RU2808166C2 - Neuroactive steroids and methods of their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to steroid compounds (shown in the claims). The invention relates to a pharmaceutical composition for positive allosteric modulation of NDMA receptor activity, containing an effective amount of a compound or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier. The invention also relates to a method of treating a CNS disease mediated by positive allosteric modulation of NDMA receptor activity in a subject in need of such treatment, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof of the invention or a pharmaceutical composition based on the compound.

EFFECT: obtaining steroid compounds and their pharmaceutically acceptable salts that act as positive allosteric modulators (PAM) of NMDA and potentiate the function of the NMDA receptor.

37 cl, 2 tbl, 12 ex

Description

Related applications

This application claims priority under 35 USC 119(e) under US Provisional Application Serial No. 61/779735, filed March 13, 2013, which is incorporated herein by reference.

State of the art

Brain excitability is defined as the animal's level of activity, with a continuum from coma to seizures, and is controlled by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductivity of ions across neuronal membranes. At rest, the neuron membrane has a potential (or membrane voltage) of approximately -70 mV, and the cell contents are negatively charged relative to the cell's external environment. Potential (voltage) is provided by the ionic (K+, Na+, Cl-, organic ions) balance of the entire semipermeable membrane of the neuron. Neurotransmitters are contained in presynaptic vesicles and are released as a result of neuronal action potentials. When released into the synaptic cleft, an excited chemical transmitter such as acetylcholine will cause membrane depolarization (a change in potential from -70 mV to -50 mV). This effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase membrane permeability of Na+ ions. A decreased membrane potential increases the likelihood of generating a postsynaptic action potential, which is expressed in increased neuronal excitability.

NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission. In some cases, activation of these receptors promotes synaptic plasticity and in other cases, excitotoxicity. These receptors are ligand-gated ion channels that accept Ca2+ upon binding of the neurotransmitters glutamate and glycine and are essential for excitatory neurotransmission and normal CNS function. NMDA receptors are heteromeric complexes including NR1, NR2 and/or NR3 subunits and have specific recognition sites for exogenous and endogenous ligands. These recognition sites include glycine and glutamate agonist binding sites and modulators. Positive modulators can be used as therapeutic agents with potential clinical applications as cognitive enhancers, and in the treatment of psychiatric disorders in which glutamatergic transmission is attenuated or impaired (see, for example, Horak et al., J. of NeuroscienCe, 2004, 24( 46), 10318-10325). In contrast, negative modulators can be used as a therapeutic agent with potential clinical applications in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically high (eg, treatment of treatment-resistant depression).

Neuroactive steroids such as pregnenolone sulfate (PS) have been shown to directly modulate several types of neurotransmitter receptors, such as GABAA, glycine, AMPA, kainate, and NMDA receptors. NMDA receptors are positively modulated by PS; However, the degree of modulation varies significantly, for example depending on the composition of the receptor subunit.

In addition to PS, several other 3β-hydroxy steroids have been shown to potentiate NMDA receptors (see, eg, Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682). Recently, a 3β-hydroxy-ergost-5-ene steroid derivative called Org-1 was reported to be a positive modulator of NMDA (NR1a/NR2A). Org-1 has been shown to selectively modulate NMDA through GABAA (see, e.g., Madau et al., Program No. 613.2/B87. 2009 NeurosCienCe Meeting Planner. ChiCago, IL: SoCiety for NeurosCienCe, 2009; ConniCk et al., Program No. 613.1/B86. 2009 NeurosCienCe Meeting Planner. ChiCago, IL: SoCiety for NeurosCienCe, 2009; Paul el al., J. NeurosCi. 2013, 33, 17290-17300).

There is a need for new and improved neuroactive steroids that modulate brain excitability to prevent and treat CNS-related conditions. The compounds, compositions and methods described herein are intended for this purpose.

The essence of the invention

The present inventors, through ongoing research into Org-1 analogues for NMDA modulation, described in part in PCT/US2012/054261, incorporated herein by reference, have discovered a number of specific combinations of elements that provide NMDA modulators with relatively superior properties. For example, as shown in Table 1, compounds containing a beta hydrogen at _C5 are less preferred than compounds containing either an alpha hydrogen at _C5 or a double bond between _C5 - _C6 , due to loss of potentiation NMDA receptors. Removal of the methyl at _C21 also results in a significant attenuation of NMDA potentiation. Disubstitution with C ₃ is expected to increase the metabolic stability of these compounds and is thus a preferred feature of the invention. Fluorination on the C ₁₇ side chain has been shown to enhance potency and limit maximum potentiation of NMDA receptors when tested down to 1 μM compound concentration. A secondary or tertiary terminal alcohol on the C ₁₇ side chain has been shown to enhance the potency and limit the maximum potentiation of the NMDA receptor when tested down to 1 μM concentration of the compound and is thus a preferred feature of the present invention, where bulky groups on the terminal are preferred. parts containing 2-3 carbon atoms, or a group containing a fluorine substituent. Such properties are expected to limit the risk of inducing glutamate-mediated neurotoxicity relative to compounds that achieve greater maximal potentiation of the NMDA receptor. The compounds of the present invention embrace various combinations of these specific features to develop superior NMDA modulators.

