD3)2). In some embodiments, each alkyl, alkenyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one to four substituents selected from OH, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CD3, CD2H, CDH2, CF3, CFH2, CHF2, OCH3, OCF3, OCFH2, OCHF2, OCD3, OCD2H and OCDH2.

[0149] In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclic ring, optionally containing one additional heteroatom selected from N, NH, N(Ci.6alkyl), O, S, S(O) and S(O)2and optionally substituted with one or more substituents selected from OH, halo, NO2, =0, Ci-isalkyl, C2-iealkenyl, C2-iealkynyl, C1-16haloalkyl, C2-iehaloalkenyl, C2-i6haloalkynyl, OCi-i6alkyl, OC2-i6alkenyl, OC2-i6alkynyl, OCi-i6haloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl, wherein each alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from OH, =0, halo, OC1-16alkyl, OC2-i6alkenyl, OC2-i6alkynyl, OCi-i6haloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0150] In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclic ring, optionally substituted with one or more substituents selected from OH, halo, =0, C1-16alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, OCi-i6alkyl, OC2-16alkenyl, OC2-i6alkynyl, OCi-i6haloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl, wherein each alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from OH, =0, halo, OCi-i6alkyl, OC2-i6alkenyl, OC2-i6alkynyl, OC1. i6haloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclic ring, optionally substituted with one to four substituents selected from OH, =0, Ci-i6alkyl, C2-i6alkenyl, Ci-i6haloalkyl, C2.ishaloalkenyl, OC1-16alkyl, OC2-iealkenyl, OCi-iehaloalkyl and OC2-iehaloalkenyl, wherein each alkyl and alkenyl groups are optionally substituted with one to four substituents selected from OH, =0, halo, OCi-i6alkyl, OC2-i6alkenyl, OCi-i6haloalkyl and OC2-i6haloalkenyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0151] In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 5 to 6 membered unsaturated heterocyclic ring, optionally substituted with one to four substituents selected from Ci-i6alkyl and C2-i6alkenyl, wherein each alkyl and alkenyl groups are optionally substituted with one to four substituents selected from OH, =0, halo, OC1-16alkyl, 0C2-iealkenyl, OCi-iehaloalkyl and OC2-i6haloalkenyl. In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 5 to 6 membered unsaturated heterocyclic ring, optionally substituted with one to four substituents selected from Ci-i2alkyl and C2-iealkenyl. In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 5 to 6 membered unsaturated heterocyclic ring, optionally substituted with one to four substituents selected from Ci.6alkyl and C2-i6alkenyl.

[0152] In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 5 to 6 membered unsaturated heterocyclic ring, substituted with one to three substituents selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH(CH3)3and C2-i6alkenyl. In some embodiments, R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 5 to 6 membered unsaturated heterocyclic ring, substituted with one to three substituents selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH(CH3)3, isoprenyl, farnesyl or geranyl.

[0153] In exemplaryR1and R2are joined to form the following structureis a point of covalent attachment to the remaining portion of the compound of Formula I.

[0154] In some embodiments, R3, R3aand R5are independently selected from H, D, halo, C1-2alkyl, Ci.2fluoroalkyl, Ci.2chloroalkyl and Ci.2deuteroalkyl. In some embodiments, R3, R3aand R5are independently selected from H, D, F, Cl, Br, CH3, CH2CH3, CF3, CFH2,CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CCl2H, CClH2, CH2CCl2H, CH2CCl3, CH2CClH2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2and CH2CD3. In some embodiments, R3, R3aand R5are independently selected from H, D, F, Cl, Br, CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, R3, R3aand R5are independently selected from H, D, F, Cl, Br, CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, R3, R3aand R5are independently selected from H, D, F, Cl, CH3, CF3, CFH2, CHF2, CD3, CD2H and CDH2.

[0155] In some embodiments, R3and R3aare independently selected from H, D, F, Cl, CH3, CF3, CFH2, CHF2, CD3, CD2H and CDH2. In some embodiments, at least one of R3and R3ais H. In some embodiments, one of R3and R3ais H and the other is selected from D, F, Cl, CH3, CF3, CFH2, CHF2, CD3, CD2H and CDH2. In some embodiments, R3and R3aare both D. In some embodiments, R3and R3aare both H.

[0156] In some embodiments, R5is selected from H, D, F, Cl, CH3, CF3, CFH2, CHF2, CD3, CD2H and CDH2. In some embodiments, R5is selected from H, D, F, Cl and CH3. In some embodiments, R5is selected from H, D, F and CL. In some embodiments, R5is selected from F or Cl. In some embodiments, R5is H.

[0157] In some embodiments, R3, R3aand R5are all H.

[0158] In some embodiments, R4is selected from H, Ci.4alkyl, C2-ioalkenyl, C2. ioalkynyl, Ci. haloalkyl, C2-iohaloalkenyl, C2-iohaloalkynyl, C6-ioaryl, C1alkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, C1-4alkyleneC3-i2cycloalkyl, C2-4alkenyleneC3-i2cycloalkyl, C2-4alkynyleneC3-i2cycloalkyl, C3. i2heterocycloalkyl, Ci. alkyleneC3-i2heterocycloalkyl, C2-4alkenyleneC3-i2heterocycloalkyl, C2-4alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-4alkyleneC5-i2heteroaryl, C2. alkenyleneC5-i2heteroaryl, C2-4alkynyleneC5-i2heteroaryl, Ci- alkyleneY3R9, C2.4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z2C1-16alkyl, Z2C2-iealkenyl, Z2C2-iealkynyl, Z2Ci-i6haloalkyl, Z2C2-iehaloalkenyl, Z2C2-i6haloalkynyl, Z2Ci.ioalkyleneY4R10, Z2C2-ioalkenyleneY4R10, Z2C2-ioalkynyleneY4R10, Z2C6. iOaryl, Z2C1-10alkyleneC6-10aryl, Z2C2-ioalkenyleneC6-ioaryl, Z2C2-ioalkynyleneC6-ioaryl, Z2C3. i2cycloalkyl, Z2Ci-ioalkyleneC3-i2cycloalkyl, Z2C2-ioalkenyleneC3-i2cycloalkyl, Z2C2-ioalkynyleneC3.i2cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci.ioalkyleneC3.i2heterocycloalkyl, Z2C2-ioalkenyleneC3-i2heterocycloalkyl, Z2C2-ioalkynyleneC3-i2heterocycloalkyl, Z2C5. i2heteroaryl, Z2Ci-ioalkyleneC5-i2heteroaryl, Z2C2-ioalkenyleneC5-i2heteroaryl and Z2C2. ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci-ealkyl,Ci-ehaloalkyl, Ci-ioalkyleneOCi-6alkyl, OCi-ealkyl, OCi-ehaloalkyl and OCi.ioalkyleneOCi.6alkyl; andwherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NC1-6alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0159] In some embodiments, R4is selected from H, Ci.4alkyl, C2-ioalkenyl, C2. ioalkynyl, Ci.4haloalkyl, C2-iohaloalkenyl, C2-iohaloalkynyl, C6-ioaryl, C1alkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3.i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C2-4alkenyleneC3.i2cycloalkyl, C2-4alkynyleneC3.i2cycloalkyl, C3. i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C2-4alkenyleneC3.i2heterocycloalkyl, C2-4alkynyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci.4alkyleneC5-i2heteroaryl, C2.4alkenyleneC5-i2heteroaryl, C2-4alkynyleneC5-i2heteroaryl, Ci.4alkyleneY3R9, C2.4alkenyleneY3R9and C2.4alkynyleneY3R9, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z2C1-16alkyl, Z2C2-iealkenyl, Z2C2-iealkynyl, Z2Ci-i6haloalkyl, Z2C2-iehaloalkenyl, Z2C2-i6haloalkynyl, Z2C6-ioaryl, Z2C1-10alkyleneC6-10aryl, Z2C3.i2cycloalkyl, Z2Ci-i0alkyleneC3. i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci.ioalkyleneC3.i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2C2-ioalkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci_4alkyl, Ci.4haloalkyl, Ci-ioalkyleneOCi.4alkyl, OCi-4alkyl, OCi.4haloalkyl and OCi.ioalkyleneOCi.4alkyl; andwherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0160] In some embodiments, R4is selected from H, Ci_4alkyl, C2-ioalkenyl, C2. iOalkynyl, Ci.4haloalkyl, C2-iohaloalkenyl and C2-iohaloalkynyl, andwherein each alkyl, alkenyl and alkynyl group is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, and =0, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R4is selected from Ci.4alkyl, C2.i0alkenyl, C2.i0alkynyl, Ci.4haloalkyl, C2.iohaloalkenyl and C2. lohaloalkynyl, each of which is optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R4is selected from Ci_4alkyl, C2.i0alkenyl, C2.i0alkynyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci.4deuteroalkyl, C2.iofluoroalkenyl, C2.iochloroalkenyl, C2.iodeuteroalkyl, C2. lofluoroalkynyl, C2.iochloroalkynyl and C2.iodeuteroalkynyl, each of which is optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring. In some embodiments, R4is selected from H, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl, each of which is optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R4is selected from H, Ci-4alkyl, Ci-4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl. In some embodiments, R4is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3and CH2CH(CD3)2. In some embodiments, R4is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3and CH2CCIH2.

[0161] In some embodiments, R4is H.

[0162] In some embodiments, R4is Ci_4alkyl. In some embodiments, R4is Ci.4alkyl selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3and CH2CH(CH3)2. In some embodiments, R4is selected from CH3, CH2CH3, CH2CH2CH3and CH(CH3)2.

[0163] In some embodiments, R4is selected from C2.i0alkenyl, C2.i0alkynyl, C2. lohaloalkenyl and C2.iohaloalkynyl, each of which is optionally disubstituted on the samecarbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with deuterium. In some embodiments, R4is selected from C2-ioalkenyl, C2-ioalkynyl, C2-iochloroalkenyl, C2-lofluoroalkenyl, C2-iodeuteroalkenyl, C2-iofluoroalkynyl, C2-iochloroalkynyl, and C2. lodeuteroalkynyl, each of which is optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring. In some embodiments, R4is selected from C2-6alkenyl, C2-6alkynyl, C2-6Chloroalkenyl, C2-6fluoroalkenyl, C2. lofluoroalkynyl and C2-6Chloroalkynyl. In some embodiments, R4is selected from CH2C=CH2, CH2C=CHCH2CI, CH2CHCH, CH2CHCCH3, C(CH3)CHCH, and C(CH3)CHCCH3.

[0164] In some embodiments, R4is selected from C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3.i2cycloalkyl, Ci-4alkyleneC3.i2cycloalkyl, C2-4alkenyleneC3.i2cycloalkyl, C2-4alkynyleneC3.i2cycloalkyl, C3. i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C2-4alkenyleneC3.i2heterocycloalkyl, C2-4alkynyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci.4alkyleneC5-i2heteroaryl, C2.4alkenyleneC5-12heteroaryl and C2-4alkynyleneC5-12heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, ON, NO2, Z2Ci-i6alkyl, Z2C2-i6alkenyl, Z2C2-i6alkynyl, Z2Ci-i6haloalkyl, Z2C2. i6haloalkenyl, Z2C2-i6haloalkynyl, Z2C6-ioaryl, Z2C1-10alkyleneC6-10aryl, Z2C3.i2cycloalkyl, Z2Ci. ioalkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-ioalkyleneC3.i2heterocycloalkyl, Z2C5-12heteroaryl and Z2Ci-ioalkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, C1-4alkyl, C1-4haloalkyl, C1-10alkyleneOC1-4alkyl, OC1-4alkyl, OC1-4haloalkyl and OC1-10alkyleneOC1-4alkyl; andwherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =O, C1-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0165] In some embodiments, R4is selected from C6-10aryl, C1alkyleneC6-10aryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-ioaryl, C3.i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C2.4alkenyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C2.4alkenyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci-4alkyleneC5-i2heteroaryl and C2-4alkenyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2C1-16alkyl, Z2C2-i6alkenyl, Z2Ci-i6haloalkyl, Z2C2.i6haloalkenyl, Z2C6-ioaryl, Z2Ci-iOalkyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci-ioalkyleneC3-i2cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci-ioalkyleneC3-i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-i0alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci-4alkyl, Ci.4haloalkyl, Ci-i0alkyleneOCi.4alkyl, OCi-4alkyl, OCi.4haloalkyl and OCi-i0alkyleneOCi.4alkyl; andwherein each alkyl, alkenyl, alkylene and alkenylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3. cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0166] In some embodiments, R4is selected from C6-ioaryl, C1alkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-10aryl, C3-i2cycloalkyl, Ci-4alkyleneC3-i2cycloalkyl, C2.4alkenyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci-4alkyleneC3-i2heterocycloalkyl, C2.4alkenyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-4alkyleneC5-i2heteroaryl and C2.4alkenyleneC5-i2heteroaryl wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-ioalkyl, Z2Ci-iofluoroalkyl, Z2Ci-iochloroalkyl, Z2C6-10aryl, Z2Ci-6alkyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci-6alkyleneC3-i2cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci-6alkyleneC3-i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci-i0alkyleneOCi.4alkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4chloroalkyl,and OCi-ioalkyleneOCi.4alkyl; andwherein each alkylene and alkenylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0167] In some embodiments, R4is selected from C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl and C2-4alkenyleneC6-10aryl, wherein each aryl group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2,Z2Ci-ioalkyl, Z2Ci-iofluoroalkyl, Z2Ci-iochloroalkyl, Z2C6-10aryl, Z2Ci-6alkyleneC6-ioaryl, Z2C3. i2cycloalkyl, Z2Ci-6alkyleneC3-i2cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci.6alkyleneC3. i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci-4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci-i0alkyleneOCi.4alkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4chloroalkyl,and OCi-i0alkyleneOCi.4alkyl; and wherein each alkylene and alkenylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R4is selected from C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl and C2-4alkenyleneC6-ioaryl, wherein each aryl group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-ioalkyl, Z2Ci-iofluoroalkyl, Z2Ci-ioChloroalkyl, Z2C6-ioaryl, Z2Ci.6alkyleneC6-ioaryl, Z2C3. i2cycloalkyl, Z2Ci-6alkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci.6alkyleneC3. i2heterocycloalkyl, Z2Cs-i2heteroaryl and Z2Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci-4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci-i0alkyleneOCi.4alkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4chloroalkyl,and OCi-i0alkyleneOCi.4alkyl; and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R4is selected from C6-10aryl, C1alkyleneC6-10aryl and C3alkyleneC6-ioaryl, wherein each aryl group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci.4alkyl, Z2Ci.4fluoroalkyl, Z2Ci.4chloroalkyl, Z2C6-10aryl, Z2Ci-4alkyleneC6-ioaryl, Z2C3.i2cycloalkyl, Z2Ci.4alkyleneC3. i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci.4alkyleneC3.i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci.4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0168] In some embodiments, R4is selected from C6-ioaryl, CialkyleneC6-ioaryl and C3alkyleneC6-ioaryl, wherein each aryl group comprised in R4is optionally substituted with one or more substituents selected from OH F, Cl, Br, CN, NO2, Z2Ci.4alkyl, Z2Ci.4fluoroalkyl,Z2C1-4chloroalkyl, Z2C6-10aryl, Z2C3-i2cycloalky, Z2C3-i2heterocycloalkyl, and Z2C5-i2heteroaryl and wherein each alkylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl, Ci.4fluoroalkyl and Ci-4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0169] In some embodiments, the C6-ioaryl in any of the aryls in R4is independently selected from a monocyclic or a bicyclic C6-10aryl. In some embodiments, the C6-10aryl in any of the aryls in R4is independently selected from phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, dihydroindenyl and indenyl. In some embodiments, the C6-ioaryl in any of the aryls in R4is phenyl.

[0170] In an exemplary embodiment, R4is selected from phenyl, Cialkylenephenyl and C3alkylenephenyl, wherein each phenyl group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci.4alkyl, Z2Ci.4fluoroalkyl, Z2Ci.4chloroalkyl, Z2phenyl, Z2Ci.4alkylenephenyl, Z2C3-i2cycloalkyl, Z2Ci.4alkyleneC3.i2cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci.4alkyleneC3-i2heterocycloalkyl, Z2C5. i2heteroaryl and Z2Ci-4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R4is selected from phenyl, Cialkylenephenyl and C3alkylenephenyl, wherein each phenyl group comprised in R4is optionally substituted with one or more substituents selected from OH F, Cl, Br, CN, NO2, Z2Ci.4alkyl, Z2Ci.4fluoroalkyl, Z2Ci.4chloroalkyl, Z2phenyl, Z2C3-i2cycloalky, Z2C3-i2heterocycloalkyl, and Z2C5-i2heteroaryl and wherein each alkylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0171] In some embodiments, R4is selected from C3-i2cycloalkyl, Ci.4alkyleneC3. i2cycloalkyl, C2-4alkenyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci.4alkyleneC3. i2heterocycloalkyl, C2-4alkenyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci.4alkyleneC5. i2heteroaryl and C2-4alkenyleneC5-i2heteroaryl wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-ioalkyl, Z2Ci-iofluoroalkyl, Z2Ci-ioChloroalkyl, Z2C6-ioaryl, Z2Ci.6alkyleneC6-ioaryl, Z2C3. i2cycloalkyl, Z2Ci.6alkyleneC3.i2cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci.6alkyleneC3. i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-6alkyleneC5-i2heteroaryl, wherein each cyclicgroup comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci-4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci-i0alkyleneOCi.4alkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4chloroalkyl,and OCi-i0alkyleneOCi.4alkyl; and wherein each alkylene and alkenylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0172] In some embodiments, R4is selected from C3-i2cycloalkyl, Ci.4alkyleneC3. i2cycloalkyl, C2.4alkenyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci.4alkyleneC3. i2heterocycloalkyl, C2.4alkenyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci-4alkyleneC5-i2heteroaryl and C2.4alkenyleneC5-i2heteroaryl wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-ioalkyl, Z2Ci-iofluoroalkyl, Z2Ci-ioChloroalkyl, Z2C6-ioaryl, Z2Ci.6alkyleneC6-ioaryl, Z2C3. i2cycloalkyl, Z2Ci-6alkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci.6alkyleneC3. i2heterocycloalkyl, Z2C5-12heteroaryl and Z2Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci-4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci-i0alkyleneOCi.4alkyl, OCi-4alkyl, OCi.4fluoroalkyl, OCi.4chloroalkyl,and OCi-ioalkyleneOCi.4alkyl; and wherein each alkylene and alkenylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0173] In some embodiments, R4is selected from C3.i2cycloalkyl, Ci.4alkyleneC3. i2cycloalkyl, C3.i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci.4alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-i0alkyl, Z2Ci. lofluoroalkyl, Z2Ci-ioChloroalkyl, Z2C6-ioaryl, Z2Ci.6alkyleneC6-ioaryl, Z2C3.i2cycloalkyl, Z2Ci.6alkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-6alkyleneC3.i2heterocycloalkyl, Z2C5-12heteroaryl and Z2Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl, Ci-i0alkyleneOCi.4alkyl, OCi.4alkyl, OCi.4fluoroalkyl, OCi.4chloroalkyl,and OCi-i0alkyleneOCi.4alkyl; and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independentlyand optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0174] In some embodiments, R4is selected from C3-i2cycloalkyl, Ci.4alkyleneC3. i2cycloalkyl, C3.i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci-4alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-4alkyl, Z2Ci.4fluoroalkyl, Z2Ci.4chloroalkyl, Z2C6-ioaryl, Z2Ci.4alkyleneC6-ioaryl, Z2C3.i2cycloalkyl, Z2Ci.4alkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci.4alkyleneC3.i2heterocycloalkyl, Z2C5. i2heteroaryl and Z2Ci-4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl, C1-4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium

[0175] In an exemplary embodiment, R4is selected from C3.i2cycloalkyl and C1-4alkyleneC3.i2cycloalkyl wherein each cycloalkyl group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci.4alkyl, Z2Ci.4fluoroalkyl, Z2Ci.4chloroalkyl, Z2C6-ioaryl, Z2Ci-4alkyleneC6-ioaryl, Z2C3.i2cycloalkyl, Z2Ci.4alkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci.4alkyleneC3.i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci.4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0176] In an exemplary embodiment, R4is selected from C3.i2cycloalkyl and C1-4alkyleneC3.i2cycloalkyl wherein each cycloalkyl group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci.4alkyl, Z2Ci.4fluoroalkyl and Z2Ci.4chloroalkyl and Z2Ci.4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0177] In some embodiments, each C3.i2cycloalkyl in R4is independently selected from a monocyclic or a bicyclic C3.i2cycloalkyl. In some embodiments, the bicyclic C3. i2cycloalkyl is a spirocyclic C3.i2cycloalkyl, bridged C3.i2cycloalkyl or fused C3.i2cycloalkyl.

[0178] In some embodiments, each C3-i2cycloalkyl in R4is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent-1 -enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl such as norbornyl, bicyclooctanyl, bicyclononanyl, bicycloundecanyl, adamantanyl, spiropentanyl, spirochexanyl, spiroheptanyl, spirococtanyl, spirononanyl and spirodecanyl.

[0179] In an exemplary embodiment, each C3-i2cycloalkyl in R4is independently selected from cyclopropyl, cyclobutyl, cyclopent-1 -enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, bicyclopentanyl, bicyclohexanyl, spiroheptanyl, spirococtanyl and spirononanyl.

[0180] In some embodiments, R4is selected from C3-i2heterocycloalkyl, Ci.4alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci.4alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-4alkyl, Z2Ci-4fluoroalkyl, Z2C1-4chloroalkyl, Z2C6-ioaryl, Z2Ci.4alkyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci.4alkyleneC3-12cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci.4alkyleneC3.i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl, C1.4fluoroalkyl and C1-4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0181] In some embodiments, R4is selected from C3-i2heterocycloalkyl, Ci.4alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-4alkyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-4alkyl, Z2Ci-4fluoroalkyl, Z2C1-4chloroalkyl, Z2C6-ioaryl, Z2Ci.4alkyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci.4alkyleneC3-12cycloalkyl, Z2C3-i2heterocycloalkyl, Z2Ci.4alkyleneC3.i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl, C1.4fluoroalkyl and C1-4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0182] In some embodiments, each C5-i2heteroaryl in R4is independently selected from a monocyclic or a bicyclic C5-i2heteroaryl. In some embodiments, each C5-i2heteroaryl in R4is independently selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, diazolyl, triazolyl (including 1,2,3 triazolyl, and 1,2,4 triazolyl) thiophenyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, adeninyl, guaninyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzodioxolyl, benzimidazolyl, azaindolyl, purinyl, isobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoisothiazolyl, benzoxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, pyridoyrimidinyl, pyridopyrazinyl, pyridopyrazinyl, pteridinyl, quinuclidinyl, azaadamantanyl, carbazolyl, dibenzofuranyl, acridinyl, phenazinyl, phenoxazinyl, phenothiazinyl and phenoxathiinyl.