Thus, in one aspect, compounds of formula (I) are provided,

and pharmaceutically acceptable salts thereof;

Where:

R ¹ represents a substituted or unsubstituted aliphatic group;

R ² is hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted cyclopropyl, or -OR ^A2 , where R ^A2 is hydrogen or substituted or unsubstituted alkyl;

R ^3a is hydrogen or -OR ^A3 , where R ^A3 is hydrogen or substituted or unsubstituted alkyl, and R ^3b is hydrogen; or R ^3a and R ^3b are linked to form an oxo (=O) group;

R ⁴ represents hydrogen, substituted or unsubstituted alkyl, or halogen;

X is -C(R ^X ) ₂ - or -O-, where R ^X is hydrogen or fluorine, or one group of R ^X and R ^5b are linked to form a double bond;

each example of R ^5a and R ^5b is independently hydrogen or fluorine;

R ^6a represents a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl and a substituted and unsubstituted heteroaryl group, wherein the non-hydrogen group is optionally substituted with fluorine; And

R ^6b represents hydrogen or a substituted or unsubstituted alkyl group, optionally substituted with fluorine;

denotes a single or double bond, with the proviso that if a single bond is present, then the hydrogen on _C5 is in alpha configuration;

and further provided that:

(1) at least one of R ^X , R ^5a and R ^5b is fluorine; or

(2) at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine; or

(3) R ^6a represents a non-hydrogen group containing two to ten carbon atoms.

In another aspect, pharmaceutical compositions are provided containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In yet another aspect, the invention provides a method of treating or preventing a CNS-related condition accompanied by NMDA modulation, comprising administering to a subject in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the CNS-related condition is an adjustment disorder, an anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, and generalized anxiety disorder), a cognitive disorder (including Alzheimer's disease and other forms of dementia), a dissociative disorder, a eating disorder, mood disorder (including depression, bipolar disorder and dysthymic disorder), schizophrenia or other psychotic disorder (including schizoaffective disorder), sleep disorder (including insomnia), alcohol or drug use disorder, personality disorder (including obsessive disorder) compulsive personality disorder), autism spectrum disorder (including those associated with mutations, including those associated with mutations in the Shank protein group), neurodevelopmental disorder (including Rett syndrome), pain (including acute and chronic pain), epilepsy (including status epilepticus and monogenic forms of epilepsy such as Dravet disease, tuberous sclerosis complex (TSC), stroke, traumatic brain injury, movement disorder (including Huntington's disease and Parkinson's disease) and tinnitus. In some embodiments, these compounds may be used to induce sedation or anesthesia.

Other objects and advantages will become apparent to those skilled in the art upon consideration of the following Detailed Description, Examples and Claims sections.

Definitions

Chemical definitions

Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are designated according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and PhysiCs, ^75th Ed., inside cover, and specific functional groups are generally defined as described in this reference. In addition, general principles of organic chemistry as well as specific functional groups and reactivity are described in OrganiC Chemistry , Thomas Sorrell, University SCienCe Books, Sausalito, 1999; Smith and MarCh , MarCh's AdvanCed Organic Chemistry , ^5th Edition, John Wiley & Sons, InC., New York, 2001; LaroCk, Comprehensive Organic Transformations , VCH Publishers, InC., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , 3R ^d Edition, Cambridge University Press, Cambridge, 1987.

The compounds described herein may have one or more asymmetric centers, and thus may exist in various isomeric forms, for example, as enantiomers and/or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be obtained by asymmetric synthesis. See, for example, JaCques et al. , Enantiomers, RaCemates and Resolutions (Wiley InterscienCe, New York, 1981); Wilen et al. , Tetrahedron 33:2725 (1977); Eliel, StereoChemistry of Carbon Compounds (MCGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and OptiCal Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention further covers the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as mixtures of different isomers.

When a range of values is specified, it is assumed to cover every value and subrange within the specified range. for example, "C _1-6 alkyl" includes C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _{1- 2} , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C 3-5, C _3-4 , C _4-6 , C _4-5 and _{C 5- 6} alkyl.

The following terms have the meanings set forth below, and are used to interpret the description and intended scope of the present invention. In describing the invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compositions and compounds, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that, when described herein, any of the moieties defined below may be substituted with a number of substituents, and that the relevant definitions include within their scope such substituted moieties as defined below. Unless otherwise specified, the term "substituted" shall be defined as follows. It should also be understood that the terms “groups” and “radicals” may be considered interchangeable when used herein. A singular reference herein is intended to refer to one or more (i.e., at least one) entities. By way of example, “analogue” means one analogue or more analogues.

The term "aliphatic" refers to an alkyl, alkenyl, alkynyl or carbocyclyl group as defined herein.

The term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical containing from 1 to 20 carbon atoms ("C _1-20 alkyl"). In some embodiments, the alkyl group contains from 1 to 12 carbon atoms ("C _1-12 alkyl"). In some embodiments, the alkyl group contains from 1 to 10 carbon atoms ("C _1-10 alkyl"). In some embodiments, the alkyl group contains from 1 to 9 carbon atoms ("C _1-9 alkyl"). In some embodiments, the alkyl group contains from 1 to 8 carbon atoms ("C _1-8 alkyl"). In some embodiments, the alkyl group contains from 1 to 7 carbon atoms (“C _1-7 alkyl”). In some embodiments, the alkyl group contains from 1 to 6 carbon atoms ("C _1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group contains from 1 to 5 carbon atoms (“C _1-5 alkyl”). In some embodiments, the alkyl group contains from 1 to 4 carbon atoms (“C _1-4 alkyl”). In some embodiments, the alkyl group contains from 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, an alkyl group contains 1 to 2 carbon atoms (“C _1-2 alkyl”). In some embodiments, the alkyl group contains 1 carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group contains from 2 to 6 carbon atoms (“C _2-6 alkyl”). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl (C ₄ ), sec-butyl ( _C4 ), iso-butyl ( _C4 ), n-pentyl ( _C5 ), 3-pentanyl ( _C5 ), amyl ( _C5 ), neopentyl ( _C5 ), 3-methyl-2- butanyl ( _C5 ), tertiary amyl ( _C5 ) and n-hexyl ( _C6 ). Additional examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ) and the like. Unless otherwise indicated, each individual example of an alkyl group is independently optionally substituted, that is, unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents; for example, 1-5 substituents, 1-3 substituents or 1 substituent. In some embodiments, the alkyl group is an unsubstituted C _1-10 alkyl (eg, -CH ₃ ). In some embodiments, the alkyl group is a substituted C _1-10 alkyl. Common alkyl abbreviations include Me (-CH ₃ ), Et (-CH ₂ CH ₃ ), iPr (-CH(CH ₃ ) ₂ ), nPr (-CH ₂ CH ₂ CH ₃ ), n-Bu (-CH ₂ CH ₂ CH ₂ CH ₃ ) or i-Bu (-CH ₂ CH(CH ₃ ) ₂ ).

As used herein, the terms "alkylene", "alkenylene" and "alkynylene" refer to the divalent radical of an alkyl, alkenyl and alkynyl group, respectively. Where a range or number of carbon atoms is defined for a particular "alkylene", "alkenylene" and "alkynylene" group, it is understood that the range or number refers to the range or number of carbon atoms in a linear divalent carbon chain. The "alkylene", "alkenylene" and "alkynylene" groups may be unsubstituted or substituted with one or more substituents as described herein.

The term "alkylene" refers to an alkyl group in which two hydrogen atoms have been removed to form a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -), hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -) and the like. Typical substituted alkylene groups, such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH ₃ )-, (-C(CH ₃ ) ₂ -), substituted ethylene (- CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -), substituted propylene (-CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH ₂ CH(CH ₃ )-, -C(CH ₃ ) ₂ CH ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ CH ₂ C(CH ₃ ) ₂ -) and the like.

The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally , one or more carbon-carbon triple bonds (eg, 1, 2, 3 or 4 carbon-carbon triple bonds) (“C _2-20 alkenyl”). In some embodiments, alkenyl does not contain triple bonds. In some embodiments, the alkenyl group contains from 2 to 10 carbon atoms ("C _2-10 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 9 carbon atoms (“C _2-9 alkenyl”). In some embodiments, the alkenyl group contains from 2 to 8 carbon atoms ("C _2-8 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 7 carbon atoms ("C _2-7 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, the alkenyl group contains from 2 to 4 carbon atoms (“C _2-4 alkenyl”). In some embodiments, the alkenyl group contains 2 to 3 carbon atoms (“C _2-3 alkenyl”). In some embodiments, the alkenyl group contains 2 carbon atoms ("C ₂ alkenyl"). One or more carbon-carbon double bonds may be in the middle (for example, in 2-butenyl) or at the end (for example, in 1-butenyl). Examples of _C2-4 alkenyl groups include ethenyl ( _C2 ), 1-propenyl ( _C3 ), 2-propenyl ( _C3 ), _{1-butenyl (C4), 2-butenyl (C4 )} , butadienyl ( _C4 ) etc. Examples of C _2-6 alkenyl groups include the above C _2-4 alkenyl groups, as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ) and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ), and the like. Unless otherwise indicated, each example of an alkenyl group may be optionally independently substituted, that is, unsubstituted (“unsubstituted alkenyl”) or substituted (“substituted alkenyl”) with one or more substituents, for example, 1-5 substituents, 1-3 substituents, or 1 deputy. In some embodiments, the alkenyl group is unsubstituted C _2-10 alkenyl. In some embodiments, the alkenyl group is C _2-10 alkenyl.

The term "alkenylene" refers to an alkenyl group in which two hydrogen atoms have been removed to form a divalent radical, and which may be substituted or unsubstituted. Typical unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (for example, -CH=CHCH₂-, -CH₂-CH=CH-). Typical substituted alkenylene groups, e.g. substituted with one or more alkyl (methyl) groups, includes, but is not limited to, substituted ethylene (-C(CH₃)=CH-, -CH=C(CH₃)-), substituted propylene (for example, -C(CH₃)=CHCH₂-, -CH=C(CH₃)CH₂-, -CH=CHCH(CH₃)-, -CH=CHC(CH₃)₂-, -CH(CH₃)-CH=CH-, -C(CH₃)₂-CH=CH-, -CH₂-C(CH₃)=CH-, -CH₂-CH=C(CH₃)-) etc.

The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally , one or more carbon-carbon double bonds (eg, 1, 2, 3 or 4 carbon-carbon double bonds) (“C _2-20 alkynyl”). In some embodiments, the alkynyl does not contain double bonds. In some embodiments, the alkynyl group contains from 2 to 10 carbon atoms (“C _2-10 alkynyl”). In some embodiments, the alkynyl group contains from 2 to 9 carbon atoms (“C _2-9 alkynyl”). In some embodiments, the alkynyl group contains from 2 to 8 carbon atoms (“C _2-8 alkynyl”). In some embodiments, the alkynyl group contains from 2 to 7 carbon atoms (“C _2-7 alkynyl”). In some embodiments, the alkynyl group contains from 2 to 6 carbon atoms (“C _2-6 alkynyl”). In some embodiments, the alkynyl group contains from 2 to 5 carbon atoms (“C _2-5 alkynyl”). In some embodiments, the alkynyl group contains from 2 to 4 carbon atoms (“C _2-4 alkynyl”). In some embodiments, the alkynyl group contains 2 to 3 carbon atoms (“C _2-3 alkynyl”). In some embodiments, the alkynyl group contains 2 carbon atoms (“C ₂ alkynyl”). One or more carbon-carbon triple bonds may be in the middle (such as in 1-butynyl) or at the end (such as in 1-butynyl). Examples of C _2-4 alkynyl groups include, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-butynyl (C ₄ ), etc. Examples of _C2-6 alkenyl groups include the above _C2-4 alkynyl groups, as well as pentynyl ( _C5 ), hexynyl ( _C6 ) and the like. Additional examples of alkynyl include heptynyl (C ₇ ), octinyl (C ₈ ), and the like. Unless otherwise indicated, each example of an alkynyl group is optionally independently substituted, that is, unsubstituted (“unsubstituted alkynyl”) or substituted (“substituted alkynyl”) with one or more substituents; for example, 1-5 substituents, 1-3 substituents or 1 substituent. In some embodiments, the alkynyl group is an unsubstituted C _2-10 alkynyl. In some embodiments, the alkynyl group is a substituted C _2-10 alkynyl.