[0183] In some embodiments, each C5-i2heteroaryl in R4is independently selected from furyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, diazolyl, thiophenyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, benzodioxolyl, benzimidazolyl, quinolinyl and isoquinolinyl.

[0184] In some embodiments, each C3-i2heterocycloalkyl in R4is independently selected from a monocyclic or a bicyclic C3-i2heterocycloalkyl. In some embodiments, the bicyclic C3.i2heterocycloalkyl is a spirocyclic C3.i2heterocycloalkyl, bridged C3. i2heterocycloalkyl or fused C3.i2heterocycloalkyl.

[0185] In some embodiments, each C3.i2heterocycloalkyl in R4is independently selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide, dioxanyl, indolinyl, 3H-indolyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, chromenyl, chromenonyl, benzodioxolyl, benzoxazinyl, quinolinonyl, azaspiropentanyl, diazaspiropentanyl, oxospiropentanyl, azaspirohexanyl, diazaspirohexanyl, oxospirohexanyl, oxoazospirohexanyl azaspiroheptanyl, diazaspiroheptanyl, oxospiroheptanyl, dioxoaspiroheptanyl oxoazaspiroheptanyl, azaspirooctanyl, diazaspirooctanyl, oxospirooctanyl dioxospirooctanyl, oxoazaspirooctanyl, azaspirononanyl, diazaspirononanyl oxospirononanyl, dioxospirononanyl, oxoazaspirononanyl, azaspirodecanyl diazaspirodecanyl, oxopirodecanyl, dioxospirodecanyl, oxoazaspirodecanyl azaspiroundecanyl, diazaspiroundecanyl, oxospiroundecanyl, dioxospiroundecanyl, and oxoazaspiroundecanyl.

[0186] In some embodiments, each C3-i2heterocycloalkyl in R4is independently selected from aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide, dioxanyl, chromenyl, chromenonyl, azaspirooctanyl, oxospirooctanyl, oxoazaspirooctanyl, azaspirononanyl, diazaspirononanyl, oxospirononanyl, dioxospirononanyl, azaspirodecanyl, diazaspirodecanyl, oxopirodecanyl, dioxospirodecanyl, azaspiroundecanyl, diazaspiroundecanyl, oxospiroundecanyl and dioxospiroundecanyl.

[0187] In an exemplary embodiment, R4is selected from phenyl, Ci.4alkylenephenyl, cyclopropyl, cyclobutyl, bicyclopentanyl, bicyclohexanyl, 1 -cyclopent-1 -enyl, 1 -cyclopent- 2-enyl, 1-cyclopent-3-enyl, spiroheptanyl, spirococtanyl, spirononanyl, Ci-4alkylenecyclopropyl, Ci.4alkylenecyclobutyl, Ci.4alkylenebicyclopentanyl, Ci.4alkylenebicyclohexanyl, Ci.4alkylene1 -cyclopent-1 -enyl, Ci.4alkylene1-cyclopent-2-enyl, Ci.4alkylene1-cyclopent-3-enyl, Ci.4alkylenespiroheptanyl, Ci.4alkylenespirococtanyl, Ci.4alkylenespirononanyl, furyl, imidazolyl, thiazolyl, pyridyl, pyrrolyl, diazolyl, thiophenyl, pyrimidinyl, pyridazinyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, benzodioxolyl, benzimidazolyl, quinolinyl, isoquinolinyl, Ci.4alkylenefuryl, Ci.4alkyleneimidazolyl, Ci.4alkylenethiazolyl, Ci.4alkylenepyridyl, Ci.4alkylenepyrrolyl, Ci.4alkylenediazolyl, Ci.4alkylenethiophenyl, Ci.4alkylenepyrimidinyl, Ci.4alkylenepyridazinyl, Ci-4alkylenebenzofuranyl, Ci.4alkyleneindolyl, Ci.4alkyleneisoindolyl, Ci_4alkyleneindolizinyl, Ci.4alkylenebenzodioxolyl, Ci.4alkylenebenzimidazolyl, Ci.4alkylenequinolinyl, Ci.4alkyleneisoquinolinyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide, dioxanyl, chromenyl, chromenonyl, azaspirooctanyl, oxospirooctanyl, oxoazaspirooctanyl, azaspirononanyl, Ci.4alkyleneaziridinyl, Ci.4alkyleneazetidinyl, Ci.4alkyleneoxetanyl, Ci.4alkylenetetrahydrofuranyl, Ci.4alkylenetetrahydrothiophenyl, Ci_4alkylenepyrrolidinyl, Ci.4alkylenepyrrolinyl, Ci.4alkylene2H-pyrrolyl, Ci.4alkyleneimidazolinyl, Ci-4alkylenethiazolidinyl, Ci-4alkyleneisothiazolidinyl, Ci.4alkylenedioxolanyl, Ci.4alkylenetetrahydropyranyl, Ci.4alkylenetetrahydrothiopyranyl (thianyl), Ci.4alkylenetetrahydrothiopyranyl oxide (thianyl oxide), Ci.4alkylenetetrahydrothiopyranyl dioxide (thianyl dioxide), Ci.4alkylenedithianyl, Ci.4alkylenepiperidinyl, Ci-4alkylenepiperazinyl, Ci-4alkylenemorpholinyl, Ci-4alkylenethiomorpholinyl, Ci-4alkylenethiomorpholinyl oxide, Ci-4alkylenethiomorpholinyl dioxide, Ci.4alkylenedioxanyl, Ci.4alkylenechromenyl, Ci-4alkylenechromenonyl, Ci.4alkyleneazaspirooctanyl, Ci-4alkyleneoxospirooctanyl, Ci-4alkyleneoxoazaspirooctanyl, and Ci-4alkyleneazaspirononanyl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-4alkyl, Z2Ci-4fluoroalkyl, Z2Ci-4chloroalkyl, Z2C6-ioaryl, Z2Ci-4alkyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci-4alkyleneC3-i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-4alkyleneC3.i2heterocycloalkyl, Z2C5-i2heteroaryl and Z2Ci-4alkyleneC5-i2heteroaryl, and wherein each alkylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl, Ci-4fluoroalkyl and Ci-4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium

[0188] In some embodiments, Z2is selected from NR16C(O)O and OC(O)NR16. In some embodiments, Z2is selected from direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR16, NR16C(O) and C(O)NR16. In some embodiments, Z2is selected from direct bond, O, C(O), S, S(O), S(O)2and NR16In some embodiments, Z2is selected from direct bond and S(O)2. In some embodiments, Z2is a direct bond.

[0189] In some embodiments, R4is selected from C1-4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein each alkylene, alkenylene and alkynylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl orwith C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NC1-4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R4is selected from Ci-4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein each alkylene, alkenylene and alkynylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl and Ci.4haloalkyl. In some embodiments, R4is selected from C1-4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9.

[0190] In some embodiments, Y3is selected from C(O)O, OC(O), NR13C(O) and C(O)NR13. In some embodiments, Y3is selected from O, S, C(O), S(O), S(O)2, NR13, NR13C(O), C(O)NR13, NR13C(O)O and OC(O)N. In some embodiments, Y3is selected from O, S, C(O), S(O), S(O)2, NR13, NR13C(O)O and OC(O)NR13.

[0191] In some embodiments, R7, R8, R9and R10are independently selected from H, Ci-iOalkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-iohaloalkyl, C2.iohaloalkenyl, C2.iohaloalkynyl, C6. iOaryl, Ci-6alkyleneC6-ioaryl, C2-6alkenyleneC6-ioaryl, C2-6alkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci-6alkyleneC3-i2cycloalkyl, C2-6alkenyleneC3-i2cycloalkyl, C2-6alkynyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci-6alkyleneC3-i2heterocycloalkyl, C2-6alkenyleneC3-i2heterocycloalkyl, C2-6alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-6alkyleneC5-i2heteroaryl, C2.6alkenyleneC5-i2heteroaryl, C2-6alkynyleneC5-i2heteroaryl, wherein each cyclic group in R7, R8, R9and R10is optionally substituted with one or more substituents selected from OH, halo, Ci-iOalkyl and Ci-iohaloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R7, R8, R9and R10are independently selected from H, Ci-ioalkyl, C2.i0alkenyl, Ci-i0haloalkyl, C2. lohaloalkenyl, C6-ioaryl, Ci.6alkyleneC6-ioaryl, C3-i2cycloalkyl, Ci.6alkyleneC3.i2cycloalkyl, C3. i2heterocycloalkyl, Ci.6alkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group in R7, R8, R9and R10is optionally substituted with one or more substituents selected from OH, halo, Ci.6alkyl and Ci.6haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R7, R8, R9and R10are independently selected from H, Ci.6alkyl, C2.6alkenyl, Ci.6fluoroalkyl, Ci.6chloroalkyl, C6-ioaryl, C1-6alkyleneC6-10aryl, C3. i2cycloalkyl, Ci-6alkyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci.6alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group in R7, R8, R9and R10is optionally substituted with one or more substituents selected from OH, F, Cl, Br, C1-4alkyl, C1-4fluoroalkyl and C1-4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0192] In some embodiments, the Ci.6alkyl, Ci.6fluoroalkyl and Ci.6chloroalkyl in R7, R8, R9and R10are independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3and CH2CH(CD3)2. In some embodiments, the Ci-6alkyl in R7, R8, R9and R10is independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2and C(CH3)3.

[0193] In some embodiments, each C3-2ocycloalkyl in R7, R8, R9and R10is independently selected from a monocyclic or a bicyclic C3-2ocycloalkyl. In some embodiments, the bicyclic C3-2ocycloalkylene is a bicyclic C3-2ocycloalkyl. In some embodiments, the bicyclic C3-2ocycloalkyl is a spirocyclic C3-2ocycloalkyl, bridged C3-20cycloalkyl or fused C3-20cycloalkyl.

[0194] In some embodiments, each C3-20cycloalkyl in R7, R8, R9and R10is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent- 1-enyl, 1-cyclopent- 2-enyl, 1-cyclopent-3-enyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclooctanyl, bicyclononanyl, bicycloundecanyl, bicycloheptanyl such as norbornyl, bicyclohexanyl, bicyclopentanyl, adamantanyl, spirodecanyl, spirococtanyl, spirocheptanyl and spiropentanyl. In some embodiments, each C3.2ocycloalkyl in R7, R8, R9and R10is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent- 1-enyl, 1-cyclopent- 2-enyl and 1-cyclopent-3-enyl, cyclohexyl.

[0195] In some embodiments, each C6-15aryl in R7, R8, R9and R10is independently selected from a monocyclic or a bicyclic Ce-isaryl. In some embodiments, each Ce-isaryl in R7, R8, R9and R10is independently selected from phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, anthracyl, dihydroindenyl, indenyl, fluroenyl, phenanthrenyl and dihydrophenanthrenyl. In some embodiments, the C6-15aryl in R7, R8, R9or R10is phenyl.

[0196] In some embodiments, each C5-2oheteroaryl in R7, R8, R9and R10is independently selected from a monocyclic or a bicyclic C5-2oheteroaryl. In some embodiments, the C5-2oheteroaryl in R7, R8, R9and R10is independently selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, diazolyl, triazolyl (including 1,2,3 triazolyl, and 1,2,4 triazolyl) thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, adeninyl, guaninyl, benzofuranyl, indolyl, isoindolyl, indolizinyl, indazolyl, benzodioxolyl, benzimidazolyl, azaindolyl, purinyl, isobenzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzothiophenyl, benzoisothiazolyl, benzoxazolyl, quinoxalinyl, phthalazinyl, cinnolinyl, naphthyridinyl, pyridoyrimidinyl, pyridopyrazinyl, pyridopyrazinyl, pteridinyl, quinuclidinyl, azaadamantanyl, carbazolyl, dibenzofuranyl, acridinyl, phenazinyl, phenoxazinyl, phenothiazinyl and phenoxathiinyl. In some embodiments, the C5-2oheteroaryl in R7, R8, R9and R10is independently selected from furyl, imidazolyl, isothiazolyl, thiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, diazolyl, triazolyl (including 1,2,3 triazolyl, and 1,2,4 triazolyl) thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl and pyrimidinyl.

[0197] In some embodiments, each C3-2oheterocycloalkyl in R7, R8, R9and R10are independently selected from a monocyclic or a bicyclic C3-2oheterocycloalkyl. In some embodiments, the bicyclic C3-2oheterocycloalkyl is a spirocyclic C3-2oheterocycloalkyl, bridged C3-2oheterocycloalkyl or fused C3-2oheterocycloalkyl.

[0198] In some embodiments, each C3-2oheterocycloalkyl in R7, R8, R9and R10is independently selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, diazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide, dioxanyl, indolinyl, 3H-indolyl, dihydroquinolinyl, tetrahydroquinolinyl, decahydroquinolinyl, chromenyl, chromenonyl, benzodioxolyl, benzoxazinyl, quinolinonyl, azaspiropentanyl, diazaspiropentanyl, oxospiropentanyl, azaspirohexanyl, diazaspirohexanyl, oxospirohexanyl, oxoazospirohexanyl azaspiroheptanyl, diazaspiroheptanyl, oxospiroheptanyl, dioxoaspiroheptanyl oxoazaspiroheptanyl, azaspirooctanyl, diazaspirooctanyl, oxospirooctanyl dioxospirooctanyl, oxoazaspirooctanyl, azaspirononanyl, diazaspirononanyl oxospirononanyl, dioxospirononanyl, oxoazaspirononanyl, azaspirodecanyl diazaspirodecanyl, oxopirodecanyl, dioxospirodecanyl, oxoazaspirodecanyl azaspiroundecanyl, diazaspiroundecanyl, oxospiroundecanyl, dioxospiroundecanyl, and oxoazaspiroundecanyl. In some embodiments, each C3-2oheterocycloalkyl in R7, R8, R9and R10is independently selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide and thiomorpholinyl dioxide.

[0199] In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, unless otherwise stated, is optionally substituted with one to four substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl, Ci.4fluoroalkyl and Ci.4chloroalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, unless otherwise stated, is optionally substituted with one to four selected from OH, F, Cl, Br, Ci.4alkyl Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, unless otherwise stated, is optionally substituted with one to four substituents selected from OH, F, Cl, Br, H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3,CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3and CH2CH(CD3)2. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is optionally substituted with one to four substituents selected from OH, F, Cl, Br, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, C(CCI3)3, CD3, CD2H, CDH2, CH2CD2H, CH2CD3, CH2CDH2and C(CD3)3. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is optionally substituted with one to four substituents selected from OH, F, Cl, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CD3, CDH2and CHD2.

[0200] In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, unless otherwise stated, is further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi-ealkyl to form a C3.7heterocycloalkyl ring. In some embodiments, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, unless otherwise stated, is optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or with C2.6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl, azetidinyl, oxetanyl, theitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, diazolyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, oxothiazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, dioxazolyl, dithiazolyl, tetrahydropyranyl, tetrahydrothiopyranyl (thianyl), tetrahydrothiopyranyl oxide (thianyl oxide), tetrahydrothiopyranyl dioxide (thianyl dioxide), dithianyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl oxide, thiomorpholinyl dioxide and dioxanyl.

[0201] In an exemplary embodiment, each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is further optionally disubstituted on the same carbon atom with C2-6alkylene interrupted with one to three of O, S, SO2, N, NH, or NCi-ealkyl to form a C3.7heterocycloalkyl ring selected from aziridinyl, diazirinyl, oxiranyl, thiiranyl, oxaxiridinyl, dioxiranyl and azetidinyl.

[0202] In some embodiments, Y4is selected from C(O)O, OC(O), NR14C(O) and C(O)NR14. In some embodiments, Y4is selected from O, S, C(O), S(O), S(O)2, NR14, NR14C(O), C(O)NR14, NR14C(O)O and OC(O)NR14. In some embodiments, Y4is selected from O, S, C(O), S(O), S(O)2, NR14, NR14C(O)O and OC(O)NR14.

[0203] In some embodiments, R4is selected fromH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0204] In some embodiments, R6is selected from Ci_6alkyl, Ci-6fluoroalkyl, Ci.6chloroalkyl and Ci.6deuteroalkyl. In some embodiments, R6is selected from Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl. In some embodiments, R6is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCl2H, CClH2, CH2CCl2H, CH2CCl3, CH2CClH2, CH(CCl3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3and CH2CH(CD3)2. In some embodiments R6is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH(CH3)3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, R6is selected from CH3, CF3, CFH2, CHF2, CCl3, CCl2H, CClH2, CD3, CD2H and CDH2. In some embodiments, R6is selected from CH3, CF3, CCl3and CD3. In some embodiments, R6is CH3.

[0205] In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, Ci-i2alkyl and Ci-i2haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, Ci-ioalkyl and Ci-lohaloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, Ci.6alkyl and Ci.6haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, Ci.4alkyl and Ci.4haloalkyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R11, R12, R13, R14, R15and R16, are independently selected from H, Ci_4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, CH2CH(CH3)2, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, C(CF3)3, CH2CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, C(CCI3)3, CH2CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2, CH(CD3)2, C(CD3)3and CH2CH(CD3)2. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH(CH3)3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H, CH3, CF3, CCI3and CD3. In some embodiments, R11, R12, R13, R14, R15and R16are independently selected from H and CH3.

[0206] In some embodiments, the compound of Formula I is a compound of Formula l-A. Therefore, in some embodiments, the application includes a compound of Formula l-A, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:OR2R3p3awhereinR1, R2, R3, R3a, R5and R6are as defined for Formula I including embodiments thereof; andR4is selected from C3-i2cycloalkyl, Ci-4alkyleneC3-i2cycloalkyl, C2-4alkenyleneC3-i2cycloalkyl, C2-4alkynyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci-4alkyleneC3-i2heterocycloalkyl, C2.4alkenyleneC3-i2heterocycloalkyl, C2-4alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci.4alkyleneC5-i2heteroaryl, C2-4alkenyleneC5-i2heteroaryl and C2-4alkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z2C1-16alkyl, Z2C2-i6alkenyl, Z2C2. i6alkynyl, Z2Ci-i6haloalkyl, Z2C2-i6haloalkenyl, Z2C2-i6haloalkynyl, Z2Ci.ioalkyleneY4R10, Z2C2. ioalkenyleneY4R10, Z2C2-ioalkynyleneY4R10, Z2C6-ioaryl, Z2Ci-iOalkyleneC6-ioaryl, Z2C2. ioalkenyleneC6-ioaryl, Z2C2-ioalkynyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci-i0alkyleneC3- i2cycloalkyl, Z2C2-ioalkenyleneC3-i2cycloalkyl, Z2C2-ioalkynyleneC3-i2cycloalkyl, Z2C3. i2heterocycloalkyl, Z2Ci-i0alkyleneC3-i2heterocycloalkyl, Z2C2-ioalkenyleneC3- isheterocycloalkyl, Z2C2-ioalkynyleneC3-i2heterocycloalkyl, Z2C5-i2heteroaryl, Z2C2. ioalkyleneC5-i2heteroaryl, Z2C2-ioalkenyleneC5-i2heteroaryl and Z2C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, halo, NO2, C1-16alkyl, C1-6haloalkyl, C1-10alkyleneOC1-6alkyl, OC1-16alkyl, OC1-16haloalkyl and OC1-10alkyleneOC1-6alkyl; and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci-4alkyl, Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NC1-6alkyl to form a C3-7heterocycloalkyl ring,Y4and Z2are as defined for Formula I including embodiments thereof; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:when R2, R3, R3aand R5are all H, R6is CH3, R4is unsubstituted 3-indolyl, then R1is not (2E)-3,7-dimethyl-2,6-octadien-1-yl.

[0207] In some embodiments, in the compound of Formula I or l-A,R1, R2, R3, R3a, R5and R6are as defined for Formula I including embodiments thereof; and R4is selected from C3-i2heterocycloalkyl, Ci-4alkyleneC3-i2heterocycloalkyl, C2.4alkenyleneC3-i2heterocycloalkyl, C2-4alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, C1-4alkyleneC5-i2heteroaryl, C2-4alkenyleneC5-i2heteroaryl and C2-4alkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or moresubstituents selected from OH, halo, CN, NO2, =0, Z2Ci-i6alkyl, Z2C2-iealkenyl, Z2C2-i6alkynyl, Z2Ci-i6haloalkyl, Z2C2-i6haloalkenyl, Z2C2-i6haloalkynyl, Z2Ci.ioalkyleneY4R10, Z2C2. ioalkenyleneY4R10, Z2C2-ioalkynyleneY4R10, Z2C6-ioaryl, Z2Ci-iOalkyleneC6-ioaryl, Z2C2. ioalkenyleneC6-ioaryl, Z2C2-ioalkynyleneC6-ioaryl, Z2C3-i2cycloalkyl, Z2Ci-ioalkyleneC3-i2cycloalkyl, Z2C2-ioalkenyleneC3-i2cycloalkyl, Z2C2-ioalkynyleneC3-i2cycloalkyl, Z2C3. i2heterocycloalkyl, Z2Ci-i0alkyleneC3-i2heterocycloalkyl, Z2C2-ioalkenyleneC3- isheterocycloalkyl, Z2C2-ioalkynyleneC3-i2heterocycloalkyl, Z2C5-i2heteroaryl, Z2C2. ioalkyleneC5-i2heteroaryl, Z2C2-ioalkenyleneC5-i2heteroaryl and Z2C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, halo, NO2, Ci-i6alkyl, Ci.6haloalkyl, Ci-ioalkyleneOCi-6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OCi-i0alkyleneOCi-6alkyl; and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci_4alkyl, Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3-7heterocycloalkyl ring,Y4and Z2are as defined for Formula I including embodiments thereof; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:when R2, R3, R3aand R5are all H, R6is CH3, R4is unsubstituted 3-indolyl, then R1is not (2E)-3,7-dimethyl-2,6-octadien-1-yl

[0208] In some embodiments, the compound of Formula I is a compound of Formula l-B. Therefore, in some embodiments, the application includes a compound of Formula l-B, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:whereinR1, R2, R3, R3a, R5and R6are as defined for Formula I including embodiments thereof; andR4is selected from H, Ci-4alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-4haloalkyl, C2-iohaloalkenyl and C2-10haloalkynyl, wherein each alkyl, alkenyl and alkynyl group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci-4alkyl, Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NC1-6alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:i) when R2, R3, R3a, R4and R5are all H and R6is CH3, then R1is not CH2OH, C2-iealkenyl or C2-i6alkenyl substituted with OH or =0;ii) when R2is CH(CH3)2, R3, R3aand R5are all H, R6is CH3, and R1is CH2OCH(CH3)2or CH2OC(O)CH3, then R4is not H;iii) when R2is CH3, R3, R3aand R5are all H, R6is CH(CH3)2, and R1is CH3. then R4is not H; andiv) when R3, R3a, R4and R5are all H, and R6is CH3, then R1and R2are not joined to form, together with the oxygen and carbon atoms therebetween, a 6 membered unsaturated ring that is disubstituted on the same carbon atom with CH3and C4-ioalkenyl or with CH3and C4. salkenyl substituted with one =0, and the ring being optionally further substituted with one OH or one =0.