The term "alkynylene" refers to a linear alkynyl group in which two hydrogen atoms have been removed to form a divalent radical, and which may be substituted or unsubstituted. Typical divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

The term “heteroalkyl” as used herein refers to an alkyl group, as defined herein, which further contains in the parent chain 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur , nitrogen, boron, silicon, phosphorus), where one or more heteroatoms are embedded between adjacent carbon atoms in the parent carbon chain, and/or one or more heteroatoms are embedded between the carbon atom and the parent molecule, that is, between the point of attachment. In some embodiments, a heteroalkyl group refers to a saturated group containing from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC _1-10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC _1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC _1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC _1-7 alkyl”). In some embodiments, a heteroalkyl group is a group containing 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC _1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC _1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC _1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 3 carbon atoms and 1 heteroatom (“heteroC _1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 to 2 carbon atoms and 1 heteroatom (“heteroC _1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 1 carbon atom and 1 heteroatom (“heteroC ₁ alkyl”). In some embodiments, a heteroalkyl group is a saturated group containing 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC _2-6 alkyl”). Unless otherwise indicated, each example of a heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted (“substituted heteroalkyl”) with one or more substituents. In some embodiments, the heteroalkyl group is unsubstituted heteroC _1-10 alkyl. In some embodiments, the heteroalkyl group is a substituted heteroC _1-10 alkyl.

The term “heteroalkenyl” as used herein refers to an alkenyl group as defined herein that further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen , boron, silicon, phosphorus), where one or more heteroatoms are embedded between adjacent carbon atoms in the parent carbon chain, and/or one or more heteroatoms are embedded between the carbon atom and the parent molecule, that is, at the point of attachment. In some embodiments, a heteroalkenyl group refers to a group containing from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-10 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-9 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-8 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-7 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC _2-6 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC _2-5 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC _2-4 alkenyl”). In some embodiments, a heteroalkenyl group contains 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC _2-3 alkenyl”). In some embodiments, a heteroalkenyl group contains from 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC _2-6 alkenyl”). Unless otherwise indicated, each example of a heteroalkenyl group is independently unsubstituted (“unsubstituted heteroalkenyl”) or substituted (“substituted heteroalkenyl”) with one or more substituents. In some embodiments, the heteroalkenyl group is unsubstituted heteroC _2-10 alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC _2-10 alkenyl.

The term “heteroalkynyl” as used herein refers to an alkynyl group as defined herein which further contains one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen , boron, silicon, phosphorus), where one or more heteroatoms are embedded between adjacent carbon atoms in the parent carbon chain, and/or one or more heteroatoms are embedded between the carbon atom and the parent molecule, that is, at the point of attachment. In some embodiments, a heteroalkynyl group refers to a group containing from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-10 alkynyl”). In some embodiments, a heteroalkynyl group contains from 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-9 alkynyl”). In some embodiments, a heteroalkynyl group contains from 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-8 alkynyl”). In some embodiments, a heteroalkynyl group contains from 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC _2-7 alkynyl”). In some embodiments, a heteroalkynyl group contains 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC _2-6 alkynyl”). In some embodiments, a heteroalkynyl group contains from 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC _2-5 alkynyl”). In some embodiments, a heteroalkynyl group contains 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC _2-4 alkynyl”). In some embodiments, a heteroalkynyl group contains 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC _2-3 alkynyl”). In some embodiments, a heteroalkynyl group contains from 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC _2-6 alkynyl”). Unless otherwise indicated, each example of a heteroalkynyl group is independently unsubstituted (“unsubstituted heteroalkynyl”) or substituted (“substituted heteroalkynyl”) with one or more substituents. In some embodiments, the heteroalkynyl group is unsubstituted heteroC _2-10 alkynyl. In some embodiments, the heteroalkynyl group is a substituted heteroC _2-10 alkynyl.

As used herein, the terms “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” refer to the divalent radical of an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. Where a range or number of carbon atoms is specified for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of atoms carbon in a linear divalent carbon chain. "Alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" groups may be substituted or unsubstituted with one or more substituents as defined herein.

The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., containing 6, 10, or 14 shared electrons in a cyclic arrangement) containing 6-14 carbon atoms in the ring and zero heteroatoms present in the aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl group contains six ring carbon atoms ("C ₆ aryl"; eg, phenyl). In some embodiments, the aryl group contains ten ring carbon atoms ("C ₁₀ aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group contains fourteen ring carbon atoms ("C ₁₄ aryl"; eg, anthracyl). The term "aryl" also includes ring systems where the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms still refers to the number of atoms carbon in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrilene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene glycol, as-indacene, s-ndacene, indane, indene , naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafene, perylene, phenanthrene phenalene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise indicated, each example of an aryl group is independently, optionally, substituted, that is, unsubstituted (“unsubstituted aryl”) or substituted (“substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted C _6-14 aryl. In some embodiments, the aryl group is a substituted C _6-14 aryl.

In some embodiments, the aryl group is substituted with one or more groups selected from halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, cyano, hydroxy, C ₁ -C ₈ alkoxy, and amino.