[0209] In some embodiments, in the compound of Formula l-B, R4is selected from H, Ci-4alkyl and Ci-4haloalkyl, wherein each alkyl group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl, Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NC1-6alkyl to form a C3-7heterocycloalkyl ring. In some embodiments, in the compound of Formula I-B, R4is selected from C1-4alkyl and C1-4haloalkyl, wherein each alkyl group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci-4alkyl, C^haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring. In some embodiments, in the compound of Formula l-B, R4is H.

[0210] In some embodiments, in the compound of Formula l-B, R4is selected from C2-ioalkenyl, C2-ioalkynyl, C2-iohaloalkenyl and C2-iohaloalkynyl, wherein each alkenyl andalkynyl group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl, Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi-ealkyl to form a C3-7heterocycloalkyl ring.

[0211] In some embodiments, the compound of Formula I is a compound of Formula l-C. Therefore, in some embodiments, the application includes a compound of Formula l-C, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:R3R3a(l-C)whereinR1, R2, R3, R3a, R5and R6are as defined for Formula I including embodiments thereof; and R4is selected from C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-10aryl and C2-ioalkynyleneC6-ioaryl, wherein each aryl group comprised in R4is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z2C1-16alkyl, Z2C2-16alkenyl, Z2C2-16alkynyl, Z2C1-16haloalkyl, Z2C2-16haloalkenyl, Z2C2-16haloalkynyl, Z2C1-10alkyleneY4R10, Z2C2-10alkenyleneY4R10, Z2C2-10alkynyleneY4R10, Z2C6-10aryl, Z2C1-10alkyleneC6-10aryl, Z2C2-10alkenyleneC6-10aryl, Z2C2-10alkynyleneC6-10aryl, Z2C3-12cycloalkyl, Z2C1-10alkyleneC3-12cycloalkyl, Z2C2-10alkenyleneC3-12cycloalkyl, Z2C2-10alkynyleneC3-12cycloalkyl, Z2C3-12heterocycloalkyl, Z2C1-10alkyleneC3-12heterocycloalkyl, Z2C2-10alkenyleneC3-18heterocycloalkyl, Z2C2-10alkynyleneC3-12heterocycloalkyl, Z2C5-12heteroaryl, Z2C2-10alkyleneC5-12heteroaryl, Z2C2-10alkenyleneC5-12heteroaryl and Z2C2-10alkynyleneC5-12heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, halo, NO2, C1-16alkyl, C1-6haloalkyl, C1-10alkyleneOC1-6alkyl, OC1-16alkyl, OC1-16haloalkyl and OC1-10alkyleneOC1-6alkyl; and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi-ealkyl to form a C3.7heterocycloalkyl ring,Y4and Z2are as defined for Formula I including embodiments thereof; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:i) when R2is CH(CH3)2, R3, R3aand R5are all H, R6is CH3, and R1is CH2OCH(CH3)2or CH2OC(O)CH3, then R4is not Cialkylenephenyl substituted with one or two OCH3;ii) when R2is CH3, R3, R3aand R5are all H, R6is CH(CH3)2, and R1is CH3. then R4is not Cialkylenephenyl substituted with one OCH3; andiii) when R2, R3, R3aand R5are all H, R6is CH3, and R4is Cialkylenephenyl or Cialkylenephenyl substituted with one or two OCH3, then R1is not I, CH2OH, 3-methylbut-2-en-1-ylCialkyleneoctahydronaphthalenyl, Cialkylenedecahydronaphthalenyl and Cialkylenedecahydronaphtho[1,2b]oxirenyl, the latter three of which are substituted with 3 to 5 substituents selected from OH, CH3, =0, =C and OCialkylenephenyl;

[0212] In some embodiments, the compound of Formula I is a compound of Formula l-D. In some embodiments, the compound of Formula I is a compound of Formula l-D and the application includes a compound of Formula l-D, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:whereinR1, R2, R3, R3a, R5and R6are as defined for Formula I including embodiments thereof; and R4is selected from Ci-4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein each alkylene, alkenylene and alkynylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl, Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2. ealkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring,Y3and R9are as defined for Formula I including embodiments thereof; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0213] In some embodiments, the compound of Formula I is a compound of Formula l-E. In some embodiments, the application includes a compound of Formula l-E, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:whereinR2, R3, R3a, R4, R5and R6are as defined for Formula I including embodiments thereof; and R1is selected from F, Cl, Br, I and Ci-i6alkyl and Ci-i6alkyl optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci-4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NC1-4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:i) when R2is CH3, R3, R3aand R5are all H, R6is CH(CH3)2, and R1is CH3. then R4is not H, C(CH3)3or Cialkylenephenyl substituted with one OCH3; andii) when R2, R3, R3aand R5are all H, R6is CH3, and R4is Cialkylenephenyl or Cialkylenephenyl substituted with one or two OCH3, then R1is not I.

[0214] In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, I and Ci-i6alkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, I, Ci-i6alkyl, Ci-i6fluoroalkyl and Ci-i6chloroalkyl. In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, I, Ci.4alkyl, Ci-4fluoroalkyl and Ci.4chloroalkyl. In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, I, Ci-3alkyl, Ci.3fluoroalkyl and Ci.3chloroalkyl. In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, CH3, CH2CH3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CH(CF3)2, CCI3, CCI2H, CCIH2, CH2CCI2H, CH2CCI3, CH2CCIH2, CH(CCI3)2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, CH(CD3)2, CH2CDH2and CH(CD3)2. In some embodiments, in the compound of Formula l-E,R1is selected from F, Cl, Br, I, Ci-2alkyl, Ci-2fluoroalkyl and Ci-2chloroalkyl. In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, I, CH3, CH2CH3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCl3, CCl2H, CClH2, CH2CCl2H, CH2CCl3, CH2CClH2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2, CH2CD3, and CH2CDH2. In some embodiments, in the compound of Formula l-E, R1is selected from F, Cl, Br, I, CH3, CF3, CFH2, CHF2, CCI3, CCl2H, CClH2, CD3, CD2H and CDH2.

[0215] In an exemplary embodiment, in the compounds of Formula I, l-A, l-B, l-C and l-D, R1is C2-16alkenyl optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In exemplary embodiments, in the compounds of Formula I, l-A, l-B, l-C and l-D, R1is C3-16alkenyl or C5-16alkenyl optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl orwith C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In an exemplary embodiment, in the compounds of Formula I, l-A, l-B, l-C and l-D, R1is isoprenyl, farnesyl or geranyl optionally substituted with one or more substituents selected from OH, halo and =0 and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0216] In an exemplary embodiment, in the compounds of Formula I, l-A, l-B, l-C and l-D, R1is C5-16alkenyl optionally substituted with one or more substituents selected from OH, halo, CN, =O, C1-4alkyl and C1-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring and R4is C1-4alkyl or C1-4halolkyl, all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium. In some embodiments, R1is isoprenyl, farnesyl or geranyl optionally substituted with one or more substituents selected from OH, halo and =O and R4is C1-4alkyl or C1-4halolkyl, all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

[0217] In an exemplary embodiment, in the compounds of Formula I, l-A, l-B, l-C and l-D, R2, R3, R3aand R5are all H and R6is CH3. In an exemplary embodiment, in the compound of Formula l-E, R2, R3, R3aand R5are all H and R6is CH3.

[0218] To be clear, a reference to an alkyl, alkenyl, alkynyl, alkylene, alkenylene and / or alkynylene group as in, for example, “wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group” as used herein includes each group which is or comprises an alkyl, alkenyl, alkynyl, alkylene, alkenylene and / or alkynylene group. For example, a reference to “alkyl” as in “each alkyl” refers to each alkyl, haloalkyl (including fluoroalkyl and chloroalkyl) and deuteroalkyl groups and the like, and a reference to “alkylene” as in “each alkylene” refers to each alkylene, haloalkylene (including fluoroalkylene and chloroalkylene), deuteroalkylene, alkyleneC6-ioaryl, alkyleneC3-i2cycloalkyl, alkyleneC3-i2heterocycloalkyl and alkyleneC5-i2heteroaryl and the like.

[0219] Accordingly, the present application includes a compound of Formula I selected from a compound listed in Table 1.Table 1CompoundI. D. Structure CHEMICAL NAME 1-1I I °H(E)-2-(cyclopropylmethyl)-5- (3,7-dimethylocta-2,6-dien-1- yl)-4-hydroxy-6- methoxyisoindolin-1-one oI-2I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-(pyrrolidin-1- / ■> y l)ethyl)isoindolin-1 -one oI-31 1 °H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(pyridin-4- ylmethyl)isoindolin-1-one0\ / \=NI-41 1 °H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-(thiophen-2- ' — ( J y l)ethyl)isoindolin-1 -one0CompoundI. D. Structure CHEMICAL NAME 1-5I I °H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-propylisoindolin- 1-one01-6I I °H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-phenylisoindolin- 1-one\3 < 01-7 4HO z / / \ \ i _ rO (E)-2-benzyl-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- methoxyisoindolin-1-one1-8 i i / / O oH(E)-2-(2-(3-(but-3-yn-1-yl)- 3H-diazirin-3-yl)ethyl)-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- methoxyisoindolin-1-one 1-9 ^"3x3^ / I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-methylisoindolin- 1-one01-10I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-(pyridin-4- o / =\X— (\ N y l)ethyl)isoindolin-1 -one 1-11(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-(pyridin-3- y l)ethyl)isoindolin-1 -one1-12I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-(pyridin-2- / =\' — (\ / ) y l)ethyl)isoindolin-1 -one 0 N^7CompoundI. D. Structure CHEMICAL NAME 1-13i OH4-hydroxy-6-methoxy-5-(3- methylbut-2-en-1-NHy l)isoindolin-1 -one01-14(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-(thiazol-2- y l)ethyl)isoindolin-1 -one1-15 / q / > G o z—0H(E)-2-(2- I I X / / ' I _ (dimethylamino)ethyl)-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- methoxyisoindolin-1-one 0x1-162-benzyl-5-(3,7- Q dimethyloctyl)-4-hydroxy-6- jT methoxyisoindolin-1-one o1-17I IOH(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3-X- \ phenylpropy l)isoindolin-1 - one° o1-18I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-2-(2-(furan-2- yl)ethyl)-4-hydroxy-6- methoxyisoindolin-1-one o c>1-19I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-2-ethyl-4-hydroxy- 6-methoxyisoindolin-1-onex0CompoundI. D. Structure CHEMICAL NAME 1-20I I OH I I I HN.N(E)-5-(3,7-dimethylocta-2,6- II JI dien-1-yl)-4-hydroxy-6- J methoxy-2-(4-phenyl-1 H- pyrazol-5-yl)isoindolin-1-one W1-21(E)-2-benzyl-5-(3,7- dimethylocta-2,6-dien-1-yl)- ( 7 T jT N— ' 4,6-dimethoxyisoindolin-1- o / oneOI-22 4> o / —X # ' z _(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(4-methyl-2-oxo- 2H-chromen-7-yl)isoindolin- X C 1-oneI-231 10H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2- (morpholinomethyl)isoindolin -1-one^—0I-24I I OH / _ (E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2- X n morpholinoethyl)-2,3- dihydro-1H-inden-1-one 0I-251 1OH(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3- — \ morpholinopropyl)isoindolin- O 1-oneQI-261 1OH(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2- methylbenzyl)isoindolin-1- one° \ / CompoundStructure CHEMICAL NAME I. D.1-27(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3-(o- tolyl)propyl)isoindolin-1 -one1-28I IOH(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3- / q / methylbenzyl)isoindolin-1- one(> o\ / — ° \ / —#\ i \ _1-29i ioh(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3-(m- tolyl)propyl)isoindolin-1 -one01-30I I0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(4- methylbenzyl)isoindolin-1-0\ / one1-31i iOH(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6-X— \ methoxy-2-(3-(p- tolyl)propyl)isoindolin-1 -one ° z / AI-32(E)-2-(2- I I0H(bicyclo[1.1.1]pentan-1- y l)ethyl)-5-(3, 7-d imethylocta- 2, 6-d i e n- 1 -y I )-4- hy d roxy-6- methoxyisoindolin-1-one 0vI-33(E)-5-(3,7-dimethylocta-2,6- I I0Hdien-1-yl)-2-(2-(1,1- dioxidothiomorpholino)ethyl)-,0 4-hydroxy-6- s; methoxyisoindolin-1-one O ' — / 0CompoundStructure CHEMICAL NAME I. D.I-341 1 °H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- / =\ methoxy-2-(2-oxo-2-(pyridin- 4-y l)ethy l)isoindolin-1 -one 0 0I-351 1 °H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2-oxo-2- / =\ / ) — <x z> phenylethyl)isoindolin-1-one 0 0I-36iiOHOw= —1 1 (> O\ z— (E)-5-(3,7-dimethylocta-2,6- X # ' I _ dien-1-yl)-4-hydroxy-6- methoxy-2-((1-methyl-1H- 0 ^"^^X> cz# N indol-2-y l)methyl)isoindolin- / / V. X0V\ 1-one\ / ° X ~Z.) '1.I-37I / i / O°h(S, E)-5-(3,7-dimethylocta- CF32, 6-d i e n- 1 -y I )-4- hy d roxy-6- JT JT / K methoxy-2-(2,2,2-trifluoro-1- phenylethyl)isoindolin-1-one oI-381 10H(E)-2-(2-(1H-pyrrol-1- y l)ethyl)-5-(3, 7-d imethylocta- 2, 6-d i e n- 1 -y I )-4- hy d roxy-6- J methoxyisoindolin-1-one 0I-39(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2- (methylamino)ethyl)isoindoli n-1-oneI-40(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2- (methy lsulfonyl)ethy l)isoindol in-1-oneCompoundI. D. Structure CHEMICAL NAME 1-41I I °H(E)-2-(2-aminoethyl)-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- NH2methoxyisoindolin-1-one 0I-42| I OH °v 1 (E)-5-(3,7-dimethylocta-2,6- 0 ). dien-1-yl)-4-hydroxy-2-(2- (isopropylsulfonyl)phenyl)-6- methoxyisoindolin-1-one / \o / 0I-431 1 > A o0Z— / / \ I \H_ (E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- <>^ oHmethoxy-2-(thiophen-3- y l)isoindolin-1 -one0I-44 ° 61 10H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(thiophen-2- S y l)isoindolin-1 -one0I-45(E)-2-(2-chlorophenyl)-5- (3,7-dimethylocta-2,6-dien-1- yl)-4-hydroxy-6- methoxyisoindolin-1-oneI-461 10H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-2-(3-fluorobenzyl)- 4-hydroxy-6- methoxyisoindolin-1-one0\ / FI-47i i0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-2- isopropyl-6-xmethoxyisoindolin-1-one 0CompoundI. D. Structure CHEMICAL NAME I-48(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3-(pyridin-4- y l)propyl)isoindolin-1 -oneI-490 (E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- ( / methoxy-2-(2-oxo-4- o / (trifluoromethyl)-2H- / q / CF3chromen-7-yl)isoindolin-1- th\ 0 one(H O z^ v y i- >*1 o _I-501 10H(E)-5-(3,7-dimethylocta-2,6- ^ZZ I dien-1-yl)-4-hydroxy-6- methoxy-2-(2- methoxyethyl)isoindolin-1- one0 0zxoI-511 10H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-2-(2- mercaptoethyl)-6-X— SH methoxyisoindolin-1-one 0I-521 10H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(2- (methy lthio)ethyl)isoindolin- 1-one0xI-531 10H(E)-2-(2-(aziridin-1-yl)ethyl)- 5-(3,7-dimethylocta-2,6-dien- 1-yl)-4-hydroxy-6- methoxyisoindolin-1-one 0I-54 (E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(6-nitro-1 H- benzo[d]imidazol-2- y l)isoindolin-1 -one0suo- L-U!|opii! OS!(|Xi|ia(| X-2-U! P! WuXd)-2)-s-Xxoi|iaw \=N N T-g-XxojpXq-t?-(|X-i,-U3!p-9'2-eioo|Xm3iU!p-z'£)-S-(3) HO 1 1l-9-l 03ieiueqjeo(|Xdojd(|X-2-uiiopuiosioxo-L-Xxoqisiu-g-XxojpXq-^ HN HO T 1-(iX-L-uaip-g's-epoiXiiiawip >0-Z'£)-S)-£) |Xinq-psi-(3) 009-1 0auo-L-uiiopuiosiXxoqiaw-g-XxojpXq-tz-(|X-!.-U3!p-9'2-eioo|Xqi3iU!p-z'£)-g-(|Xdojd(ou!iue|Xqi3iU!p)-£)-2-(3) HO 1 T69-1 03UO-L-U!|opii! OS!(|X-9-UBpo[g'2]oJ!ds)-2-Xxoqisw-g-XxojpXq-t?-(|X-i,-U3!p-9'2-Eioo|Xqi3iU!p-z'£)-S-(3) HO 1 189-1 f^Osuo-L-uiiopuiosiXxoqisw-g-XxojpXq-tz ( ) O-(|X-L-U3!p-9's-Eioo|Xqi3LU!p \-Z'£)-S-(|Aqiaiu|X-g-UEOspIg tdoJidsExoip-t7‘U)-2-(3)HO 1 1Z9-I / =N 0suo- p-ui|opuios!(| X / \ —- / -u!|ouinb)-2-Xxoqisiu-g-XxojpXq-tHlX-kuaip vJ / -9'2-Eioo|XqisiU!p-z's)-g-(3)HO 1 199-1 0suo- p-ui|opuios!(|X-g-UEisxo)-2-Xxoqisiu-g-XxojpXq-tHlX-kuaip-9'2-Eioo|XqisiU!p-z's)-g-(3)HO 1 199-1 3IAIVN 3VOIIAI3HO sjnjonjis O’l punodwoo890090 / 9303YD / IDdCompoundI. D. Structure CHEMICAL NAME I-628-benzyl-5-methoxy-2,2- dimethyl-3, 4,8,9- tetrahydropyrano[2,3- e]isoindol-7(2H)-oneI-63 (E)-tert-butyl 3-(6-(2-benzyl- BocN-'A 1 9H4-hydroxy-6-methoxy-1- / / q q / — \ / oxoisoindolin-5-yl)-4- methylhex-4-en-1- p 4 <o °X # / / V I. _ ylidene)azetidine-1- 0 carboxylate1-63 P>OZ(E)-5-(6-(azetidin-3-ylidene)-HN3< 1 S ±Q O 3-methylhex-2-en-1-yl)-2- benzy l-4-hyd roxy-6- methoxyisoindolin-1-one oI-652-benzyl-5-cinnamyl-4- p hydroxy-6- rY jf methoxyisoindolin-1-one 01-662-benzy l-4-hyd roxy-6- methoxy-5-methylisoindolin- 1-one1-661 10H5-(3,7-dimethyloctyl)-4- hydroxy-6- jf j^ NH methoxyisoindolin-1-one 0I-671 10H(E)-2-(2-cyclohexylethyl)-5- (3,7-dimethylocta-2,6-dien-1- yl)-4-hydroxy-6- ' — < r~\ ) methoxyisoindolin-1-one 0 ' — 'CompoundStructure CHEMICAL NAME I. D.I-68I I °H(E)-2-(2-(cyclohex-2-en-1- y l)ethyl)-5-(3, 7-d imethylocta- 2, 6-d i e n- 1 -y I )-4- hy d roxy-6- ' — ( / =\ ) methoxyisoindolin-1-one o ' — 'I-69(E)-2-allyl-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- methoxyisoindolin-1-one / \o / I-70I I > A O z— / / I _0H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(3-methylbut-2-x— ( en-1-yl)isoindolin-1-one 0 \I-71I I0H2-((E)-4-chlorobut-2-en-1-yl)- 5-((E)-3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxyisoindolin-1-one 0 ClI-721 10H(E)-5-(3,7-dimethylocta-2,6- dien-1-yl)-4-hydroxy-6- methoxy-2-(prop-2-yn-1- y l)isoindolin-1 -one0I-731 10H(E)-2-(but-2-yn-1-yl)-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- >= — methoxyisoindolin-1-one 0I-741 10H(E)-2-(but-3-yn-2-yl)-5-(3,7- dimethylocta-2,6-dien-1-yl)-N-( 4-hydroxy-6- methoxyisoindolin-1-one "'° 1 \CompoundI. D. Structure CHEMICAL NAME I-759 (E)-2-benzyl-4-( benzyloxy )- Q 5-(3,7-dimethylocta-2,6-dien- 1-yl)-6-methoxyisoindolin-1- oneJi0I-76(E)-2-benzyl-5-(3,7- dimethylocta-2,6-dien-1-yl)- P 4-isopropoxy-6- methoxyisoindolin-1-one o o JO - I-77 poxA\ \ / ° °2-benzyl-5-((E)-3,7- (y 6 o— dimethylocta-2,6-dien-1-yl)- 6-methoxy-4- < o (((2S,3R,4S,5R)-3,4,5- J ' tri hyd roxytetrahyd ro-2H- pyran-2-yl)oxy)isoindolin-1- oneI-78I I0H(E)-2-benzyl-7-chloro-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6- methoxyisoindolin-1-one bI-79I I0H(E)-2-benzyl-5-(3,7- dimethylocta-2,6-dien-1-yl)- 4-hydroxy-6-methoxy-3- methylisoindolin-1-onebor a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0220] In an embodiment the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., " Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0221] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basiccompounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0222] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0223] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water(resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0224] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0225] The compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0226] The compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0227] The compounds of the present application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application. The compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure.III. Compositions of the Application

[0228] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.

[0229] In some embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein

[0230] Therefore, the present application further includes a method or use of stimulating neuritogenesis or inhibiting neurodegeneration, or treating or preventing a disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, inhibiting neurodegeneration, and / or increasing neural plasticity) as described above by administering or using a composition comprising a compound of Formula I or a pharmaceutically acceptable salt, prodrug and / or solvate thereof

[0231] The compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0232] Parenteral administration includes systemic delivery routes other than the gastrointestinal (Gl) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0233] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR orContin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0234] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0235] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0236] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereofwith or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0237] In some embodiments, a compound of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0238] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air oran organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0239] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0240] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0241] In some embodiments a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0242] The compounds of the application are particularly amenable to administration with the air of nano-carrier systems, such as liposomes, micelles, nanoparticles, nano-emulsions, lipidic nano-systems and the like (see for example, Bhat, M. et al. Chem. and Phys, of Lipids, 2021, 236, 105053). Accordingly, the present application includes a composition comprising one or more compounds of the application and one or more components of a nano-carrier system.

[0243] In some embodiments, compounds of the application may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers

[0244] A compound of the application including pharmaceutically acceptable salts and / or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[0245] In some embodiments, the compounds of the application including pharmaceutically acceptable salts and / or solvates thereof are used are administered in a composition comprising an additional therapeutic agent. Therefore, the present application also includes a pharmaceutical composition comprising one of more compounds of the application, or pharmaceutically acceptable salts and / or solvates thereof and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent useful for treatment of a disease, disorder or condition by activation of a serotonin receptor, for example those listed in the Methods and Uses section below. In some embodiments, the additional therapeutic agent is a psychoactive drug.

[0246] In the above, the term "a compound" also includes embodiments wherein one or more compounds are referenced.IV. Methods and Uses of the Application

[0247] The compounds of the application have been shown to stimulate neuritogenic activity in cultures of primary cortical neurons. Cortical neurons are located in the centralnervous system (CNS) and are involved in functions such as, but not limited to, cognition, motor control, and sensory processing. Therefore, the compounds of the application can be used to stimulate neuritogenesis and / or to inhibit neurodegeneration, and also to treat or prevent diseases, disorders or conditions that benefit from stimulating neuritogenesis and / or inhibiting neurodegeneration, such as CNS or PNS related disorders, including, for example, neurodegenerative and neuropsychiatric disorders. In some embodiments, the compounds of the application may be shown to have improved biological activity as described, reduced toxicity, and / or improved pharmacokinetic properties compared to NDPIH and / or isohericerin.

[0248] Accordingly, the present application includes a method of stimulating neuritogenesis in a neuronal cell, either in a biological sample or in a patient, comprising administering an effective amount of a compound of the application to the neuronal cell.

[0249] The present application also includes a use of a compound of the application for stimulating neuritogenesis in a neuronal cell as well as a use of a compound of the application for the preparation of a medicament for stimulating neuritogenesis in a neuronal cell. The application further includes one or more compounds of the application for stimulating neuritogenesis in a neuronal cell.

[0250] In some embodiment, stimulating neuritogenesis is by promoting neurite elongation, promoting neurite growth and / or restoring neurite formation. In some embodiments, stimulating neuritogenesis is by promoting neurite elongation and growth.

[0251] In some embodiments, neuritogenesis is studied by any method known in the art for studying neuritogenesis. For example, in some embodiments, neuritogenesis is studied from an imaged neuron by evaluating number of neurite branches, number of primary neurites, total neurite length, and / or length of longest neurite.

[0252] In some embodiments, the number of neurite branches and / or total length of neurite network is measured.

[0253] In some embodiments, the imaging technique used to provide the imaged neuron is any suitable high resolution imaging technique known in the art. In some embodiments, the imaging technique is selected from immunofluorescent and microscopy.

[0254] In some embodiments, stimulating neuritogenesis decreases or inhibits neurodegeneration.

[0255] Accordingly, in some embodiments, the application also includes a method of decreasing or inhibiting neurodegeneration comprising administering a therapeutically effective amount of a compound of the application to a subject in need thereof.

[0256] The present application also includes a use of a compound of the application for decreasing or inhibiting neurodegeneration, as well as a use of a compound of the application for the preparation of a medicament for decreasing or inhibiting neurodegeneration. The application further includes a compound of the application for use in decreasing or inhibiting neurodegeneration.

[0257] In some embodiments, stimulating neuritogenesis increases neural plasticity. Accordingly, in some embodiments, the application also includes a method of increasing neural plasticity comprising administering a therapeutically effective amount of a compound of the application to a subject in need thereof.

[0258] The present application also includes a use of a compound of the application for increasing neural plasticity, as well as a use of a compound of the application for the preparation of a medicament increasing neural plasticity. The application further includes a compound of the application for use in increasing neural plasticity.

[0259] In some embodiments, stimulating neuritogenesis and / or decreasing or inhibiting neurodegeneration provides neuroprotection.

[0260] Accordingly, in some embodiments, the application also includes a method of providing neuroprotection comprising administering a therapeutically effective amount of a compound of the application to a subject in need thereof.

[0261] The present application also includes a use of a compound of the application for providing neuroprotection, as well as a use of a compound of the application for the preparation of a medicament for providing neuroprotection. The application further includes a compound of the application for use in providing neuroprotection.

[0262] In some embodiments, providing neuroprotection is by decreasing or inhibiting neurodegeneration.

[0263] Therefore, in some embodiments, the stimulating neuritogenesis decreases or inhibits neurodegeneration, increases neural plasticity and / or provides neuroprotection.

[0264] As the compounds of the application have been shown to stimulate neuritogenesis, the compounds of the application are useful for treating diseases, disorders or conditions that benefit from neuritogenesis. Therefore, the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.

[0265] Accordingly, the present application also includes a method of treating a disease, disorder or condition that benefits from neuritogenesis comprising administering atherapeutically effective amount of a compounds of the application to a subject in need thereof.

[0266] The present application also includes a use of a compound of the application for treating a disease, disorder or condition that benefits from neuritogenesis, as well as a use of a compound of the application for the preparation of a medicament for treating a disease, disorder or condition that benefits from stimulating neuritogenesis. The application further includes a compound of the application for use in treating a disease, disorder or condition that benefits from neuritogenesis.

[0267] In some embodiments, the administration or use of the compound stimulates neuritogenesis (optionally, provides neuroprotection, decreases or inhibits neurodegeneration, and / or increases neural plasticity).

[0268] In some embodiments, stimulating neuritogenesis provides neuroprotection and therefore, the present application also includes a method of treating a disease, disorder or condition that benefits from neuroprotection, comprising administering a therapeutically effective amount of a compound of the application to a subject in need thereof

[0269] The present application also includes a use of a compound of the application for treating a disease, disorder or condition that benefits from neuroprotection, as well as a use of a compound of the application for the preparation of a medicament for treating a disease, disorder or condition that benefits from neuroprotection. The application further includes a compound of the application for use in treating a disease, disorder or condition that benefits from neuroprotection.

[0270] In some embodiments, stimulating neuritogenesis decreases or inhibits neurodegeneration, and / or increases neural plasticity. Therefore, in some embodiments, a compound of the application is for administration or use for decreasing or inhibiting neurodegeneration, and / or increasing neural plasticity. Therefore, in some embodiments, a compound of the application is for administration or use for treating a disease, disorder or condition that benefits from decreasing or inhibiting neurodegeneration, and / or increasing neural plasticity.

[0271] Accordingly, the present application also includes a method of treating a disease, disorder or condition that benefits from decreasing or inhibiting neurodegeneration, comprising administering a therapeutically effective amount of a compound of the application to a subject in need thereof

[0272] The present application also includes a use of a compound of the application for treating a disease, disorder or condition that benefits from decreasing or inhibitingneurodegeneration, as well as a use of a compound of the application for the preparation of a medicament for treating a disease, disorder or condition that benefits from decreasing or inhibiting neurodegeneration. The application further includes a compound of the application for use in treating a disease, disorder or condition that benefits from decreasing or inhibiting neurodegeneration.

[0273] The present application also includes a method of treating a disease, disorder or condition that benefits from increasing neural plasticity, comprising administering a therapeutically effective amount of a compound of the application to a subject in need thereof

[0274] The present application also includes a use of a compound of the application for treating a disease, disorder or condition that benefits from increasing neural plasticity, as well as a use of a compound of the application for the preparation of a medicament for treating a disease, disorder or condition that benefits from increasing neural plasticity. The application further includes a compound of the application for use in treating a disease, disorder or condition that benefits from increasing neural plasticity.

[0275] In some embodiments, the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, inhibiting neurodegeneration, and / or increasing neural plasticity) is a neurological disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, inhibiting neurodegeneration, and / or increasing neural plasticity).

[0276] In some embodiments, the neurological disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, inhibiting neurodegeneration, and / or increasing neural plasticity) is any neurological disorder which affects the brain’s structure and function that benefits from neuritogenesis and / or neuroprotection (optionally, inhibiting neurodegeneration, and / or increasing neural plasticity.

[0277] In some embodiments, the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, decreasing or inhibiting neurodegeneration, and / or increasing neural plasticity) is a neuropsychiatric disorder and / or a neurodevelopmental disorder. Therefore, in some embodiments, the application includes a compound of the application or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a neuropsychiatric disorder and / or a neurodevelopmental disorder.

[0278] The present application also includes a use of a compound of the application, or a pharmaceutically acceptable salt and / or solvate thereof, for treating a neuropsychiatric disorder and / or a neurodevelopmental disorder, a use of a compound of the application, or a pharmaceutically acceptable salt and / or solvate thereof, for preparation of a medicament for treating a neuropsychiatric disorder and / or a neurodevelopmental disorder and acompound of the application, or a pharmaceutically acceptable salt and / or solvate thereof, for use to treat a neuropsychiatric disorder and / or a neurodevelopmental disorder.

[0279] In some embodiments, the neuropsychiatric disorder is selected from: an anxiety disorder, a mood disorder, a psychotic disorder, an addiction disorder; a personality disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD); a stress response syndrome (formerly called adjustment disorders), a factitious disorder, a sexual and gender disorder, a somatic symptom disorder (formerly known as a psychosomatic disorder or somatoform disorder); and combinations thereof.

[0280] In some embodiments, the anxiety disorder is selected from generalized anxiety disorder, panic disorder, social anxiety disorder and specific phobias.

[0281] In some embodiments, the mood disorder is selected from depression, bipolar disorder and cyclothymic disorder.

[0282] In some embodiments, the depression is selected from major depressive disorder, treatment-resistant depression, cancer-related depression, postpartum depression and symptoms such as hopelessness, anhedonia (loss of pleasure), fatigue and suicidal ideation.

[0283] In some embodiments, the psychotic disorder is selected from hallucinations±delusions, schizophrenia and impulse control.

[0284] In some embodiments, the personality disorder is selected from antisocial personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, dissociative disorder (formerly called multiple personality disorder, or "split personality") and depersonalization disorder.

[0285] In some embodiments, the addiction disorder, is selected from pyromania, kleptomania, compulsive gambling; alcohol addiction and drug addiction. In some embodiments, the drug addiction is opioid addiction.

[0286] In some embodiments, the gender disorder is selected from sexual dysfunction, gender identity disorder and paraphilia.

[0287] In some embodiments, the neurodevelopmental disorder is selected from autism spectrum disorder, an attention deficit disorder, Rett Syndrome, intellectual disabilities and fragile X syndrome.

[0288] In some embodiments, the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, decreasing or inhibiting neurodegeneration, and / or increasing neural plasticity) is a central nervous system (CNS)disease, disorder or condition or a peripheral nervous system (PNS). disease, disorder or condition. In some embodiments, the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection (optionally, inhibiting neurodegeneration, and / or increasing neural plasticity) is a central nervous system (CNS) disorder or a peripheral nervous system disorder (PNS).

[0289] In some embodiments, the CNS disease, disorder or condition is selected from, Multiple Sclerosis (MS), ataxia, axonal injury, stroke-induced neuronal injury, Down syndrome, chronic hearing loss, tinnitus, hyperacusis, presbycusis, balance disorders such as those associated with cochlear synaptopathy and vestibular synaptopathy, myelopathy, entrapment neuropathy, traumatic brain injury, stroke, brachial plexus injury, epilepsy, Charcot-Marie-Tooth Disease, neuronal ceroid lipofuscinosis, dementia such as frontotemporal dementia, dystonia, cerebral palsy, Rett Syndrome, hereditary spastic paraplegia, Spinocerebellar Ataxia, Tourette syndrome, and Duchenne muscular dystrophy (DMD). In some embodiments, the CNS disorder is selected from, Multiple Sclerosis (MS), ataxia, axonal injury, stroke-induced neuronal injury, Down syndrome, chronic hearing loss, tinnitus, hyperacusis, presbycusis, balance disorders such as those associated with cochlear synaptopathy and vestibular synaptopathy, myelopathy, entrapment neuropathy, traumatic brain injury, stroke, brachial plexus injury, epilepsy, Charcot-Marie-Tooth Disease, neuronal ceroid lipofuscinosis, dementia such as frontotemporal dementia, dystonia, cerebral palsy, Rett Syndrome, hereditary spastic paraplegia, Spinocerebellar Ataxia, Tourette syndrome, and Duchenne muscular dystrophy (DMD).

[0290] In some embodiments, the motor neuron disease is selected from one or more of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive bulbar palsy, pseudobulbar palsy, progressive muscle atrophy and spinal muscular atrophy and Kennedy's Disease.

[0291] In some embodiments, the CNS disease, disorder or condition is selected from a neurodegenerative disease, disorder or condition, a neurodevelopmental disorder and a psychological disease, disorder or condition. In some embodiments, the CNS disorder is selected from neurodegenerative disorders, neurodevelopmental disorders and a psychological disorder.

[0292] In some embodiments the CNS disease, disorder or condition is selected from a neurodegenerative disease, disorder or condition such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS, also known as motor neurone disease), ataxia-telangiectasia, progressive bulbar palsy, progressive muscular atrophy, dementia with Lewy bodies, multiple system atrophy, spinocerebellarataxia type 1 (SCA 1), a retinal degenerative disease, an age-related neurodegenerative disorder, and spinal cord injury.

[0293] In some embodiments, the neurodegenerative disorder is selected from motor neuron diseases, Alzheimer's disease, Huntington's disease, Friedreich's ataxia, Lewy body disease, Parkinson's disease, frontotemporal dementia and Lewy body disease.

[0294] In some embodiments, the psychological disorder is selected from neurodevelopmental disorders (including but not limited to, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)), addiction, bipolar disorders, mania, anxiety disorders (including but not limited to generalize anxiety disorder, social anxiety disorder, phobias, panic disorder and separation anxiety disorder), trauma and stressor-related disorders (including but not limited to acute stress disorder, adjustment disorders, post-traumatic stress disorder, reactive attachment disorder), dissociative disorders, somatic symptom disorders, feeding and eating disorders (including but not limited to anorexia nervosa, bulimia nervosa and binge eating disorder), sleep wake disorders, disruptive and impulse control disorders, conduct disorders, depressive disorders, substance use disorders, addictive disorders, neurocognitive disorders, schizophrenia spectrum and other psychotic disorders, obsessive-compulsive and related disorders and personality disorders.

[0295] In some embodiments, the neurodevelopmental disorders are selected from attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

[0296] In some embodiments, the PNS disease, disorder or condition is selected from acute motor axonal neuropathy, Charcot-Marie-Tooth disease types 1A, 1B and 1X, Guillain-Barre syndrome, Lambert-Eaton syndrome, diabetic neuropathy, chemotherapy induced peripheral neuropathy, cisplatin neuropathy, familial amyloid neuropathy, diphtheritic neuropathy, neuropathy with lgM1 anti-myelin-associated glycoprotein, pyridoxine neuropathy, Refsum's disease, and neuropathy associated with Leprosy and Botulism, and the like.

[0297] In some embodiments, the PNS disorder is selected from entrapment neuropathy, thoracic outlet syndrome, brachial plexus injury, direct open traumatic injury, diabetic nerve problems, Guillain-Barre syndrome and hereditary sensory and autonomic neuropathies (HSANs) (including but not limited to familial dysautonomia).

[0298] In some embodiments, the entrapment neuropathy is carpal tunnel syndrome. In some embodiments, the subject is a mammal. In another embodiment, the subject is human.

[0299] In some embodiments, the subject is a mammal. In some embodiments, the subject is human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is canine. In some embodiments, the subject is feline. Accordingly, the compounds, methods and uses of the present application are directed to both human and veterinary diseases, disorders and conditions

[0300] In some embodiments, the “subject in need thereof” is a subject having the disease, disorder or condition to be treated. In some embodiments, the “subject in need thereof’ has a disease, disorder or condition that benefits from neuritogenesis. In some embodiments, the “subject in need thereof’ has a disease, disorder or condition that benefits from neuroprotection. In some embodiments, the “subject in need thereof’ has a disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection. In some embodiments, the “subject in need thereof’ has a central nervous system (CNS) disorder or a peripheral nervous system disorder (CNS) including embodiments thereof as described above.

[0301] In some embodiments the disease, disorder or condition is a disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection and the one or more compounds of the application are administered or used in combination with one or more additional agents for treating disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection and embodiments thereof as described herein.

[0302] Compounds of the application are either used alone or in combination with other known agents useful for treating disease, disorder or condition is a disease, disorder or condition that benefits from neuritogenesis. When used in combination with other agents useful in treating disease, disorder or condition is a disease, disorder or condition that benefits from neuritogenesis, it is an embodiment that the compounds of the application are administered contemporaneously with those agents. As used herein, “contemporaneous administration” of two substances to a subject means providing each of the two substances so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion. In some embodiments, compounds of the present application are administered with anothertherapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of the application (e.g. a compound of Formula I), an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0303] Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations, and optionally comprise concurrent administration or use of one or more other therapeutic agents. For example, in some embodiments, the compounds of the application may be administered at least once a week. In some embodiments, the compounds may be administered to the subject from about one time per two or three weeks, or about one time per week to about once daily for a given treatment. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or the activity of the compounds of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject. In some embodiments treatment comprise prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition of the application to prevent recurrence.

[0304] The dosage of compounds of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. Compounds of the application may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compounds of the application from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of one or more compounds of the application will range between about 0.05 mg per day to about 1000 mg per day for an adult, suitably about 0.1 mg per day to about 500 mg per day, more suitablyabout 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg. Compounds of the application may be administered in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three or four daily doses.

[0305] In an embodiment, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject. In a further embodiment, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.

[0306] To be clear, in the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced. Likewise, the term “compounds of the application” also includes embodiments wherein only one compound is referenced.V. Processes of the Application

[0307] The present application includes a novel process for preparing compounds of Formula I wherein R1comprises an allyl group covalently attached to the remaining portion of the compound of Formula I through the methylene (CH2) of the allyl group and the remaining variables are as defined in Formula I unless otherwise stated, and R2is H. The process of the application is an efficient three step process, which can be conveniently modified at the last step using various amino compounds, e.g. NH2-R4, to provide compounds of Formula I with corresponding various R4groups.

[0308] Accordingly, in some embodiments, the application includes a process for preparing a compound of Formula I wherein R2and R3aare both H,the process comprising:reacting a compound of Formula AOH Owith a compound of Formula B, R1-Hal (B), wherein Hal is selected from F, Cl, Br and I, in the presence of a base to provide a compound of Formula COR1Osubjecting the compound of Formula C to conditions to induce a rearrangement to provide a compound of Formula Dreacting the compound of Formula D with a compound of Formula E, NH2-R4(E), in the presence of a reducing agent to provide the compound of Formula I,whereinR3is selected from H, Ci-2alkyl and Ci-2haloalkyl including embodiments thereof as defined for Formula I;R4, R5and R6are as defined for Formula I including embodiments thereof;R1is selected from C2-i6alkenyl, C2-ioalkenyleneC6-ioaryl, C2-ioalkenyleneC3-i2cycloalkyl, C2-ioalkenyleneC3-i2heterocycloalkyl, C2-ioalkenyleneC5-i2heteroaryl and C2-ioalkenyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-iealkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2. i0alkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2. ioalkenyleneC6-ioaryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-ioalkyleneC3. i2cycloalkyl, Z1C2-ioalkenyleneC3-i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C2-ioalkenyleneC3. isheterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2. ioalkyleneC5-i2heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci. ehaloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-i0alkyleneOCi-6alkyl, and wherein each alkenyl and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, and including embodiments thereof described above;provided the C2-iealkenyl or C2-ioalkenylene group in R1comprises an allyl group wherein the CH2of the allyl group is covalently attached to the remaining portion of the compound of Formula I.

[0309] In some embodiments, in the process of the application, R3is selected from H, D, C1-2alkyl, Ci.2fluoroalkyl, Ci.2chloroalkyl and Ci.2deuteroalkyl. In some embodiments, in the process of the application, R3is selected from H, D, CH3, CH2CH3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, CCI3, CChH, CCIH2, CH2CCl2H, CH2CCI3, CH2CCIH2, CD3, CD2H, CDH2, CH2CD2H, CH2CDH2 and CH2CD3. In some embodiments, in the process of the application, R3is selected from H, D, CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2. In some embodiments, in the process of the application, R3is selected from H, D, CH3, CF3, CFH2, CHF2, CCI3, CCI2H, CCIH2, CD3, CD2H and CDH2.. In some embodiments, in the process of the application, R3is selected from H, D, CH3, CF3, CFH2, CHF2, CD3, CD2H and CDH2.. In some embodiments, in the process of the application, R3is selected from H, D, CH3, CF3, CFH2, CHF2, CD3, CD2H and CDH2. In some embodiments, in the process of the application, R3is selected from H, D, CH3, CF3and CD3. In some embodiments, in the process of the application, R3is H.