Examples of typical substituted aryls include the following

wherein one of R ⁵⁶ and R ⁵⁷ may be hydrogen and at least one of R ⁵⁶ and R ⁵⁷ is each independently selected from C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C ₁ -C ₈ alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ⁵⁸ COR ⁵⁹ , NR ⁵⁸ SOR ⁵⁹ NR ⁵⁸ SO ₂ R ⁵⁹ , COOalkyl, COOaryl, CONR ⁵⁸ R ⁵⁹ , CONR ⁵⁸ OR ⁵⁹ , NR ⁵⁸ R ⁵⁹ , SO ₂ NR ⁵⁸ R ⁵⁹ , S-alkyl, SOalkyl, SO ₂ alkyl, Saryl, SOaryl, SO ₂ aryl; or R ⁵⁶ and R ⁵⁷ may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R ⁶⁰ and R ⁶¹ are, independently, hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₄ haloalkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, substituted C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl.

Other typical aryl groups having a fused heterocyclyl group include the following:

where each W is selected from C(R ⁶⁶ ) ₂ , NR ⁶⁶ , O and S; and each Y is selected from carbonyl, NR ⁶⁶ , O and S; and R ⁶⁶ is, independently, hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl.

"Fused aryl" refers to an aryl containing two ring carbons together with a second aryl or heteroaryl ring or a carbocyclyl or heterocyclyl ring.

"Aralkyl" is a subgroup of alkyl and aryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

The term "heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 common π electrons in a cyclic arrangement) containing carbon atoms in the ring and 1-4 heteroatoms in the ring , presented in an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency allows. Heteroaryl bicyclic ring systems may include one or more heteroatoms on one or both rings. “Heteroaryl” includes ring systems where the heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members also refers to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems where the heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl or heteroaryl ring, and in such cases the number of ring members refers to the number of ring members in the fused (aryl/heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (for example, indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on any ring, that is, either on a ring containing a heteroatom (for example, 2-indolyl), or on a ring that does not contain a heteroatom (for example, 5-indolyl).

In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms forming an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur atoms ("5-10 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms forming an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur atoms ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms forming an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur atoms ("5-6 member heteroaryl"). In some embodiments, the 5-6 membered heteroaryl contains 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur atoms. In some embodiments, the 5-6 membered heteroaryl contains 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur atoms. In some embodiments, the 5-6 membered heteroaryl contains 1 ring heteroatom selected from nitrogen, oxygen, and sulfur atoms. Unless otherwise indicated, each example of a heteroaryl group is independently optionally substituted, that is, unsubstituted (“unsubstituted heteroaryl”) or substituted (“substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

Typical 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Typical 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Typical 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Typical 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Typical 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Typical 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Representative 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizine silt and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of typical heteroaryls include the following:

where each Y is selected from carbonyl, N, NR ⁶⁵ , O and S; and R ⁶⁵ is, independently, hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl and 5-10 membered heteroaryl.

“Heteroaralkyl” is a subgroup of alkyl and heteroaryl as defined herein, and refers to an optionally substituted alkyl group substituted with an optionally substituted heteroaryl group.

"Carbocyclyl" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon radical containing 3 to 10 ring carbon atoms ("C _3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclyl group contains from 3 to 8 ring carbon atoms ("C _3-8 carbocyclyl"). In some embodiments, the carbocyclyl group contains from 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, the carbocyclyl group contains from 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, the carbocyclyl group contains from 5 to 10 ring carbon atoms ("C _5-10 carbocyclyl"). Typical _C3-6 carbocyclyl groups include, but are not limited to, cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl ( C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ) and the like. Typical C _3-8 carbocyclyl groups include, but are not limited to, the above C _3-6 carbocyclyl groups, as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2,2,1]heptanyl (C ₇ ), bicyclo[2,2,2]octanyl (C ₈ ) and the like. Examples of C _3-10 carbocyclyl groups include, but are not limited to, the above C _3-8 carbocyclyl groups, as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H- indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4,5]decanyl (C ₁₀ ) and the like. As illustrated by the examples above, in some embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes ring systems where the carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbon atoms also denotes the number of carbon atoms in the carbocyclyl ring system. Unless otherwise indicated, each example of a carbocyclyl group is independently optionally substituted, that is, unsubstituted (“unsubstituted carbocyclyl”) or substituted (“substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C _3-10 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C _3-10 carbocyclyl.

In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group containing from 3 to 10 ring carbon atoms ("C _3-10 cycloalkyl"). In some embodiments, the cycloalkyl group contains from 3 to 8 ring carbon atoms ("C _3-8 cycloalkyl"). In some embodiments, the cycloalkyl group contains from 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl"). In some embodiments, the cycloalkyl group contains from 5 to 6 ring carbon atoms ("C _5-6 cycloalkyl"). In some embodiments, the cycloalkyl group contains from 5 to 10 ring carbon atoms ("C _5-10 cycloalkyl"). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include the above C _5-6 cycloalkyl groups, as well as cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-8 cycloalkyl groups include the above C _3-6 cycloalkyl groups, as well as cycloheptyl (C ₇ ) and cyclooctyl (C ₈ ). Unless otherwise indicated, each example of a cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In some embodiments, the cycloalkyl group is an unsubstituted C _3-10 cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C _3-10 cycloalkyl.

"Heterocyclyl" or "heterocyclic" refers to a radical of a 3 to 10 membered non-aromatic ring system containing ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ( "3-10 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence allows. The heterocyclyl group may be either a monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems where a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups where the point of attachment is on either the carbocyclyl or heterocyclyl ring, or ring systems where a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members also denotes the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, each example of a heterocyclyl is independently optionally substituted, that is, unsubstituted (“unsubstituted heterocyclyl”) or substituted (“substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In some embodiments, the heterocyclyl group is a substituted 3-10 membered heterocyclyl.