[0310] The present application includes a process for preparing a compound of Formula I,OH R3ft3ajf £ N-R4R6O^Y ^R5 0(i)the process comprising:reacting a compound of Formula AOH ORS°££O-R5 0(A)with a compound of Formula B, R1-Hal (B), wherein Hal is selected from F, Cl, Br and I, in the presence of a base to provide a compound of Formula Csubjecting the compound of Formula C to conditions to induce a rearrangement to provide a compound of Formula Dreacting the compound of Formula D with a compound of Formula E, NH2-R4(E), in the presence of a reducing agent to provide the compound of Formula I,wherein R3, R3a, R4, R5and R6are as defined for Formula I including embodiments thereof; andR1is selected from C2-i6alkenyl, C2-ioalkenyleneC6-ioaryl, C2-ioalkenyleneC3-i2cycloalkyl, C2-ioalkenyleneC3-i2heterocycloalkyl, C2-ioalkenyleneC5-i2heteroaryl and C2-ioalkenyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-iealkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2. i0alkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2. ioalkenyleneC6-ioaryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-ioalkyleneC3. i2cycloalkyl, Z1C2-ioalkenyleneC3-i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C2-ioalkenyleneC3. isheterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2. ioalkyleneC5-i2heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci. ehaloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-i0alkyleneOCi-6alkyl, and wherein each alkenyl and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, and including embodiments thereof described above;provided the C2-iealkenyl or C2-ioalkenylene group in R1comprises an allyl group wherein the CH2of the allyl group is covalently attached to the remaining portion of the compound of Formula I.

[0311] In some embodiments, the application includes a process for preparing a compound of Formula I wherein R2, R3and R3are all H,the process comprising:reacting a compound of Formula AOH O(A)with a compound of Formula B, R1-Hal (B), wherein Hal is selected from F, Cl, Br and I, in the presence of a base to provide a compound of Formula COR1O(C);subjecting the compound of Formula C to conditions to induce a rearrangement to provide a compound of Formula Dreacting the compound of Formula D with a compound of Formula E, NH2-R4(E), in the presence of a reducing agent to provide the compound of Formula I,wherein R4, R5and R6are as defined for Formula I including embodiments thereof; and R1is selected from C2-iealkenyl, C2-ioalkenyleneC6-ioaryl, C2-ioalkenyleneC3-i2cycloalkyl, C2- ioalkenyleneC3.i2heterocycloalkyl, C2-ioalkenyleneC5-i2heteroaryl and C2-ioalkenyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-iealkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2. i0alkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2. loalkenyleneC6-10aryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-ioalkyleneC3-i2cycloalkyl, Z1C2-ioalkenyleneC3-i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C2-ioalkenyleneC3- isheterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2. ioalkyleneC5-i2heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci-shaloalkyl, Ci-ioalkyleneOCi-6alkyl, OCi-ealkyl, OCi-ehaloalkyl and OCi-ioalkyleneOCi-6alkyl, and wherein each alkenyl and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci-4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NC1-6alkyl to form a C3-7heterocycloalkyl ring, and including embodiments thereof described above;provided the C2.i6alkenyl or C2.i0alkenylene group in R1comprises an allyl group wherein the CH2of the allyl group is covalently attached to the remaining portion of the compound of Formula I.

[0312] In some embodiments, the compound of Formula A is reacted with an excess amount (for example, about 1. 2 to about 2.5 molar equivalents, about 1.2 to about 2 molar equivalents, about 1.2 to about 1.8 molar equivalents, or about 1.5 molar equivalents) of the compound of Formula B to provide the compound of Formula C.

[0313] In some embodiments, the compound of Formula A is reacted with an excess amount of the compound of Formula B in the presence of a base, in a suitable inert solvent at a temperature and a time for the reaction of compound of Formula A with the compound of Formula B to provide the compound of Formula C. In some embodiments, the inert solvent is selected from aliphatic or cyclic ethers such as diethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran or dioxane, esters such as ethyl acetate, hydrocarbon solvents such as n-heptane, benzene, toluene or xylene, halogenated solvents such as methylene chloride (DCM), chloroform, carbon tetrachloride and chlorobenzene, formamides such as dimethylformamide (DMF), and sulfoxides such as dimethyl sulfoxide (DMSO).

[0314] As representative, non-limiting examples, the temperature and time for reacting the compound of Formula A with the compound of Formula B in the presence of a base is about 18 °C to about 25 °C, about 20 °C to about 25 °C or room temperature for about 12 hours to about 36 hours, about 18 hours to about 30 hours, about 18 hours to about 28 hours or about 24 hours. In some embodiments, the temperature and time for reacting the compound of Formula A with the compound of Formula B in the presence of a base is about 18 °C to about 25 °C for about 24 hours.

[0315] In some embodiments, the compound of Formula A is reacted with the compound of Formula B in the presence of any suitable base known in the art. For example, in some embodiments, the base is selected from amine bases (including, but not limited to, triethylamine (TEA), trimethylamine, N, N'-diisopropylethylamine(DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO),hydrides (including, but not limited to, sodium hydride, lithium hydride and potassium hydride), alkoxides of an alkali or alkaline earth metals (including, but not limited to, sodium or potassium methoxide, ethoxide or tert-butoxide), carbonates and bicarbonates of an alkali or alkaline earth metals (including, but not limited to, potassium carbonate or cesium carbonate), phosphates of an alkali or alkaline earth metals (including, but not limited to, potassium phosphate). In some embodiments, the base is a carbonate of an alkali or alkaline earth metal. In some embodiments, the base is selected from sodium carbonate, potassium carbonate, cesium carbonate and barium carbonate. In some embodiments, the base is cesium carbonate.

[0316] In some embodiments, the compound of Formula A is reacted with the compound of Formula B in the presence of a slight excess amount (for example, about 1.1 to about 1.5 molar equivalents, about 1.2 to about 1.5 molar equivalents or about 1.2 molar equivalents) of the base.

[0317] In some embodiments, the compound of Formula A is reacted with the compound of Formula B in the presence of a base and further in the presence of a catalyst. In some embodiments, the catalyst is any suitable catalyst known in the art. In some embodiments, the catalyst is selected from sodium iodide, potassium iodide, tetrabutylammonium Iodide (TBAI), a phase transfer catalyst (including but not limited to tetrabutylammonium bromide (TBAB) or methyltrioctylammonium chloride (Aliquat® 336), Lewis Acids, and fluoride salts (such as potassium fluoride). In some embodiments, the catalyst is selected from sodium iodide, potassium iodide, tetrabutylammonium Iodide (TBAI). In some embodiments, the catalyst is potassium iodide.

[0318] In some embodiments, the compound of Formula A is reacted with the compound of Formula B in the presence of a base and with about an equivalent molar amount of the catalyst to Formula A.

[0319] In an exemplary embodiment, the compound of Formula A is reacted with a compound of Formula B in the presence of cesium carbonate and potassium iodide. In an exemplary embodiment, the compound of Formula A is reacted with about 1.2 to about 2 molar equivalents, about 1.2 to about 1.8 molar equivalents, or about 1.5 molar equivalent of the compound of Formula B in the presence of about 1.1 to about 1.5 molar equivalents of cesium carbonate and about an equivalent molar amount of potassium iodide to provide the compound of Formula C.

[0320] In some embodiments, Hal is selected from Cl, Br and I. In some embodiments, Hal is Br.

[0321] In some embodiments, the rearrangement is a [1,3]* rearrangement.

[0322] In some embodiments, the conditions to induce a rearrangement of the compound of Formula C to provide the compound of Formula D are any suitable conditions to induce a rearrangement of the compound of Formula C to provide the compound of Formula D known in the art. In some embodiments, the conditions to induce a rearrangement of the compound of Formula C to provide the compound of Formula D comprise using one or more of heat (thermal activation), Lewis Acids (including but not limited to aluminum trichloride (AICI3), boron trifluoride, titanium tetrachloride, and zinc chloride), and sorbents (including but not limiting to magnesium silicate (such as Florisil®), silica and alumina). In some embodiments, the conditions to induce a rearrangement of the compound of Formula C to provide the compound of Formula D comprise using magnesium silicate (e.g., Florisil®).

[0323] In some embodiments, the conditions to induce a rearrangement of the compound of Formula C to provide the compound of Formula D comprise a suitable inert solvent. In some embodiments, the inert solvent is selected from esters such as ethyl acetate, aliphatic or cyclic ethers such as dioxane, hydrocarbon solvents such as n-heptane, benzene, toluene or xylene, halogenated solvents such as chlorobenzene, formamides such as dimethylformamide (DMF), and sulfoxides such as dimethyl sulfoxide (DMSO). In some embodiments, the inert solvent is ethyl acetate or toluene. In some embodiments, the inert solvent is toluene.

[0324] In some embodiments, the compound of Formula C is subjected to the conditions to induce a rearrangement of the compound of Formula C to provide the compound of Formula D at a temperature and a time forthe rearrangement of the compound of Formula C to provide the compound of Formula D. As representative, non-limiting examples, the temperature and time to induce a rearrangement of the compound of Formula C to provide the compound of Formula D is about 50°C to about 150°C, about 60 °C to about 120 °C, about 80 °C to about 120 °C, about 100 °C to about 120 °C, or about 80 °C, 90 °C, 100 °C, 110 °C, or 120 °C for about 0.5 to about 4 hours, about 1 hour to about 3.5 hours, about 1 hour to about 3 hours, about 1.5 hours to about 2.5 hours or about 1, about 2 hours, about 3 hours or about 4 hours. In some embodiments, the temperature and time to induce a rearrangement of the compound of Formula C to provide the compound of Formula D is about 80 °C to about 120 °C, or about 110 °C, for about 1.5 hours to about 2.5 hours or about 2 hours.

[0325] In an exemplary embodiment, the process comprises subjecting the compound of Formula Cto magnesium silicate such as Florisil® to induce a rearrangement to provide a compound of Formula D.

[0326] In some embodiments, the process comprises subjecting the compound of Formula C to about 3 to about 20 weight equivalents, about 3 to about 15 weight equivalents, about 3 to about 12 weight equivalents, about 3 to about 12 weight equivalents, about 3 to about 10 weight equivalent, or about 5 to about 12 weight equivalents; or about 3 weight equivalents, about 5 weight equivalents, about 10 weight equivalents, about 15 weight equivalents or about 20 weight equivalents of magnesium silicate such (e.g. Florisil®) to induce a rearrangement to provide a compound of Formula D.

[0327] In some embodiments, the compound Formula D is reacted with an excess amount (for example, about 1. 2 to about 2.5 molar equivalents, about 1.2 to about 2 molar equivalents, about 1.2 to about 1.8 molar equivalents, or about 1.5 molar equivalents) of the compound of Formula E to provide the compound of Formula I.

[0328] In some embodiments, the compound of Formula D is reacted with compound of Formula E in the presence of a reducing agent, in a suitable inert solvent at a temperature and a time for the reaction of compound of Formula A with the compound of Formula E to provide the compound of Formula I. In some embodiments, the inert solvent is selected from alcohols such as methanol or ethanol, aliphatic or cyclic ethers such as diethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran or dioxane, esters such as ethyl acetate, hydrocarbon solvents such as n-heptane, benzene, toluene or xylene, halogenated solvents such as methylene chloride (DCM), chloroform, carbon tetrachloride and chlorobenzene, formamides such as dimethylformamide (DMF), and sulfoxides such as dimethyl sulfoxide (DMSO). In some embodiments, the inert solvent is selected from alcohols such as methanol or ethanol. In some embodiments, the inert solvent is methanol.

[0329] As representative, non-limiting examples, the temperature and time for reacting the compound of Formula D with the compound of Formula E in the presence of a reducing agent is about 40 °C to about 80 °C, about 50 °C to about 80 °C, about 60 °C to about 80 °C or about 50 °C, about 60 °C, about 70 °C, or about 80 °C for about 5 minutes to about 24 hours. In some embodiments, the temperature and time for reacting the compound of Formula D with the compound of Formula E in the presence of a reducing agent is about 60 °C to about 80 °C or about 60 °C about 70 °C, or about 80 °C for about 5 minutes to about 24 hours. In some embodiments, the temperature and time are selected based on the steric hindrance of the amine, with the more sterically hindered the amine, the longer the reaction time and higher the temperature that is used as would be known to those skilled in the art.

[0330] In some embodiments, the compound of Formula D is reacted with the compound of Formula E in the presence of any suitable reducing agent known in the art. Forexample, in some embodiments, the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, potassium borohydride and sodium triacetoxyborohydride. In some embodiments, the reducing agent is sodium borohydride or sodium triacetoxyborohydride. In some embodiments, the reducing agent is sodium borohydride.

[0331] In an exemplary embodiment, the compound of Formula D is reacted with a compound of Formula E in the presence of sodium borohydride.

[0332] In some embodiments, the compound of Formula A is commercially available or can be prepared from commercially available starting material using methods known in the art. For example, the compound of Formula A is prepared using modified methods disclosed in Du Z-T et al, 2010.

[0333] Therefore, in some embodiments, the process further includes reacting a compound of Formula A'with a Lewis acid to provide a compound of Formula A. In some embodiments, R3ais H, and the process further includes reacting a compound of Formula A'with a Lewis acid to provide a compound of Formula A.

[0334] In some embodiments, the compound Formula A is reacted with an excess amount (for example, about 1.5 to about 5 molar equivalents, about 2 to about 4 molar equivalents, about 2.5 to about 3.5 molar equivalents, or about 3 molar equivalents) of the Lewis acid to provide the compound of Formula A or salt thereof.

[0335] In some embodiments, the compound of Formula A' is reacted with a Lewis acid in a suitable inert solvent at a temperature and a time for the reaction of compound of Formula A' with the Lewis Acid to provide the compound of Formula A. In some embodiments, the inert solvent is selected from aliphatic or cyclic ethers such as diethyl ether, diethyl ether, methyl tert-butyl ether (MTBE), tetra hydrofuran or dioxane, esters suchas ethyl acetate, hydrocarbon solvents such as n-heptane, benzene, toluene or xylene, halogenated solvents such as methylene chloride (DCM), chloroform, carbon tetrachloride and chlorobenzene, formamides such as dimethylformamide (DMF), and sulfoxides such as dimethyl sulfoxide (DMSO). In some embodiments, the inert solvent is selected from halogenated solvents such as methylene chloride (DCM), chloroform, carbon tetrachloride and chlorobenzene. In some embodiments, the inert solvent is methylene chloride.

[0336] In some embodiments, the compound of Formula A' is reacted with the Lewis acid in the inert solvent at a temperature of about 0 °C to about 10 °C or about 5 °C to about 10 °C or about 5 °C to form for about 5 minutes to about 20 minutes, about 10 minutes to about 15 minutes, or about 15 minutes to form a reaction mixture, and the reaction mixture is allowed to warm to about 18 °C to about 25 °C, about 20 °C to about 25 °C or room temperature for about 12 hours to about 36 hours, about 18 hours to about 30 hours, about 18 hours to about 28 hours or about 24 hours to provide the compound of Formula A.

[0337] In some embodiments, the compound of Formula A' is reacted with any suitable Lewis acid known in the art. For example, in some embodiments, the Lewis acid is selected aluminum trichloride (AICI3), boron trifluoride (BF3), titanium tetrachloride, and zinc chloride. In some embodiments, the Lewis acid is selected aluminum trichloride (AICI3).

[0338] A person skilled in the art would also appreciate that in the compounds of Formula I provided by the process of the application wherein R1comprises an allyl group covalently attached to the remaining portion of the compound of Formula I through the methylene as defined above can be further reacted using methods known in the art to provide further compounds of Formula I wherein R1is as defined above for compounds of Formula I. Similarly, a person skilled in the art would also appreciate that in the compounds of Formula I wherein R2is H provided by the process of the application can be further reacted using methods known in the art to provide further compounds of Formula I wherein R2is other than H as defined above for compounds of Formula I.

[0339] In some embodiments, the compounds of Formula I provided by the process of the application wherein R1comprises an allyl group covalently attached to the remaining portion of the compound of Formula I through the methylene as defined above are hydrogenated in the presence of a suitable catalyst such as palladium on carbon (Pd / C) and hydrogen gas to provide compounds of Formula I wherein R1comprises the corresponding alkyl or alkylene groups (e.g., R1is selected from C2-16alkyl, C2-10alkyleneC6-10aryl, C2-10alkyleneC3-12cycloalkyl, C2-10alkyleneC3-12heterocycloalkyl, C2-10alkyleneC5-12heteroaryl and C2-10alkyleneY1R7 including substituted version thereof as defined above).

[0340] The compounds of the present application can also be prepared by various synthetic processes known in the art. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art.

[0341] In some embodiments, the compounds of Formula are synthesized using methods known in the art, for example, using the synthetic procedures disclosed in EP4219450A1 and / or WO2021112574A1.

[0342] The compounds of Formula I generally can also be prepared according to the processes illustrated in the Schemes below. In the structural formulae shown below the variables are as defined in Formula I unless otherwise stated. A person skilled in the art would appreciate that many of the reactions depicted in the Schemes below would be sensitive to oxygen and water and would know to perform the reaction under an anhydrous, inert atmosphere if needed. Reaction temperatures and times are presented for illustrative purposes only and may be varied to optimize yield as would be understood by a person skilled in the art.

[0343] Accordingly, in some embodiments, the compounds of Formula I are prepared as shown in Scheme 1.Scheme 1

[0344] Therefore, a compound of Formula F is reacted with an amino compound of Formula E in combination with formaldehyde in a suitable solvent such as methanol and at a suitable temperature such as about 50°C to about 80°C to provide the compound of Formula I.

[0345] In some embodiments, compounds of Formula I are prepared as shown in Scheme 2.Scheme 2

[0346] Therefore, in some embodiments, a compound of Formula F is formylated to provide a compound of Formula G using any suitable formylation conditions known in the art, such as Vilsmeier-Haack reaction conditions or Duff reactions conditions. The compound of Formula G is then reacted with an amino compound of Formula E in a suitable solvent and at a suitable temperature such as about 20°C to about 80°C to provide the compound of Formula I.

[0347] In some embodiments, compounds of Formula I are prepared from compounds of Formula I wherein R1is halo as shown in Scheme 3.OR2OR2Scheme 3

[0348] Therefore, a compound of Formula I wherein R1is halo is coupled with a suitable R1precursor coupling reagent including but not limited to R1B(OH)2, R1Sn(alkyl)3, R1Si(alkyl)(Hal)'2, R1ZnHal", R1MgHal'" wherein Hal', Hal" and Hal'" are independently selected from suitable halogens in the presence of a suitable catalyst such as palladium under suitable coupling conditions such a Suzuki cross coupling, Stille, Hiyama, Negishi or Kumana reaction conditions respectively; or a compound of Formula I wherein R1is halo is coupled with a suitable R1precursor coupling reagent comprising an allyl group in the presence of suitable catalyst such as palladium under suitable coupling conditions such as Heck reaction conditions.

[0349] In some embodiments, compounds of Formula I are prepared from compounds of Formula G wherein R1is halo (e.g., compound of Formula G') as shown in Scheme 4.Scheme 4

[0350] Therefore, in some embodiments, a compound of Formula G' wherein Halo' is a suitable halogen is coupled with a suitable boronic acid compound of Formula H wherein R is, for example, H, under suitable palladium catalyzed cross coupling conditions such as, Suzuki cross coupling conditions, to provide the compound of Formula J which is then coupled with an amino compound of Formula E in the presence of a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride, potassium borohydride or sodium triacetoxyborohydride, to provide the compounds of Formula I.

[0351] A person skilled in the art would appreciate that the compounds of Formula I wherein R2is H provided by processes described above can be further reacted using methods known in the art to provide further compounds of Formula I wherein R2is as defined above for compounds of Formula I.

[0352] It would be appreciated by a person skilled in the art that deuterated of compounds of Formula I and pharmaceutically acceptable salts and / or solvates thereof, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using suitable deuterated reagents and / or intermediates, such as, for example, sodium borodeuteride.

[0353] In some embodiments, compounds of Formula I, wherein one or more of R1-R6are deuterium or comprises deuterium are available, for example, using a hydrogendeuterium exchange reaction on a suitable starting substrate, wherein this exchange reaction is catalyzed by Pd / C in D2O as described in Esaki, H. et al. Tetrahedron, 2006, 62:10954-10961, and modifications thereof known to a person skilled in the art.

[0354] Amide bond forming conditions comprise any known method for the coupling of carboxylic acids and amines that is compatible with the intermediates and products shown in the above Schemes orthat may be used to prepare a compound of the application. Known methods to prepare amides by the coupling of carboxylic acids and amines comprise use of either a coupling reagent or by prior conversion of the carboxylic acid into an activated derivative. Coupling reagents include, but are not limited to, any of the known peptide coupling reagents, such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) diisopropylcarbodiimide (DIC), hexafluorophosphate benzotriazole tetramethyl uranium (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and propanephosphonic acid anhydride.

[0355] In some embodiments, racemization of an enantiomer of a carboxylic acid occurs during amide bond formation using coupling reagents. In some embodiments, racemization is circumvented with 'racemization suppressing' additives such as the triazoles 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt) and ethyl cy a n o hyd roxy i m i n oacet ate (Oxy m a).

[0356] Nucleophilic displacement reaction conditions comprise any known method for the reaction of a nucleophile to displace a leaving group to form a bond that is compatible with the intermediates and products shown in the above Schemes or that may be used to prepare a compound of the application. In some embodiments, such conditions comprise combining reactants in the presence of a base in a suitable solvent.

[0357] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T. W. Green, P. G. M. Wuts, Wiley-lnterscience, New York, (1999).

[0358] It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive OrganicTransformations- A Guide to Functional Group Preparations” R. C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry", March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994).

[0359] Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0360] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

[0361] Generally, the reactions described above are performed in a suitable inert organic solvent and at temperatures and for times that will optimize the yield of the desired compounds. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetra hydrofuran (THF), toluene, and the like.

[0362] Salts of compounds of Formula I may be formed by methods known to those of ordinary skill in the art, for example, by reacting compounds of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0363] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available hydroxy or amino groups may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).

[0364] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[0365] The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0366] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0367] Specific enantiomers or diastereomers of the compounds of the application are available by using corresponding single enantiomers or diastereomers of the corresponding starting materials.EXAMPLES

[0368] The following non-limiting examples are illustrative of the present application:A. ChemistrySynthesis of exemplary compounds of the applicationGeneral

[0369] Chemical shifts in1H NMR and13C NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (TMS), with calibration to TMS (8H, 8C 0.0) or the residual solvent peaks according to values reported by Gottlieb et al. (chloroform: 8H7.26, 8C77.16; acetone: 8H2.05, 8C29.84, 206.26; methanol: 8H3.31, 8C49.00; DMSO: 8H2.50, δC39.52) (Gottlieb, H. G et al. 1997). When peak multiplicities are given, the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; sept., septet; dd, doublet of doublets; m, multiplet; br, broad; app., apparent; gem, geminal.1H NMR spectra were acquired at 400 or 700 MHz with a default digital resolution (Bruker™ parameter: FIDRES) of 0.22 and 0.15 Hz / point, respectively. Coupling constants reported herein therefore have uncertainties of ±0.4 Hz and ±0.3 Hz, respectively. All assignments of protons and carbons relied on data from 2-dimensional NMR experiments including COSY, HMQC, and HMBC. The13C NMR spectra provided herein (13C{1H} DEPTQ-135; Bruker pulse program deptqgpsp) show CH and CH3carbon signals above the baseline and C and CH2carbons below the baseline. Melting points (mp) are uncorrected. Reactions were carried out at room temperature (rt) if temperature is not specified. Compounds purified by normal or reversephase flash chromatography used Teledyne CombiFlash Rf+ and NextGen 300+ purification systems (www.teledyneisco.com) with pre-packed silica cartridges (either 40–63 μM or 20–40 μM particle size). High-resolution mass spectrometry (HRMS) data was obtained using a Bruker micrOTOF II system with electrospray ionization (ESI) and paired with an Agilent HPLC and UV detector. Solvents used were anhydrous unless noted and dried by solvent purification system (SPS) or using 4A molecular sieves.Synthesis of Precursor Aldehyde 4geranyl bromide (1.5 eq)Methyl 2-formyl-3-hydroxy-5-methoxybenzoate (2)OMeO OH O1 70% BRSM 2

[0370] 2 was synthesized via modified procedure (Du Z-T et al, 2010). Aldehyde 1 (13.9 g, 224 mmol, 1 eq.) was added to a dry 2-neck round bottom flask and secured under an argon atmosphere. DCM (125 mL) was added to the flask and the mixture stirred at 0 °C for 10 minutes. AICI3(24.9 g, 187 mmol, 3 equiv) was added to the mixture and the reaction re-secured under argon atmosphere. The resultant solution was stirred for 24 h slowly warming from 0 °C to room temperature. The solution was re-cooled to 0 °C, diluted further with DCM, and then cold ice water was slowly added to the reaction with rapid stirring. The collected mixture was transferred to a separatory funnel and extracted with DCM three times. The collected organic fractions were washed with 5% HCI, water, brine and then the organic fraction was dried over Na2SO4. The crude residue was filtered and concentrated in vacuo. The isolated crude material was purified by normal-phase flash chromatography EtOAc: Hexanes isolated 1 as a white solid (6.42 g, 49%)

[0371] 1H NMR (400 MHz, CDCI3) 5 12.74 (s, 1H), 10.44 (s, 1H), 7.02 (d, J= 2.5 Hz, 1 H), 6.56 (d, J = 2.5 Hz, 1 H), 3.95 (s, 3H), 3.88 (s, 3H). Spectral data is consistent with data previously reported (Mashiko, T et al. 2021.(E)-methyl 3-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-2-formyl-5-methoxybenzoate (3)geranyl bromide (1.5 eq)Cs2CO3(1.2 eq) KI (1 eq) DMFrt94%

[0372] Aldehyde 2 (5.0 g, 23.8 mml, 1 equiv.) was added to an oven-dried round bottom flask along with Cs2CO3(9.32 g, 28.6 mmol, 1.2 equiv.) and KI (3.95 g, 23.8 mmol, 1 equiv.). The flask was secured under argon Cand charged with DMF (80 ml_). The mixture was stirred at room temperature and geranyl bromide (7.75 g, 35.7 mmol, 1.5 equiv.) was added dropwise via syringe. The reaction was stirred at room temperature for 24 h until TLC indicated completed consumption of 2. The mixture was diluted with water and extracted with ethyl acetate three times. The combined organic fraction was washed with water five times, brine once, dried with Na2SO3, filtered and concentrated in vacuo. The crude isolate was purified by flash column chromatography (25% EtO Ac: hexanes) to collect 3 as a pale yellow oil (7.97 g, 97%).

[0373] 1H NMR (400 MHz, CDCI3): 10.31 (d, J = 0.7 Hz, 1H), 6.53 (dd, J = 2.2, 0.7 Hz, 1H), 6.50 (d, J= 2.2 Hz, 1H), 5.45 (m, 1H), 5.10 - 5.02 (m, 1H), 4.62 (d, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.16 -2.05 (m, 4H), 1.74 (d, J= 1.4 Hz, 3H), 1.66 (d, J= 1.4 Hz, 3H), 1.60 (d, J= 1.4 Hz, 3H).(E)-methyl 4-(3,7-dimethylocta-2,6-dien-1-yl)-2-formyl-3-hydroxy-5-methoxybenzoate (4)Florisil toluene110 °C25%

[0374] Aldehyde 3 (1.03 g, 2.97 mmol, 1 equiv.) was added to a dried round bottom flask 2-neck flask. The flask was equipped with a reflux condenser and secured under an Ar atmosphere. Anhydrous toluene was added, followed by the quick addition of Florisil® (10.3 g, 10 wt equiv.), and the set-up re-secured under an atmosphere of Ar. The slurry was stirred at 110 °C for 2 h when TLC indicated completed consumption of 3. The reaction was cooled to room temperature and the Florisil® filtered off. The pad of Florisil® was rinsed thoroughly with ethyl acetate. The organic solution collected was concentrated in vacuo to yield the crude residue which was purified by flash column chromatography (15% EtO Ac: hexanes). Aldehyde 4 was isolated as a white solid (0.256 g, 25%).1H NMR (400 MHz, CDCh) 12.68 (s, 1H), 10.48 (s, 1H), 7.05 (s, 1 H), 5.16 (tq, J = 7.2, 1.3 Hz, 1H), 5.08 -5.01 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.38 (d, J= 7.1 Hz, 2H), 2.09 -2.00 (m, 2H), 1.99 -1.92 (m, 2H), 1.77 (d, J = 1.3 Hz, 3H), 1.63 (d, J = 1.4 Hz, 3H), 1.56 (d, J = 1.2 Hz, 3H). General Procedure Ao o4

[0375] Aldehyde 4 (1 equiv.), or derivative of, containing the same ortho aldehydeester functionality, was added to a sealed vial. Amine (1.5 equiv.) was added to the vial followed by methanol (0.2M) and the vial sealed with cap. The reaction mixture was heated in methanol at 60 °C until TLC indicated complete formation of the new imine species. At this point, NaBH4(2.75 equiv.) was added, and the reaction was returned to heat. Careful monitoring by TLC indicated complete consumption of the intermediate imine and the reaction was quenched with a few drops of saturated NaHCO3If solids crashed out they could be collected by filtration washing thoroughly with water and pentane to yield desired product. Alternatively, the reaction mixture could be subjected to aqueous work-up extracting the water / methanol reaction with ethyl acetate three times. The collected organic layers were washed with brine, then dried with Na2SO4, filtered and concentrated in vacuo. The collected crude reside was purified by reverse phase C-18 column chromatography (10%^-100% MeCN:water) to yield the desired pure product.Example 1: Synthesis of 1-1O

[0376] Following General Procedure A: aldehyde 4 (20 mg, 0.06 mmol), cyclopropylmethanamime (6 mg, 0.09 mmol), MeOH (0.3 mL), NaBH4(6 mg, 0.16 mmol). Following aqueous workup 1-1 was isolated as a white solid (14 mg, 64%).1H NMR (700 MHz, CDCh): 86.97 (s, 1H), 6.38 (s, 1 H), 5.25 (tq, J = 7.2, 1.3 Hz, 1 H), 5.04 (tq, J = 7.0, 1.5 Hz, 1H), 4.41 (s, 2H), 3.50 (d, J= 7.1 Hz, 2H), 3.47 (d, J= 7.2 Hz, 2H), 2.15 -2.01 (m, 4H), 1.82 (d, J = 1.3 Hz, 3H), 1.67 (d, J = 1.5 Hz, 3H), 1.59 (d, J = 1.3 Hz, 3H), 1.03 (tt, J = 7.6, 4.7 Hz, 1H), 0.59 - 0.50 (m, 2H), 0.31 (dd, J= 6.1, 4.6 Hz, 2H). HRMS (ESI-TOF) m / z: [M -H]- calcd for C23H30NO3368.2231; Found 368.2226.Example 2: Synthesis of 1-2

[0377] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 2- (pyrrolid in-1-yl)ethan-1-amine (7 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.16 mmol). After aqueous workup and purification, I-2 was isolated as a white powder (4 mg, 20%).1H NMR (700 MHz, CDCh): 86.95 (s, 1H), 5.28 -5.18 (m, 1H), 5.04 (tq, J= 6.8, 3.4 Hz, 1H), 4.36 (s, 2H), 3.85 (s, 3H), 3.74 (t, J = 6.7 Hz, 2H), 3.49 (d, J = 7.1 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 2.58 (d, J = 6.1 Hz, 5H), 2.09 (dt, J = 24.8, 7.3 Hz, 5H), 1.82 (s, 3H), 1.80 - 1.74 (m, 4H), 1.67 (d, J= 1.6 Hz, 3H), 1.59 (s, 3H). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C25H35N2O3 411.2653; Found 411.2644.Example 3: Synthesis of 1-3

[0378] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), pyridinylamine (7.0 mg, 0.07 mmol), MeOH (0.22 ml_), NaBH4(4.5 mg, 0.12 mmol). I-3 was isolated as a white solid (8 mg, 47%).1H NMR (700 MHz, Chloroform-d) 0 8.53 - 8.47 (m, 2H), 7.18 - 7.12 (m, 2H), 7.01 (s, 1H), 6.78 (s, 1H), 5.24 (tq, J= 7.2, 1.3 Hz, 1H), 5.02 (tdt, J= 5.7, 2.8, 1.4 Hz, 1H), 4.78 (s, 2H), 4.16 (s, 2H), 3.87 (s, 3H), 3.54 - 3.44 (m, 2H), 2.13 -2.02 (m, 4H), 1.80 (d, J= 1.3 Hz, 3H), 1.65 (d, J= 1.4 Hz, 3H), 1.57 (d, J= 1.3 Hz, 3H). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C25H30N2O3405.2184; Found 405.2177.Example 4: Synthesis of 1-4

[0379] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 2-thiophene-ethylamine (8 mg, 0.07 mmol), MeOH (0.3 ml_), NaBH4(4.5 mg, 0.12 mmol). I-4 was isolated as a white solid (5 mg, 25%).

[0380] 1H NMR (700 MHz, Chloroform-d) 0 7.06 (dd, J = 5.1, 1.2 Hz, 1H), 6.89 (s, 1H), 6.83 (dd, J= 5.1, 3.4 Hz, 1H), 6.78 (dd, J= 3.4, 1.1 Hz, 1H), 5.91 (s, 1H), 5.17 (tq, J = 7.1, 1.3 Hz, 1H), 4.96 (ddq, J = 6.9, 5.4, 1.5 Hz, 1H), 4.10 (s, 2H), 3.81 (t, J = 7.2 Hz, 2H),3.78 (s, 3H), 3.42 (d, J = 7.1 Hz, 2H), 3.18 - 3.10 (m, 2H), 2.02 (dq, J= 14.0, 7.3 Hz, 4H), 1.74 (d, J= 1.3 Hz, 3H), 1.60 (d, J= 1.6 Hz, 3H), 1.52 (d, J= 1.3 Hz, 3H).. HRMS (ESI-TOF) m / z: [M - H]- calcd for C25H30NO3S 424.1952; Found 424.1942.Example 5: Synthesis of 1-5o

[0381] Following General Procedure A: aldehyde 4 (20 mg, 0.06 mmol), propylamine (5 mg, 0.09 mmol), MeOH (0.3 ml_), NaBH4 (6 mg, 0.16 mmol). I-5 was isolated as a white solid (5 mg, 25%).1H NMR (400 MHz, CDCb): 5. HRMS (ESI-TOF) m / z: [M - H]’ calcd for C22H30NO3 356.2231; Found 356.2227.1H NMR (700 MHz, Chloroform-d) 0 6.97 (s, 1H), 6.03 (s, 1 H), 5.25 (tq, J = 7.2, 1.3 Hz, 1 H), 5.04 (tdd, J = 6.9, 3.4, 1.9 Hz, 1 H), 4.27 (s, 2H), 3.85 (s, 3H), 3.56 (dd, J = 8.0, 6.6 Hz, 2H), 3.54 - 3.45 (m, 2H), 2.17 - 2.06 (m, 4H), 1.82 (d, J = 1.3 Hz, 3H), 1.73 - 1.66 (m, 5H), 1.59 (d, J = 1.3 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). Example 6: Synthesis of 1-6o

[0382] Following General Procedure A: aldehyde 4 (15 mg, 0.06 mmol), aniline (6 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4 (5 mg, 0.12 mmol). KCB-2010 was isolated as a white solid (3 mg, 18%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C25H28NO3 390.2077; Found 390.2084.1H NMR (700 MHz, DMSO-cfe) 07.98 - 7.72 (m, 2H), 7.51 - 7.38 (m, 2H), 7.16 (dd, J = 8.0, 6.7 Hz, 1H), 5.21 - 5.10 (m, 1H), 5.10 - 4.96 (m, 1H), 4.82 (s, 2H), 3.84 (s, 3H), 3.36 (d, J = 7.3 Hz, 3H), 2.50 (p, J = 1.9 Hz, 2H), 2.00 (q, J = 7.5 Hz, 2H), 1.91 (dd, J = 9.0, 6.3 Hz, 2H), 1.74 (d, J = 1.3 Hz, 3H), 1.59 (d, J = 1.5 Hz, 3H), 1.52 (d, J = 1.3 Hz, 3H).Example 7 Synthesis of 1-7

[0383] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), benzylamine (9 mg, 0.09 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.12 mmol). I-7 was isolated as a whitesolid (14 mg, 81%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C26H30NO3404.2231; Found 404.2241.1H NMR (400 MHz, Chloroform-c / ) 07.36 - 7.20 (m, 5H), 7.00 (s, 1 H), 5.27 - 5.19 (m, 1H), 5.02 (ddq, J= 6.8, 5.3, 1.4 Hz, 1H), 4.75 (s, 2H), 4.17 (s, 2H), 3.84 (s, 3H), 3.49 (d, J= 7.1 Hz, 2H), 2.14 - 1.99 (m, 4H), 1.80 (d, J= 1.3 Hz, 3H), 1.65 (d, J= 1.4 Hz, 3H), 1.57 (d, J= 1.4 Hz, 3H).Example 8: Synthesis of 1-8 =

[0384] Following General Procedure A: aldehyde 4 (30 mg, 0.09 mmol), 3-(3-Butyn-1-yl)-3 / - / -diazirine-3-ethanamine (18 mg, 18 L, 0.13 mmol), MeOH (0.5 ml_), NaBH4(9 mg, 0.24 mmol). l-8was isolated as a white solid (21 mg, 62%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C26H32N3O3434.2449; Found 434.2448.1H NMR (700 MHz, Chloroform-c / ) 06.96 (s, 1 H), 5.94 - 5.86 (m, 1 H), 5.26 (ddt, J = 8.5, 7.2, 1.3 Hz, 1 H), 5.04 (ddq, J = 6.9, 5.4, 1.5 Hz, 1 H), 4.24 (s, 2H), 3.86 (s, 3H), 3.54 (t, J = 7.2 Hz, 2H), 3.52 - 3.47 (m, 2H), 2.62 (s, 1 H), 2.17 - 2.07 (m, 3H), 2.02 (td, J= 7.3, 2.6 Hz, 2H), 1.98 (t, J= 2.6 Hz, 1H), 1.82 (d, J = 1.3 Hz, 3H), 1.78 (t, J = 7.2 Hz, 2H), 1.71 (t, J = 7.3 Hz, 2H), 1.68 (d, J = 1.4 Hz, 3H), 1.60 (d, J = 1.4 Hz, 3H).Example 9: Synthesis of 1-9o

[0385] Following General Procedure A with a slight modification to include sodium acetate and increased equivalents: aldehyde 4 (15 mg, 0.04 mmol), methylamine hydrochloride (14.5 mg, 0.22 mmol), sodium acetate (18 mg, 0.22 mmol), MeOH (0.2 ml_), NaBH4(6 mg, 0.16 mmol). I-9 was isolated as a white solid (5 mg, 36%). HRMS (ESI-TOF) m / z: [M - H]- calcd for C20H26NO3 328.1918; Found 328.1928.1H NMR (700 MHz, Chloroform-c / ) 06.96 (s, 1H), 6.04 (s, 1H), 5.25 (tt, J= 5.7, 1.4 Hz, 1H), 5.11 -5.00 (m, 1H), 4.26 (s, 2H), 3.85 (s, 3H), 3.50 (d, J= 7.1 Hz, 2H), 3.18 (s, 3H), 2.19 -2.02 (m, 4H), 1.82 (d, J = 1.4 Hz, 3H), 1.68 (d, J = 1.5 Hz, 3H), 1.59 (d, J = 1.3 Hz, 3H).Example 10: Synthesis of 1-10

[0386] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 4-pyridineethanamine (8 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.12 mmol). 1-10 was isolated as a white solid (13 mg, 74%). HRMS (ESI-TOF) m / z: [M - H]_calcd for C26H31N2O3 419.2340; Found 419.2351.1H NMR (400 MHz, Chloroform-d) 08.52 - 8.37 (m, 2H), 7.22 -7.11 (m, 2H), 6.93 (s, 1H), 5.23 (tq, J= 7.1, 1.2 Hz, 1H), 5.03 (tdd, J= 6.8, 2.9, 1.5 Hz, 1H), 4.16 (s, 2H), 3.88 (t, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.48 (d, J = 7.1 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.06 (qd, J = 8.7, 7.3, 4.9 Hz, 4H), 1.79 (d, J = 1.3 Hz, 3H), 1.65 (d, J = 1.4 Hz, 3H), 1.57 (d, J= 1.4 Hz, 3H).Example 11: Synthesis of 1-11

[0387] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 3-pyridineethanamine (8 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.12 mmol). 1-11 was isolated as a white solid (13 mg, 74%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C26H31N2O3 419.2340; Found 419.2342.1H NMR (400 MHz, Chloroform-d) 08.47 - 8.40 (m, 2H), 7.59 (dt, J= 7.9, 2.0 Hz, 1H), 7.21 (ddd, J= 7.8, 4.8, 0.8 Hz, 1H), 6.93 (s, 1H), 6.81 (s, 1H), 5.23 (tq, J = 7.1, 1.3 Hz, 1H), 5.03 (tdd, J = 6.8, 3.0, 1.5 Hz, 1H), 4.17 (s, 2H), 3.90 - 3.80 (m, 5H), 3.48 (d, J = 6.9 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.14 - 2.00 (m, 4H), 1.80 (d, J = 1.4 Hz, 3H), 1.65 (d, J = 1.3 Hz, 3H), 1.58 (d, J = 1.3 Hz, 3H).Example 12: Synthesis of 1-12

[0388] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 2-pyridineethanamine (8 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.12 mmol). 1-12 was isolated as a white solid (10 mg, 56%). HRMS (ESI-TOF) m / z: [M - H]_calcd for C26H31N2O3 419.2340; Found 419.2347.1H NMR (700 MHz, Chloroform-d) 08.56 - 8.50 (m, 1H), 7.58 (td, J = 7.6, 1.8 Hz, 1H), 7.22 (dt, J = 7.8, 1.1 Hz, 1H), 7.13 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 6.95 (s, 1H), 6.05 (s, 1H), 5.27 - 5.19 (m, 1H), 5.02 (ddt, J= 6.9, 5.4, 1.4 Hz, 1H), 4.17 (s,2H), 4.01 (t, J = 7.3 Hz, 2H), 3.85 (d, J = 0.9 Hz, 3H), 3.48 (d, J = 6.1 Hz, 2H), 3.16 (t, J = 7.3 Hz, 2H), 2.14 - 2.03 (m, 4H), 1.80 (t, J = 1.2 Hz, 3H), 1.66 (d, J = 1.6 Hz, 3H), 1.58 (d, J = 1.4 Hz, 3H).Example 13: Synthesis of 1-13

[0389] Aldehyde bearing ortho-prenyl phenol (30 mg, 0.11 mmol, 1 equiv.) was added to a dried sealed tube, with hydroxylamine hydrochloride (11 mg, 0.16 mmol, 1.5 equiv.) and dissolved in absolute ethanol (0.4 ml_). The vial was secured under argon, capped and heated at 40 °C until oxime formation was complete. With the oxime formed, the reaction was cool to room temperature and HCI was added to the mixture (36 pL, 0.43 mmol, 4 equiv.) and then Zn dust (18 mg, 0.27 mmol, 2.5 equiv.) was added to the solution. The Zn containing slurring was stirred at room temperature for 30 min. 6M NaOH was added dropwise to quench the reaction and was stopped when pH 10-11 was achieved. The slurry was stirred for 15 minutes to generate the Zn salts and then acetonitrile was added to dilute the solution. The mixture was carefully concentrated in vacuo and taken up in water. The aqueous solution was extracted five times with ethyl acetate. The ethyl acetate fractions were washed with brine, and dried over Na2SO3, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography (12 g C18 column, 10— >100% MeCN / water) to isolate 1-13 as a white solid (4 mg, 16%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C14H16NO3246.1136; Found 246.1148.Example 14: Synthesis of 1-14

[0390] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 2-thiazolylethylamine (8 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.16 mmol). 1-14 was isolated as a white solid (12 mg, 66%). HRMS (ESI-TOF) m / z: [M - H]_calcd for C24H29N2O3S 425.1904; Found 425.1910.1H NMR (700 MHz, Chloroform-d) 5 7.70 (dd, J = 3.2, 1.4 Hz, 1H), 7.20 (dt, J= 3.3, 1.1 Hz, 1H), 6.95 (d, J= 1.4 Hz, 1H), 6.17 (s, OH), 5.29 - 5.16 (m, 1H), 5.09 - 4.92 (m, 1 H), 4.20 (s, 2H), 4.04 (t, J = 6.9 Hz, 2H), 3.87 - 3.81 (m, 3H), 3.49 (d, J = 7.2 Hz, 2H), 3.41 (t, J = 7.0 Hz, 2H), 2.16 - 2.00 (m, 4H), 1.83 - 1.76 (m, 3H), 1.72 - 1.64 (m, 3H), 1.59 (s, 3H).Example 15: Synthesis of 1-15