In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 member heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur atoms (“5-8 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur atoms (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl contains 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur atoms. In some embodiments, the 5-6 membered heterocyclyl contains 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur atoms. In some embodiments, the 5-6 membered heterocyclyl contains one ring heteroatom selected from nitrogen, oxygen and sulfur atoms.

Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thioranyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanyl, and tiepanil. Examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Examples of 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Specific examples of heterocyclyl groups are shown in the following illustrative examples:

where each W is selected from CR ⁶⁷ , C(R ⁶⁷ ) ₂ , NR ⁶⁷ , O and S; and each Y is selected from NR ⁶⁷ , O and S; and R ⁶⁷ independently represents hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl. Said heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy , azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O) ₂ -alkyl and -S(O) ₂ -aryl. Substituent groups include carbonyl or thiocarbonyl, which form, for example, lactam and urea derivatives.

"Hetero", when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound are replaced by a heteroatom of nitrogen, oxygen or sulfur. The term hetero can be applied to any of the hydrocarbon groups described above, such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocyclyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like, having from 1 to 5 , in particular from 1 to 3 heteroatoms.

"Acyl" refers to the radical -C(O)R ²⁰ , where R ²⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein. "Alkanoyl" represents an acyl group, where R ²⁰ represents a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH ₃ ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O) )CH ₂ Ph), -C(O)-C ₁ -C ₈ alkyl, -C(O)-(CH ₂ ) _t (C ₆ -C ₁₀ aryl), -C(O)-(CH ₂ ) _t (5-10 membered heteroaryl), -C(O)-(CH ₂ ) _t (C ₃ -C ₁₀ cycloalkyl) and -C(O)-(CH ₂ ) _t (4-10 membered heterocyclyl), where t denotes an integer from 0 to 4. In some embodiments, R ²¹ is C ₁ -C ₈ alkyl substituted with halogen or hydroxy; or C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, arylalkyl, 5-10 member heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy.

"Acylamino" refers to the radical -NR ²² C(O)R ²³ where each example of R ²² and R ²³ is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl , substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined herein, or R ²² is an amino protecting group. Typical "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino and benzylcarbonylamino. Specific examples of "acylamino" groups are -NR ²⁴ C(O)-C ₁ -C ₈ alkyl, -NR ²⁴ C(O)-(CH ₂ ) _t (C ₆ -C ₁₀ aryl), -NR ²⁴ C(O )-(CH ₂ ) _t (5-10 membered heteroaryl), -NR ²⁴ C(O)-(CH ₂ ) _t (C ₃ -C ₁₀ cycloalkyl) and -NR ²⁴ C(O)-(CH ₂ ) _t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and each R ²⁴ independently represents H or C ₁ -C ₈ alkyl. In some embodiments, R ²⁵ is H, C ₁ -C ₈ alkyl substituted with halogen or hydroxy; C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, arylalkyl, 5-10 member heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy; and R ²⁶ represents H, C ₁ -C ₈ alkyl substituted with halogen or hydroxy; C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, arylalkyl, 5-10 member heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxyl; provided that at least one of R ²⁵ and R ²⁶ is other than H.

"Acyloxy" refers to the radical -OC(O)R ²⁷ where R ²⁷ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl as defined herein. Typical examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In some embodiments, R ²⁸ is C ₁ -C ₈ alkyl substituted with halogen or hydroxy; C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, arylalkyl, 5-10 member heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy.

"Alkoxy" refers to the group -OR ²⁹ where R ²⁹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, that is, containing from 1 to 6 carbon atoms. In addition, partial alkoxy groups contain from 1 to 4 carbon atoms.

In some embodiments, R ²⁹ is a group that contains 1 or more substituents, such as 1 to 5 substituents, and especially 1 to 3 substituents, particularly 1 substituent selected from the group consisting of amino, substituted with amino , C ₆ -C ₁₀ aryl, aryloxy, carboxyl, cyano, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O )-, aryl-S(O)-, alkyl-S(O) ₂ - and aryl-S(O) ₂ -. Examples of 'substituted alkoxy' groups include, but are not limited to, -O-(CH ₂ ) _t (C ₆ -C ₁₀ aryl), -O-(CH ₂ ) _t (5-10 membered heteroaryl), -O-( CH ₂ ) _t (C ₃ -C ₁₀ cycloalkyl) and -O-(CH ₂ ) _t (4-10 membered heterocyclyl), where t denotes an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present may in turn be substituted by unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy. Specific examples of 'substituted alkoxy' groups are -OCF ₃ , -OCH ₂ CF ₃ , -OCH ₂ Ph, -OCH ₂ -cyclopropyl, -OCH ₂ CH ₂ OH and -OCH ₂ CH ₂ NMe ₂ .

"Amino" refers to the radical -NH ₂ .

"Substituted amino" refers to an amino group of formula -N(R ³⁸ ) ₂ where R ³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, wherein at least one of R ³⁸ is not hydrogen. In some embodiments, each R ³⁸ is independently selected from hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C ₃ -C ₁₀ cycloalkyl; or C ₁ -C ₈ alkyl substituted with halogen or hydroxy; C ₃ -C ₈ alkenyl substituted with halogen or hydroxy; C ₃ -C ₈ alkynyl substituted with halogen or hydroxy or -(CH ₂ ) _t (C ₆ -C ₁₀ aryl), -(CH ₂ ) _t (5-10 membered heteroaryl), -(CH ₂ ) _t (C ₃ -C ₁₀ cycloalkyl) or -(CH ₂ ) _t (4-10 membered heterocyclyl), where t denotes an integer from 0 to 8, each of which is substituted by unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy; or both R ³⁸ groups are linked to form an alkylene group.