[0391] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), N, N-dimethylethylenediamine (6 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.12 mmol). I-15 was isolated as a white solid (9 mg, 52%). HRMS (ESI-TOF) m / z: [M - H]_calcd for C23H33N2O3 385.2497; Found 385.2506.1H NMR (700 MHz, Chloroform-d) 0 6.91 (s, 1H), 6.45 (s, 1H), 5.22 (tq, J = 7.1, 1.3 Hz, 1H), 5.04 (ddt, J = 7.0, 5.5, 1.4 Hz, 1H), 4.35 (s, 2H), 3.83 (s, 3H), 3.71 (t, J = 6.5 Hz, 2H), 3.52 - 3.41 (m, 2H), 2.56 (t, J = 6.5 Hz, 2H), 2.27 (s, 6H), 2.15 - 2.00 (m, 4H), 1.81 (d, J = 1.3 Hz, 3H), 1.67 (q, J = 1.3 Hz, 3H), 1.59 (d, J = 1.3 Hz, 3H).Example 16: Synthesis of 1-17

[0392] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), benzenepropanamine (9 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5.0 mg, 0.12 mmol). 1-17 was isolated as a white solid (12 mg, 63%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C28H34NO3432.2544; Found 432.2541.1H NMR (400 MHz, Chloroform-d) 07.32 - 7.22 (m, 1H), 7.22-7.11 (m, 3H), 6.97 (s, 1H), 5.25 (tq, J = 7.2, 1.2 Hz, 1H), 5.04 (tq, J = 5.5, 1.6 Hz, 1H), 4.27 (s, 2H), 3.84 (s, 3H), 3.65 (t, J = 7.2 Hz, 2H), 3.51 (d, J = 7.1 Hz, 2H), 2.66 (dd, J = 9.0, 6.7 Hz, 2H), 2.16-2.03 (m, 4H), 1.98 (tt, J = 7.8, 6.3 Hz, 2H), 1.82 (d, J = 1.4 Hz, 3H), 1.68 (d, J = 1.4 Hz, 3H), 1.59 (d, J = 1.4 Hz, 3H).Example 17: Synthesis of 1-18 =

[0393] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), 2-furanylethylamine (7 mg, 0.07 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.16 mmol). 1-18 was isolated as a white solid (12 mg, 71%). HRMS (ESI-TOF) m / z: [M - H]_calcd for C25H30NO4408.2180; Found 408.2170.1H NMR (400 MHz, Chloroform-d) 0 7.30 (dd, J = 1.9, 0.8 Hz, 1H), 6.95 (s, 1H), 6.25 (dd, J= 3.2, 1.9 Hz, 1H), 6.22 (s, 1H), 6.06 (dd, J= 3.2, 0.8 Hz, 1H),5.24 (ddt, J= 7.3, 5.9, 1.4 Hz, 1H), 5.03 (ddt, J= 6.8, 5.4, 1.9 Hz, 1H), 4.14 (s, 2H), 3.89 (t, J= 6.9 Hz, 2H), 3.83 (s, 3H), 3.54 - 3.43 (m, 2H), 3.04 -2.93 (m, 2H), 2.15 -2.01 (m, 4H), 1.81 (d, J= 1.3 Hz, 3H), 1.66 (d, J= 1.5 Hz, 3H), 1.58 (d, J= 1.4 Hz, 3H).Example 18: Synthesis of 1-19

[0394] Following General Procedure A: aldehyde 4 (15 mg, 0.04 mmol), ethylaminehydrochloride (11 mg, 0.13 mmol), MeOH (0.2 ml_), NaBH4(5 mg, 0.12 mmol). 1-19 was isolated as a white solid (7.1 mg, 64%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C21H28NO3 342.2075; Found 342.2066.1H NMR (400 MHz, Chloroform-d) 06.96 (s, 1H), 6.21 (s, 1H), 5.25 (ddt, J = 8.4, 7.1, 1.3 Hz, 1H), 5.04 (tq, J= 5.4, 1.6 Hz, 1H), 4.28 (s, 2H), 3.84 (s, 3H), 3.66 (q, J = 7.3 Hz, 2H), 3.57 - 3.40 (m, 2H), 2.15 - 1.99 (m, 4H), 1.82 (d, J = 1.3 Hz, 3H), 1.67 (d, J = 1.3 Hz, 3H), 1.61 - 1.51 (m, 3H), 1.25 (t, J = 7.2 Hz, 3H).Example 19: Synthesis of 1-20

[0395] Aldehyde 4 (150 mg, 0.06 mmol), 4-benzylpyrazol-2-amine (14 mg, 0.09 mmol), DOE (0.2 mL) and AcOH (4.9 pL, 0.09 mmol) were added to a sealed vial and heated at 60 °C for 5 h. NaBH(OAc)3(14 mg, 0.07 mmol) was then added and the reaction returned to heat for 22 h. Upon consumption of starting material the reaction was diluted with water, the DOE removed in vacuo, and the aqueous contents extracted three times with ethyl acetate. The organic fractions were rinsed with brine one time, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography (25 g C18 column, 10— >100% MeCN / water) to isolate I-20 as orange flaks (3.4 mg, 18%). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C28H30N3O3 456.2293; Found 456.2297.1H NMR (700 MHz, Chloroform-d) 57.55 (s, 1H), 7.36 - 7.17 (m, 4H), 6.95 (d, J = 8.0 Hz, 1H), 5.22 (t, J = 7.2 Hz, 1H), 5.00 (t, J = 6.9 Hz, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 3.46 (d, J= 7.2 Hz, 2H), 2.13 - 1.90 (m, 4H), 1.78 (s, 3H), 1.62 (d, J= 1.6 Hz, 3H), 1.56 (s, 3H).Example 20: Synthesis of I-22

[0396] Aldehyde 4 (30 mg, 0.09 mmol), 5-trifluoromethylcoumarin (30 mg, 0.13 mmol), MeOH (0.4 ml_), and 1 drop acetic acid were added to a reaction vial. The mixture was stirred at 60 °C for 1 h, at which time NaCNBH3(8 mg, 0.13 mmol) was added to the reaction. The reaction was returned to heat to continue stirring for 18 h. Solids had formed in the reaction and this were collected by vacuum filtration rinsing with water. The collected crude crystals were recrystallized from DMSO to yield KCB-2035 as white crystals (2.2 mg, 5%). HRMS (ESI-TOF) m / z: [M + H]+calcd for C29H29F3NO5+528.1992; Found 528.1992.1H NMR (700 MHz, DMSO-cfe) 5 8.13 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 9.0, 2.2 Hz, 1H), 7.80 (dd, J = 8.9, 1.9 Hz, 1 H), 6.95 (s, 1H), 6.89 (s, 1H), 5.14 (ddd, J = 8.6, 6.6, 1.6 Hz, 1H), 5.03 (tt, J = 7.0, 1.5 Hz, 1H), 4.91 (s, 2H), 3.84 (s, 3H), 3.37 (d, J = 7.4 Hz, 2H), 2.00 (q, J = 7.5 Hz, 2H), 1.91 (dd, J = 9.0, 6.3 Hz, 2H), 1.74 (d, J = 1.3 Hz, 3H), 1.59 (d, J = 1.6 Hz, 3H), 1.52 (dd, J = 1.3 Hz, 3H).

[0397] Following General Procedure A: aldehyde (20 mg, 0.06 mmol), cyclopropylmethanamime (6 mg, 0.09 mmol), MeOH (0.3 ml_), NaBH4(6 mg, 0.16 mmol). KCB-2005 was isolated as a white solid (14 mg, 64%).1H NMR (400 MHz, CDCI3): 5. HRMS (ESI-TOF) m / z: [M - H]’ calcd for C23H30NO3368.2231; Found 368.2226.Synthesis of comparator compounds

[0398] Comparator compounds can be synthesized using similar methods to those described above for synthesizing the exemplary compound of the application Example 21: Synthesis of Comparator compound C-1 (NDPIH)

[0399] Aldehyde 4 (170 mg, 0.49 mmol, 1 equiv.) was added to a dried sealed tube, with hydroxylamine hydrochloride (41 mg, 0.59 mmol, 1.2 equiv.) and dissolved in absolute ethanol (1 ml_). The vial was secured under argon, capped and heated at 40 °C until oxime formation was complete. With the oxime formed, the reaction was cool to room temperature and HCI was added to the mixture (0.16 ml_, 1.96 mmol, 4 equiv.) and then Zn dust (80 mg, 1.23 mmol, 2.5 equiv.) was added to the solution. The Zn containing slurring was stirred atroom temperature for 30 min. 6M NaOH was added dropwise to quench the reaction and was stopped when pH 10-11 was achieved. The slurry was stirred for 15 minutes to generate the Zn salts and then acetonitrile was added to dilute the solution. The mixture was carefully concentrated in vacuo and taken up in water. The aqueous solution was extracted five times with ethyl acetate. The ethyl acetate fractions were washed with brine, and dried over Na2SO3, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography (25 g C18 column, 10— >100% MeCN / water) to isolate C-1 (NDPIH) as a white solid (46 mg, 30%). LCMS ESI+ RT: 4.37 min, [M-H]:314.1763.1H NMR (700 MHz, cL-MeOD) 6.91 (s, 1H), 5.17 (tq, J= 7.2, 1.3 Hz, 1H), 5.05 - 5.01 (m, 1H), 4.31 (s, 2H), 3.85 (s, 3H), 3.42 (d, J = 7.2 Hz, 1 H), 2.06 - 2.01 (m, 2H), 1.97 - 1.92 (m, 2H), 1.78 (d, J = 1.4 Hz, 3H), 1.59 (d, J = 1.4 Hz, 3H), 1.54 (d, J = 1.3 Hz, 3H). Spectral data is consistent with previous reported data (Li, W. et al. 2015).Example 22: Synthesis of Comparator compound C-2 (Isohericerin)isohericerin O

[0400] Following General Procedure A: aldehyde 4 (98 mg, 0.28 mmol), phenethylamine (51 mg, 0.42 mmol), MeOH (1.4 mL), NaBH4(29 mg, 0.77 mmol). C-2 was isolated as a white solid (73 mg, 62%).1H NMR (400 MHz, CDCI3): 5 7.32 - 7.27 (m, 2H), 7.25- 7.23 (m, 2H), 7.23- 7.18 (m, 1H), 6.96 (s, 1H), 5.81 (br, s, 1H), 5.24 (dd, J= 7.1, 1.3 Hz, 1 H), 5.03 (tq, J = 6.8, 1.4 Hz, 1 H), 4.13 (s, 2H), 3.89 - 3.83 (m, s overlapping t, 5H), 3.49 (d, J = 7.1 Hz, 2H), 2.98 (t, J= 7.4 Hz, 1H), 2.16 - 2.04 (m, 4H), 1.81 (s, 3H), 1.67 (s, 3H), 1.59 (s, 3H). HRMS (ESI-TOF) m / z: [M - H]’ calcd for C27H32O3418.2388; Found 418.2426 Bioactivity DataExample 24: Evaluation of neuritogenic activity of the compounds of the application in primary rat cortical neurons

[0401] NDPIH (C-1) and isohericerin (C-2) were tested for their neuritogenic activity in primary rat cortical neurons, which play a role in cognition and motor function. To study the effects of NDPIH (C-1) and isohericerin (C-2) on neuritogenesis, primary cortical neurons were isolated from rat fetuses. Primary cortical neurons were treated with NDPIH (C-1) or isohericerin (C-2) for 72 h at concentrations 1000, 100, 10 and 1 nM. BDNF was tested at 50 ng / mL as a positive control and the vehicle (0.1 % DMSO) served as the untreated control. NDPIH (C-1) and isohericerin (C-2) both significantly stimulated neuritogenesis, with activity observed at concentrations as low as 10 and 1 nM, respectively (Table 2).

[0402] Exemplary compounds of the application were synthesized and the neuritogenic activity of the exemplary compounds of the application was evaluated in the primary rat cortical neurons. A summary of the neuritogenic activity for the exemplary compounds of the application is provided in Table 2.Table 2: Summary of the minimum compound concentration at which neuritogenesis is observedChemical Name Minimum neuritogenesis cone.C-1 ++++C-2 +++++1-1 +I-2 +I-3 +++++I-4 +I-5 ++++++I-6 +I-7 +++++I-8 +++I-9 ++++1-10 +1-11 +1-12 +1-13 +1-14 +++++1-15 +++1-17 +1-18 +1-19 +I-20 +Legend:+ (>1000 nM) ++ (1000 nM) +++ (100 nM) ++++ (10 nM) +++++ (1 nM) ++++++ (0.01 nM)Biological Experimental ProceduresPrimary culture of cortical neurons

[0403] Rat cortical neurons were cultured as described by N. Callizot, 2013 with modifications. Briefly pregnant female rats (Wistar, Janvier) of 15 days of gestation were killed using a deep anesthesia with CO2chamber and a cervical dislocation. Fetuses were collected and immediately placed in ice-cold L15 Leibovitz medium with a 2% penicillin (10,000 U / mL) and streptomycin (10 mg / mL) solution (PS) and 1% bovine serum albumin (BSA). Cortex was specifically dissected and treated for 20 min at 37°C with a trypsin- EDTA solution at a final concentration of 0.05% trypsin and 0.02% EDTA. The enzymatic dissociation was stopped by addition of Dulbecco’s modified Eagle’s medium (DMEM) with 4.5 g / L of glucose, containing DNAse I grade II (final concentration 0.5 mg / mL) and 10% fetal calf serum (FCS). Cells were mechanically dissociated by three forced passages through the tip of a 10-mL pipette. Cells were then centrifuged at 515 x g for 10 min at 4°C. The supernatant was discarded, and the pellet was resuspended in a defined culture medium consisting of Neurobasal medium with a 2% solution of B27 supplement, 2 mmol / liter of L-glutamine, 2% of PS solution, and 10 ng / mL of brain-derived neurotrophic factor (BDNF). Viable cells were counted in a Neubauer cytometer, using the trypan blue exclusion test. The cells were seeded at a density of 25,000 per well in 96-well plate precoated with poly-L-lysine and were cultured at 37°C in an air (95%)-CO2(5%) incubator. For 96 well-plates, only 60 wells were used. To avoid any edge effect, the first and last columns as well as first and last rows of the plate were not used in the study. Empty wells were filled with water.Test compoundsVehicle: culture medium (0.1% DMSO)

[0404] Treatment: On day 1 (day of seeding), the test compounds were diluted in the appropriate vehicle and applied to the culture and incubation was for 3 days. Test compounds were tested on cultures in 96-well plates (n=6 culture wells per condition). BDNF was used as a positive control at a concentration of 50 ng / mL. The vehicle was tested as the no treatment control.Immunostaining: MAP-2

[0405] 72 hours after treatment, the cell culture supernatant was removed, and then the cells were washed with phosphate-buffered saline (PBS). The cortical neurons were fixed with a cold solution of ethanol (95%) and acetic acid (5%) for 5 min at -20°C. They were washed twice again in PBS, and then permeabilized. Non-specific sites were blocked with a solution of PBS containing 0.1% saponin and 1% FCS, for 15 min at room temperature (RT). Cells were then incubated for 2 hours with a mouse monoclonal antibody anti microtubule-associated-protein 2 (MAP-2), at a dilution of 1 / 400 in PBS, with 1% fetal calf serum and 0.1% of saponin. This antibody binds specifically neurons and neurites, allowing study ofneuronal cell survival and neurite network. This antibody was revealed with a secondary antibody, goat anti-mouse IgG coupled with an Alexa Flour488 at the dilution 1 / 400 in PBS containing 1% FCS, 0.1% saponin, for 1 h at RT. Cell nucleus were counterstained with a fluorescent dye, Hoechst, at a 1 / 1000 dilution (Sigma-Aldrich).Automated image analysis

[0406] For each condition, 30 images per well were automatically captured using ImageXpress® (Molecular Devices) or Operetta CLSTM(PerkinElmer) at 20x magnification. All images were generated using the same acquisition parameters. Image analyses were automatically performed by MetaXpress® (Molecular Devices) or Harmony™ (PerkinElmer). To evaluate the neuritogenic activity of the treatments, the following read-outs were investigated (see Figure 1):

[0407] - Total neurite network (lengths of MAP-2 positive neurite in pm)

[0408] - Analysis of roots (number of neurite branches) and extremities Statistical analysis

[0409] All values are expressed as mean + / - standard error of the mean (SEM). Results were analyzed with GraphPad Prism, version 9. Statistical analyses were performed by one-way ANOVA, followed by Fisher’s LSD test. P<0.05 will be considered significant. NUMBERED EMBODIMENTS OF THE APPLICATION1. A compound of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:OR2R3o3awhereinR1is selected from halo, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C6-ioaryl, C1-10alkyleneC6-10aryl, C2-iOalkenyleneC6-ioaryl, C2.ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci-ioalkyleneC3-i2cycloalkyl, C2-ioalkenyleneC3-i2cycloalkyl, C2. ioalkynyleneC3.i2cycloalkyl, C3-i2heterocycloalkyl, Ci-i0alkyleneC3-i2heterocycloalkyl, C2. ioalkenyleneC3.i2heterocycloalkyl, C2-i0alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci. ioalkyleneC5-i2heteroaryl, C2-ioalkenyleneC5-i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, Ci-ioalkyleneY1R7, C2-ioalkenyleneY1R7and C2-ioalkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2. ishaloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-ioalkyleneY2R8, Z1C2-ioalkenyleneY2R8, Z1C2-i0alkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2-ioalkenyleneC6-ioaryl, Z1C2. ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-i0alkyleneC3-i2cycloalkyl, Z1C2-ioalkenyleneC3. i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3.i2heterocycloalkyl, Z1Ci-i0alkyleneC3. i2heterocycloalkyl, Z1C2-ioalkenyleneC3-i8heterocycloalkyl, Z1C2-ioalkynyleneC3. i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2-10alkyleneC5-12heteroaryl, Z1C2-ioalkenyleneC5- i2heteroaryl and Z1C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci.6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-ioalkyleneOCi-6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring;R2is selected from H, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C3.i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C6-ioaryl, Ci-ioalkyleneC6ioaryl, C3-i2heterocycloalkyl, Ci-ioalkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci-ioalkyleneC5-12heteroaryl, wherein each alkyl, alkenyl, alkynyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more ...

Claims

CLAIMS:

1. A compound of Formula I, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:OR2R3o3awhereinR1is selected from halo, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2-i6haloalkynyl, C6-10aryl, C1-10alkyleneC6-10aryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-iOaryl, C3-i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C2-i0alkenyleneC3.i2cycloalkyl, C2. ioalkynyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci-i0alkyleneC3.i2heterocycloalkyl, C2. ioalkenyleneC3.i2heterocycloalkyl, C2.ioalkynyleneC3.i2heterocycloalkyl, C5-12heteroaryl, Ci-ioalkyleneC5-i2heteroaryl, C2-i0alkenyleneC5-i2heteroaryl, C2-i0alkynyleneC5-i2heteroaryl, Ci. i0alkyleneY1R7, C2.i0alkenyleneY1R7and C2.i0alkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2.i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2. i6haloalkenyl, Z1C2.i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2.i0alkenyleneY2R8, Z1C2. i0alkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2-iOalkenyleneC6-ioaryl, Z1C2. ioalkynyleneC6-ioaryl, Z1C3.i2cycloalkyl, Z1Ci-i0alkyleneC3.i2cycloalkyl, Z1C2-i0alkenyleneC3. i2cycloalkyl, Z1C2.ioalkynyleneC3.i2cycloalkyl, Z1C3.i2heterocycloalkyl, Z1Ci-ioalkyleneC3. i2heterocycloalkyl, Z1C2-10alkenyleneC3-18heterocycloalkyl, Z1C2-i0alkynyleneC3. i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2-10alkyleneC5-12heteroaryl, Z1C2-i0alkenyleneC5- i2heteroaryl and Z1C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci.6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OCi-ioalkyleneOCi-6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring;R2is selected from H, C1-16alkyl, C2-i6alkenyl, C2-iealkynyl, C1-16haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C3-i2cycloalkyl, Ci-i0alkyleneC3-i2cycloalkyl, C6-ioaryl, Ci-iOalkyleneC6ioaryl, C3.i2heterocycloalkyl, Ci-i0alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-i0alkyleneC5- i2heteroaryl, wherein each alkyl, alkenyl, alkynyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one or more substituents selected from OH, halo, Ci-iOalkyl, C-Mohaloalkyl, OCi-i0alkyl and OC1. lohaloalkyl; orR1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclic ring, optionally containing one additional heteroatom selected from N, NH, N(Ci-6alkyl), O, S, S(O) and S(O)2 and optionally substituted with one or more substituents selected from OH, halo, NO2, =0, Ci-i6alkyl, C2. i6alkenyl, C2-i6alkynyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, OCi-i6alkyl, 0C2. isalkenyl, 0C2-iealkynyl, OCi-iehaloalkyl, OC2-iehaloalkenyl and OC2-iehaloalkynyl, wherein each alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from OH, =0, halo, OCi-i6alkyl, OC2-i6alkenyl, OC2-i6alkynyl, OCi. i6haloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl;R3, R3aand R5are independently selected from H, halo, C1-2alkyl and Ci.2haloalkyl;R4is selected from H, Ci-4alkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-4haloalkyl, C2-iohaloalkenyl, C2-lohaloalkynyl, C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2-4alkenyleneC6-ioaryl, C2. ioalkynyleneC6-ioaryl, C3.i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C2-4alkenyleneC3. i2cycloalkyl, C2-4alkynyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci-4alkyleneC3. i2heterocycloalkyl, C2-4alkenyleneC3.i2heterocycloalkyl, C2-4alkynyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci-4alkyleneC5-i2heteroaryl, C2-4alkenyleneC5-i2heteroaryl, C2-4alkynyleneC5- i2heteroaryl, Ci-4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z2Ci-i6alkyl, Z2C2-i6alkenyl, Z2C2-i6alkynyl, Z2Ci-i6haloalkyl, Z2C2-i6haloalkenyl, Z2C2-i6haloalkynyl, Z2Ci-ioalkyleneY4R10, Z2C2-10alkenyleneY4R10, Z2C2. ioalkynyleneY4R10, Z2C6-ioaryl, Z2Ci-ioalkyleneC6-ioaryl, Z2C2-ioalkenyleneC6-ioaryl, Z2C2. ioalkynyleneC6-ioaryl, Z2C3.i2cycloalkyl, Z2Ci-i0alkyleneC3-i2cycloalkyl, Z2C2-ioalkenyleneC3. i2cycloalkyl, Z2C2-ioalkynyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-ioalkyleneC3. i2heterocycloalkyl, Z2C2-10alkenyleneC3-18heterocycloalkyl, Z2C2-ioalkynyleneC3. i2heterocycloalkyl, Z2C5-i2heteroaryl, Z2Ci-i0alkyleneC5-i2heteroaryl, Z2C2-ioalkenyleneC5- i2heteroaryl and Z2C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 16 groups is optionally substituted with or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci-6haloalkyl, Ci-i0alkyleneOCi-6alkyl, OCi.6alkyl, OCi.6haloalkyl and OC1. ioalkyleneOCi-6alkyl; and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene andalkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3-7heterocycloalkyl ring, R6is selected from Ci.6alkyl and Ci.6haloalkyl;Y1is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR11, NR11C(O), C(O)NR11, NR11C(O)O and OC(O)NR11;Y2is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR12, NR12C(O), C(O)NR12, NR12C(O)O and OC(O)NR12;Y3is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR13, NR13C(O), C(O)NR13, NR13C(O)O and OC(O)NR13;Y4is selected from O, S, C(O), C(O)O, OC(O), S(O), S(O)2, NR14, NR14C(O), C(O)NR14, NR14C(O)O and OC(O)NR14;Z1is selected from a direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR15, NR15C(O), C(O)NR15, NR15C(O)O and OC(O)NR15;Z2is selected from a direct bond, O, C(O), C(O)O, OC(O), S, S(O), S(O)2, NR16, NR16C(O), C(O)NR16, NR16C(O)O and OC(O)NR16;R7, R8, R9and R10are independently selected from H, Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, C1-16haloalkyl, C2-i6haloalkenyl, C2-i6haloalkynyl, C6-10aryl, C-i-ioalkyleneC6-10aryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3-i2cycloalkyl, Ci-ioalkyleneC3-i2cycloalkyl, C2-ioalkenyleneC3-i2cycloalkyl, C2-ioalkynyleneC3-i2cycloalkyl, C3.i2heterocycloalkyl, Ci. ioalkyleneC3-i2heterocycloalkyl, C2-ioalkenyleneC3-i2heterocycloalkyl, C2-ioalkynyleneC3- i2heterocycloalkyl, C5-i2heteroaryl, Ci-i0alkyleneC5-i2heteroaryl, C2-ioalkenyleneC5- i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, wherein each cyclic group in R7, R8, R9and R10is optionally substituted with one or more substituents selected from OH, halo, Ci-i6alkyl and Ci-6haloalkyl;R11, R12, R13, R14, R15and R16are independently selected from H, Ci-i6alkyl and Ci. i6haloalkyl; andall available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium,provided:i) when R2, R3, R3a, R4and R5are all H and R6is CH3, then R1is not CH2OH, C6-16alkenyl or C6-16alkenyl substituted with OH or =O;ii) when R2is CH(CH3)2, R3, R3aand R5are all H, R6is CH3, and R1is CH2OCH(CH3)2or CH2OC(O)CH3, then R4is not H or Cialkylenephenyl substituted with one or two OCH3; iii) when R2is CH3, R3, R3aand R5are all H, R6is CH(CH3)2, and R1is CH3. then R4is not H, C(CH3)3or Cialkylenephenyl substituted with one OCH3;iv) when R2, R3, R3aand R5are all H, R6is CH3, and R4is Cialkylenephenyl or Cialkylenephenyl substituted with one or two OCH3, then R1is not I, CH2OH, 3-methylbut-2-en-1-ylCialkyleneoctahydronaphthalenyl, Cialkylenedecahydronaphthalenyl and Cialkylenedecahydronaphtho[1,2b]oxirenyl, the latterthree of which are substituted with 3 to 5 substituents selected from OH, CH3, =0, =C and OCialkylenephenyl;v) when R2, R3, R3aand R5are all H, R6is CH3, R4is unsubstituted 3-indolyl, then R1is not (2E)-3,7-dimethyl-2,6-octadien-1-yl; andvi) when R3, R3a, R4and R5are all H, and R6is CH3, then R1and R2are not joined to form, together with the oxygen and carbon atoms therebetween, a 6 membered unsaturated ring that is disubstituted on the same carbon atom with CH3and C4-ioalkenyl or with CH3and C4. salkenyl substituted with one =0, and the ring being optionally further substituted with one OH or one =0.

2. The compound of claim 1, wherein R1is selected from F, Cl, Br, I, Ci-i6alkyl, C2. isalkenyl, C2.i6alkynyl, C1-16haloalkyl, C2.i6haloalkenyl, C2.i6haloalkynyl, C6-10aryl, C1-ioalkyleneC6-ioaryl, C2-ioalkenyleneC6-ioaryl, C2-ioalkynyleneC6-ioaryl, C3.i2cycloalkyl, C1-ioalkyleneC3.i2cycloalkyl, C2-i0alkenyleneC3-i2cycloalkyl, C2-i0alkynyleneC3-i2cycloalkyl, C3-i2heterocycloalkyl, Ci-i0alkyleneC3-i2heterocycloalkyl, C2-i0alkenyleneC3-i2heterocycloalkyl, C2-i0alkynyleneC3-i2heterocycloalkyl, C5-i2heteroaryl, Ci-i0alkyleneC5-i2heteroaryl, C2. ioalkenyleneC5-i2heteroaryl, C2-ioalkynyleneC5-i2heteroaryl, Ci-ioalkyleneY1R7, C2. i0alkenyleneY1R7and C2.i0alkynyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2.i6alkynyl, Z1Ci-i6haloalkyl, Z1C2.i6haloalkenyl, Z1C2. i6haloalkynyl, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C3.i2cycloalkyl, Z1Ci-ioalkyleneC3. i2cycloalkyl, Z1C3.i2heterocycloalkyl, Z1Ci-i0alkyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl and Z1C2-10alkyleneC5-12heteroaryl, wherein each cyclic group comprised in the latter 8 groups is optionally substituted with one or more substituents selected from OH, F, Cl, Br, NO2, Ci-i6alkyl, Ci.6haloalkyl, Ci-6alkyleneOCi-6alkyl, OCi-i6alkyl, OCi-i6haloalkyl and OC1. ioalkyleneOCi.6alkyl, and wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene andalkynylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

3. The compound of claim 2, wherein, R1is selected from F, Cl, Br, I, Ci-i6alkyl, C2. i6alkenyl, C2-i6alkynyl, Ci-i6fluoroalkyl, Ci-i6chloroalkyl, C2-i6fluoroalkenyl, C2-i6Chloroalkenyl, C2-i6fluoroalkynyl and C2-i6Chloroalkynyl, each of which is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci_4alkyl, Ci.4fluoroalkyl and C1-4chloroalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

4. The compound of claim 2, wherein R1is selected from C6-10aryl, C1-10alkyleneC6-10aryl, C2-ioalkenyleneC6-ioaryl, C3.i2cycloalkyl, Ci.ioalkyleneC3.i2cycloalkyl, C2. ioalkenyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci.ioalkyleneC3.i2heterocycloalkyl, C2. ioalkenyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, C1-10alkyleneC5-12heteroaryl and C2-ioalkenyleneC5-i2heteroaryl, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z1C1-16alkyl, Z1C2-i6alkenyl, Z1C2-i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl and Z1C2-i6haloalkynyl, and wherein each alkyl, alkenyl, alkynyl, alkylene and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and C1-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring,Z1is selected from a direct bond, C(0), C(0)0, 0C(0), S, S(0)2, NR15, NR15C(O) and C(O)NR15; andR15is selected from H, Ci.4alkyl and Ci.4haloalkyl,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

5. The compound of claim 2, wherein R1is selected from C1-10alkyleneY1R7, C2. i0alkenyleneY1R7and C2-ioalkynyleneY1R7, and optionally disubstituted on the same carbonatom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3. cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring,R7is selected from H, Ci-iOalkyl, C2-ioalkenyl, C-Mohaloalkyl, C2-iohaloalkenyl, C6-ioaryl, Ci. ealkyleneC6-10aryl, C3.i2cycloalkyl, Ci-6alkyleneC3.i2cycloalkyl, C3.i2heterocycloalkyl, Ci-6alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group in R7is optionally substituted with one or more substituents selected from OH, halo, C1-6alkyl and C1-6haloalkyl; andY1is selected from O, S, C(O), S(O), S(O)2, NR11, NR11C(O)O and OC(O)NR11,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

6. The compound of claim 1, wherein R1is selected from F, Cl, Br, I, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CF3, CFH2, CHF2, CH2CF2H, CH2CF3, CH2CFH2, C(CF3)3, CH2CH(CF3)2, CCI3, CChH, CCIH2, CH2CCl2H,CH2CCI3, CH2CCIH2,, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

7. The compound of any one of claim 1 to 6, wherein R2is selected from H, Ci-i6alkyl, C2-i6alkenyl, Ci-i6haloalkyl, C2-i6haloalkenyl, C3.i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C6. ioaryl, Ci-4alkyleneC6-ioaryl, C3.i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C5-i2heteroaryl and Ci.4alkyleneC5-i2heteroaryl, wherein each alkyl, alkenyl, alkylene, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group in R2is independently and optionally substituted with one to four substituents selected from OH, halo, Ci.6alkyl, OCi-i0alkyl and OCi-iohaloalkyl and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

8. The compound of claim 1, wherein R1and R2are joined to form, together with the oxygen atom and carbon atoms therebetween, a 4 to 6 membered unsaturated heterocyclicring, optionally containing one additional heteroatom selected from N, NH, N(Ci-6alkyl), O, S, S(O) and S(O)2and optionally substituted with one or more substituents selected from OH, halo, NO2, =0, Ci-i6alkyl, C2-i6alkenyl, C2.i6alkynyl, Ci-i6haloalkyl, C2.i6haloalkenyl, C2. i6haloalkynyl, OC1-16alkyl, OC2.i6alkenyl, OC2.i6alkynyl, OCi-iehaloalkyl, OC2.i6haloalkenyl and OC2-i6haloalkynyl, wherein each alkyl, alkenyl and alkynyl groups are optionally substituted with one or more substituents selected from OH, =0, halo, OCi-i6alkyl, OC2-16alkenyl, OC2-i6alkynyl, OCi-i6haloalkyl, OC2-i6haloalkenyl and OC2-i6haloalkynyl, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

9. The compound of any one of claims 1 to 8, wherein R3, R3aand R5are independently selected from H, D, halo, Ci.2alkyl, Ci.2fluoroalkyl, Ci.2chloroalkyl and Ci.2deuteroalkyl, and wherein R6is selected from Ci.4alkyl, Ci.4fluoroalkyl, Ci.4chloroalkyl and Ci.4deuteroalkyl.

10. The compound of any one of claims 1 to 9, wherein R4is selected from H, C1-4alkyl, C2-10alkenyl, C2-10alkynyl, Ci.4haloalkyl, C2.iohaloalkenyl, C2.iohaloalkynyl, C6-ioaryl, CialkyleneC6-ioaryl, C3alkyleneC6-ioaryl, C2.4alkenyleneC6-ioaryl, C2-10alkynyleneC6-10aryl, C3. i2cycloalkyl, Ci.4alkyleneC3.i2cycloalkyl, C2.4alkenyleneC3.i2cycloalkyl, C2.4alkynyleneC3. i2cycloalkyl, C3.i2heterocycloalkyl, Ci.4alkyleneC3.i2heterocycloalkyl, C2.4alkenyleneC3. i2heterocycloalkyl, C2.4alkynyleneC3.i2heterocycloalkyl, C5-i2heteroaryl, Ci.4alkyleneC5. i2heteroaryl, C2.4alkenyleneC5-i2heteroaryl, C2.4alkynyleneC5-i2heteroaryl, Ci.4alkyleneY3R9, C2.4alkenyleneY3R9and C2.4alkynyleneY3R9, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, =0, Z2C1-16alkyl, Z2C2.i6alkenyl, Z2C2.i6alkynyl, Z2Ci-i6haloalkyl, Z2C2.i6haloalkenyl, Z2C2. i6haloalkynyl, Z2C6-ioaryl, Z2C1-10alkyleneC6-10aryl, Z2C3.i2cycloalkyl, Z2Ci-i0alkyleneC3. i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-ioalkyleneC3.i2heterocycloalkyl, Z2C5-12heteroaryl and Z2C2.ioalkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, Ci_4alkyl, Ci.4haloalkyl, Ci-ioalkyleneOCi.4alkyl, OCi-4alkyl, OCi.4haloalkyl and OCi.ioalkyleneOCi.4alkyl;wherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, Ci.4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2.6alkylene to form a C3.7cycloalkyl or with C2.6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

11. The compound of claim 10, wherein R4is selected from H, C1-4alkyl, C2-10alkenyl, C2-10alkynyl, C1-4haloalkyl, C2-10haloalkenyl and C2-10haloalkynyl, andwherein each alkyl, alkenyl and alkynyl group is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, and =0, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3-7heterocycloalkyl ring, and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

12. The compound of claim 10, wherein R4is selected from C6-10aryl, C1alkyleneC6-10aryl, C3alkyleneC6-10aryl, C2-4alkenyleneC6-10aryl, C2-10alkynyleneC6-10aryl, C3-12cycloalkyl, C1-4alkyleneC3-12cycloalkyl, C2-4alkenyleneC3-12cycloalkyl, C2-4alkynyleneC3-12cycloalkyl, C3-12heterocycloalkyl, C1-4alkyleneC3-12heterocycloalkyl, C2-4alkenyleneC3-12heterocycloalkyl, C2-4alkynyleneC3-12heterocycloalkyl, C5-12heteroaryl, C1-4alkyleneC5-12heteroaryl, C2-4alkenyleneC5-12heteroaryl and C2-4alkynyleneC5-12heteroaryl, wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2Ci-i6alkyl, Z2C2-iealkenyl, Z2C2-iealkynyl, Z2Ci-i6haloalkyl, Z2C2-i6haloalkenyl, Z2C2-i6haloalkynyl, Z2C6-ioaryl, Z2C1-10alkyleneC6-10aryl, Z2C3.i2cycloalkyl, Z2Ci. ioalkyleneC3.i2cycloalkyl, Z2C3.i2heterocycloalkyl, Z2Ci-i0alkyleneC3.i2heterocycloalkyl, Z2C5. i2heteroaryl and Z2Ci-ioalkyleneC5-i2heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, C1-4alkyl, C1-4haloalkyl, C1-10alkyleneOC1-4alkyl, OC1-4alkyl, OC1-4haloalkyl and OC1-10alkyleneOC1-4alkyl; andwherein each alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =O, C1-4alkyl and Ci.4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.4alkyl to form a C3.7heterocycloalkyl ring,Z2is selected from direct bond, O, C(0), C(0)0, 0C(0), S, S(0), S(0)2, NR16, NR16C(O) and C(O)NR16; andR16is selected from H, Ci.4alkyl and Ci.4haloalkyl,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

13. The compound of claim 10, wherein R4is selected from C3-12cycloalkyl, C1-4alkyleneC3-12cycloalkyl, C2-4alkenyleneC3-12cycloalkyl, C3-12heterocycloalkyl, C1-4alkyleneC3-12heterocycloalkyl, C2-4alkenyleneC3-12heterocycloalkyl, C5-12heteroaryl, C1-4alkyleneC5-12heteroaryl and C2-4alkenyleneC5-12heteroaryl wherein each cyclic group comprised in R4is optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, NO2, Z2C1-10alkyl, Z2C1-10fluoroalkyl, Z2C1-10chloroalkyl, Z2C6-10aryl, Z2C1-6alkyleneC6-10aryl, Z2C3-12cycloalkyl, Z2C1-6alkyleneC3-12cycloalkyl, Z2C3-12heterocycloalkyl, Z2C1-6alkyleneC3-12heterocycloalkyl, Z2C5-12heteroaryl and Z2C1-6alkyleneC5-12heteroaryl, wherein each cyclic group comprised in the later 8 groups is optionally substituted with or more substituents selected from OH, F, Cl, Br, NO2, C1-4alkyl, C1-4fluoroalkyl, C1-4chloroalkyl, C1-10alkyleneOC1-4alkyl, OCi-4alkyl, OC1-4fluoroalkyl, OC1-4chloroalkyl, and OCi-i0alkyleneOCi.4alkyl;, and wherein each alkylene and alkenylene group comprised in R4, including in any of the optional substituents in R4, is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl C1-4fluoroalkyl and C1-4chloroalkyl,Z2is selected from direct bond, O, C(0), C(0)0, 0C(0), S, S(0), S(0)2, NR16, NR16C(O) and C(O)NR16; andR16is selected from H, Ci-4alkyl and C^haloalkyl,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

14. The compound of claim 10, wherein R4is selected from C1-4alkyleneY3R9, C2-4alkenyleneY3R9and C2-4alkynyleneY3R9, wherein each alkylene, alkenylene and alkynylene group comprised in R4is independently and optionally substituted with one or more substituents selected from OH, F, Cl, Br, CN, =0, C1-4alkyl and C1-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3-7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(O), S, SO2, SO, N, NH, or NC1-4alkyl to form a C3-7heterocycloalkyl ring,R9is selected from H, Ci- alkyl, C2-ioalkenyl, C-Mohaloalkyl, C2-iohaloalkenyl, C6-10aryl, C1-6alkyleneC6-ioaryl, C3-i2cycloalkyl, Ci.6alkyleneC3.i2cycloalkyl, C3-i2heterocycloalkyl, C1-6alkyleneC3-i2heterocycloalkyl, C5-i2heteroaryl and Ci-6alkyleneC5-i2heteroaryl, wherein each cyclic group in R9is optionally substituted with one or more substituents selected from OH, halo, C1-6alkyl and C1-6haloalkylY3is selected from O, S, C(O), S(O), S(O)2, NR13, NR13C(O)O and OC(O)NR13, and R13is selected from H, C1-4alkyl and C1-4haloalkyl,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

15. The compound of any one of claims 1 to 9, wherein R4is selected fromH, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2,and all available hydrogen atoms are optionally and independently replaced with a fluorine atom and / or a deuterium.

16. The compound of claim 1, wherein the compound of Formula I selected from the compounds listed in Table 1,or a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof and a pharmaceutically acceptable carrier.

18. A method of stimulating neuritogenesis and / or providing neuroprotection or for treating a disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof to a subject in need thereof.

19. The method of claim 18, wherein the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection is a neuropsychiatric disorder and / or a neurodevelopmental disorder; orwherein the disease, disorder or condition that benefits from neuritogenesis and / or neuroprotection is a central nervous system (CNS) disease, disorder or condition or a peripheral nervous system disease, disorder or condition (PNS).

20. A process for preparing a compound of Formula I wherein R2and R3aare both H,the process comprising:reacting a compound of Formula AOH Owith a compound of Formula B, R1-Hal (B), wherein Hal is selected from F, Cl, Br and I, in the presence of a base to provide a compound of Formula COR1Osubjecting the compound of Formula C to conditions to induce a rearrangement to provide a compound of Formula Dreacting the compound of Formula D with a compound of Formula E, NH2-R4(E), in the presence of a reducing agent to provide the compound of Formula I,whereinR3is selected from H, Ci-2alkyl and Ci-2haloalkyl;R4, R5and R6are as defined for Formula I in any one of claims 1 to 16; andR1is selected from C2-16alkenyl, C2-10alkenyleneC6-10aryl, C2-10alkenyleneC3-12cycloalkyl, C2-10alkenyleneC3-12heterocycloalkyl, C2-10alkenyleneC5-12heteroaryl and C2-10alkenyleneY1R7, wherein each cyclic group comprised in R1is optionally substituted with one or more substituents selected from OH, halo, CN, NO2, =0, Z1Ci-i6alkyl, Z1C2-i6alkenyl, Z1C2. i6alkynyl, Z1Ci-i6haloalkyl, Z1C2-i6haloalkenyl, Z1C2-i6haloalkynyl, Z1Ci-i0alkyleneY2R8, Z1C2. i0alkenyleneY2R8, Z1C2-ioalkynyleneY2R8, Z1C6-ioaryl, Z1Ci-i0alkyleneC6-ioaryl, Z1C2. ioalkenyleneC6-ioaryl, Z1C2-ioalkynyleneC6-ioaryl, Z1C3-i2cycloalkyl, Z1Ci-ioalkyleneC3. i2cycloalkyl, Z1C2-ioalkenyleneC3-i2cycloalkyl, Z1C2-ioalkynyleneC3-i2cycloalkyl, Z1C3. i2heterocycloalkyl, Z1Ci-ioalkyleneC3.i2heterocycloalkyl, Z1C2-ioalkenyleneC3. isheterocycloalkyl, Z1C2-ioalkynyleneC3-i2heterocycloalkyl, Z1C5-i2heteroaryl, Z1C2. ioalkyleneC5-i2heteroaryl, Z1C2-ioalkenyleneC5-i2heteroaryl and Z1C2-ioalkynyleneC5- i2heteroaryl, wherein each cyclic group comprised in the latter 16 groups is optionally substituted with one or more substituents selected from OH, halo, NO2, Ci_6alkyl, Ci. ehaloalkyl, Ci-ioalkyleneOCi-6alkyl, OCi-ealkyl, OCi-ehaloalkyl and OCi-ioalkyleneOCi-6alkyl, and wherein each alkenyl and alkenylene group comprised in R1, including in any of the optional substituents in R1, is optionally substituted with one or more substituents selected from OH, halo, CN, =0, Ci-4alkyl and Ci-4haloalkyl, and further optionally disubstituted on the same carbon atom with C2-6alkylene to form a C3.7cycloalkyl or with C2-6alkylene interrupted with one to three of O, C(0), S, SO2, SO, N, NH, or NCi.6alkyl to form a C3.7heterocycloalkyl ring, and including embodiments thereof described above;provided the C2-16alkenyl or C2-10alkenylene group in R1comprises an allyl group wherein the CH2of the allyl group is covalently attached to the remaining portion of the compound of Formula I.

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