Typical "substituted amino" groups include, but are not limited to, -NR ³⁹ -C ₁ -C ₈ alkyl, -NR ³⁹ -(CH ₂ ) _t (C ₆ -C ₁₀ aryl), -NR ³⁹ -(CH ₂ ) _t (5-10 membered heteroaryl), -NR ³⁹ -(CH ₂ ) _t (C ₃ -C ₁₀ cycloalkyl) and -NR ³⁹ -(CH ₂ ) _t (4-10 member heterocyclyl), where t denotes an integer from 0 to 4, for example 1 or 2, each R ³⁹ independently represents H or C ₁ -C ₈ alkyl; and any alkyl groups present may in turn be substituted by halogen, substituted or unsubstituted amino or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present may in turn be substituted by unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy. For the avoidance of doubt, the term 'substituted amino' includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino, as defined below. Substituted amino includes both monosubstituted amino and disubstituted amino groups.

"Azido" refers to the radical -N ₃ .

"Carbamoyl" or "amido" refers to the radical -C(O)NH ₂ .

"Substituted carbamoyl" or "substituted amido" refers to the radical -C(O)N(R ⁶² ) ₂ where each R ⁶² independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or an amino protecting group, wherein at least one of R ⁶² is not hydrogen. In some embodiments, R ⁶² is selected from H, C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C ₁ -C ₈ alkyl substituted with halogen or hydroxy; or C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, aralkyl, 5-10 member heteroaryl or heteroaralkyl, each of which is substituted with unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy; provided that at least one R ⁶² was other than H.

Examples of "substituted carbamoyl" groups include, but are not limited to, -C(O)NR ⁶⁴ -C ₁ -C ₈ alkyl, -C(O)NR ⁶⁴ -(CH ₂ ) _t (C ₆ -C ₁₀ aryl), -C(O)N ⁶⁴ -(CH ₂ ) _t (5-10 membered heteroaryl), -C(O)NR ⁶⁴ -(CH ₂ ) _t (C ₃ -C ₁₀ cycloalkyl) and -C(O)NR ⁶⁴ -(CH ₂ ) _t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, each R ⁶⁴ independently represents H or C ₁ -C ₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present in may in turn be substituted by unsubstituted C ₁ -C ₄ alkyl, halogen, unsubstituted C ₁ -C ₄ alkoxy, unsubstituted C ₁ -C ₄ haloalkyl, unsubstituted C ₁ -C ₄ hydroxyalkyl or unsubstituted C ₁ -C ₄ haloalkoxy or hydroxy.

"Carboxy" refers to the radical -C(O)OH.

"Cyano" refers to the -CN radical.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is either fluorine or chlorine.

"Hydroxy" refers to the -OH radical.

"Nitro" refers to the radical -NO ₂ .

"Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is replaced by a cycloalkyl group. Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl and cyclooctylethyl and the like.

"Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is replaced by a heterocyclyl group. Examples of heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl and the like.

"Cycloalkenyl" refers to a substituted or unsubstituted carbocyclyl group containing from 3 to 10 carbon atoms and having a cyclic ring or polyfused rings, including fused and bridged ring systems, and containing at least one and in particular from 1 to 2 area of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl and the like.

“Fused cycloalkenyl” refers to a cycloalkenyl having two ring carbon atoms in common with a second aliphatic or aromatic ring and having olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.

"Ethenyl" refers to substituted or unsubstituted -(C=C)-.

"Ethylene" refers to substituted or unsubstituted -(C-C)-.

"Ethynyl" refers to -(C≡C)-.

"Nitrogen-containing heterocyclyl" group means a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but not limited to, morpholine, piperidine (for example, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkyl piperazines such as N-methyl piperazine. Specific examples include azetidine, piperidone and piperazone.

"Tioketo" belongs to the =S group.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" "alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). Generally, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (for example, a carbon or nitrogen atom) is replaced by an acceptable substituent, for example, a substituent that, when substituted, results in a stable compound, for example, a compound that does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. The term "substituted" is intended to include substitution with all possible substituents of organic compounds, any of the substituents described herein, which results in the formation of a stable compound. The present invention contemplates any and all such combinations that result in a stable connection. For purposes of the present invention, heteroatoms, such as nitrogen, may have hydrogen substituents and/or any suitable substituents as described herein that satisfy the valency of the heteroatoms and result in the formation of a stable moiety.

Examples of carbon atom substituents include, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON(R ^bb ) ₂ , - N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^CC )R ^bb , -SH, -SR ^aa , -SSR ^CC , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^CC ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC( =O)N(R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC (=NR ^bb )N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , - SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(= O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^CC ) ₂ , -P(=O) ₂ N (R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , -NR ^bb P(= O)(OR ^CC ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^CC ) ₂ , -P(R ^CC ) ₃ , -OP(R ^CC ) ₂ , -OP(R ^CC ) ₃ , -B(R ^aa ) ₂ , -B(OR ^CC ) ₂ , -BR ^aa (OR ^CC ), C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, _C3-10 carbocyclyl, 3-14 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3 , 4 or 5 groups R ^dd ;

or two geminal (attached to the same atom) hydrogen atoms on a carbon atom are replaced by a group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(= O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^CC ;

each example of R ^aa is independently selected from C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5 -14 membered heteroaryl or two R aa groups ^are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3 , 4 or 5 groups R ^dd ;

each example R ^bb is independently selected from hydrogen, -OH, -OR ^aa , -N(R ^CC ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^CC ) ₂ , - CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^CC )OR ^aa , -C(=NR ^CC )N(R ^CC ) ₂ , -SO ₂ N(R ^CC ) ₂ , -SO ₂ R ^CC , -SO ₂ OR ^CC , -SOR ^aa , -C(=S)N(R ^CC ) ₂ , -C(=O)SR ^CC , -C(=S)SR ^CC , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^CC ) ₂ , -P(=O)(NR ^CC ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^bb groups linked to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl ring is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

each R ^CC example is independently selected from hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and a 5-14 membered heteroaryl, or two R ^CC groups are linked to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2 , 3, 4 or 5 groups R ^dd ;

each example R ^dd is independently selected from halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N(R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , -NR ^ff C( =O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff )R ^ee , - OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff )N(R ^ff ) ₂ ,-NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si (R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , -SC(=S )SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two R ^dd substituents attached to the same atom can be combined to form =O or =S;

each example of R ^ee is independently selected from C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl and 3 -10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

each example R ^ff is independently selected from hydrogen, C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl and a 5-10 membered heteroaryl, or two R ^ff groups are linked to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2 , 3, 4 or 5 groups R ^gg ; And

each example R ^gg is, independently, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl ) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl), -NH(OH), - SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), - OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , - OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=NH)(C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N( C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC (NH)NH(C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _{1 -6} alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _{1 -6} alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ -C(=S)N(C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S) SC _1-6 alkyl, -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP (=O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 perhaloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two R ^gg substituents attached to the same atom can be combined to form =O or =S; where X ^- represents a counterion.

A "counterion" or "anionic counterion" is a negatively charged group bonded to a cationic quaternary amino group to maintain electronic neutrality. Typical counterions include halogen ions (eg, F ^- , Cl ^- , Br ^- , I ^- ), NO ₃ ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , SO ₄ ^-2 sulfonate ions ( for example, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate and the like), and carboxylate ions (eg acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate and the like).

Nitrogen atoms may be substituted or unsubstituted as valency allows and include primary, secondary, tertiary and quaternary nitrogen atoms. Typical nitrogen substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(R ^CC ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^CC ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^CC )OR ^aa , -C(=NR ^CC )N(R ^CC ) ₂ , - SO ₂ N(R ^CC ) ₂ , -SO ₂ R ^CC , -SO ₂ OR ^CC , -SOR ^aa , -C(=S)N(R ^CC ) ₂ , -C(=O)SR ^CC , -C( =S)SR ^CC , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^CC ) ₂ , -P(=O)(NR ^CC ) ₂ , _C1-10 alkyl, _C1-10 perhaloalkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-10 carbocyclyl, 3-14 membered heterocyclyl, _C6-14 aryl and 5-14 member heteroaryl, or two R ^CC groups attached to a nitrogen atom, are linked to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 groups R ^dd , and where R ^aa , R ^bb , R ^CC and R ^dd have the meanings defined above.

These and other typical substituents are described in more detail in the Detailed Description, Examples and Claims sections. The invention should not be limited in any way by the above list of examples of substituents.

Other definitions

The term "pharmaceutically acceptable salt" refers to salts that are medically suitable for use in contact with tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reaction, or the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. PharmaCeutiCal SCienCes (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic acids and organic bases. And examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid , maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C ₁ - ₄ alkyl) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate.

The "subject" to which administration is contemplated includes, but is not limited to, a human (i.e., a man or woman of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young, middle-aged or elderly person)) and/or a non-human animal, for example, a mammal such as primates (eg, cynomolgus, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and /or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is an animal, not a human. The terms "person", "patient" and "subject" are used interchangeably herein.

The terms disease, disorder and condition are used interchangeably herein.

As used herein, and unless otherwise indicated, the terms “treat,” “treatment,” and “treatment” imply an action that occurs while a subject is suffering from a specified disease, disorder, or condition and that reduces the severity of the disease, disorder or condition, or inhibits or slows the progression of a disease, disorder or condition ("therapeutic treatment"), and involves an action that occurs before the subject begins to suffer from said disease, disorder or condition ("preventive treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to produce the desired biological response. One of ordinary skill in the art will appreciate that the effective amount of a compound of the invention may vary depending on factors such as the desired biological effect, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health and condition of the subject. The effective amount covers therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic effect in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with a disease, disorder or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other types of therapeutic agents, that provides a therapeutic effect in treating a disease, disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves overall therapy, reduces or eliminates symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is one sufficient to prevent the disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent recurrence thereof. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic effect in preventing a disease, disorder or condition. The term “prophylactically effective amount” may encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

Detailed Description of Some Embodiments of the Invention

In the course of researching Org-1 analogues for NMDA modulation, part of which is described in PCT/US2012/054261, incorporated herein by reference, the present inventors have discovered a certain combination of elements that provides NMDA modulators with relatively superior properties. For example, as shown in Table 1, compounds containing a beta hydrogen at _C5 are less preferred than compounds containing either an alpha hydrogen at _C5 or a double bond between _C5 - _C6 , due to reduced NMDA receptor potentiation . Removal of the methyl at _C21 also results in a significant attenuation of NMDA potentiation. Disubstitution with C ₃ is expected to increase the metabolic stability of these compounds and is thus a preferred feature of the invention. Fluorination on the C ₁₇ side chain has been shown to increase potency and limit maximum potentiation of NMDA receptors, when studied, to a compound concentration of 1 μM. A secondary or tertiary alcohol terminal group on the _C17 side chain has been shown to enhance potency and limit maximum potentiation of the NMDA receptor to a compound concentration of 1 µM and is thus a preferred feature of the present invention, with preference for bulk groups at the end containing 2-3 carbon atoms, or a group containing a fluorine substituent. Such properties are expected to limit the risk of inducing glutamate-mediated neurotoxicity compared to compounds that achieve greater maximal potentiation of the NMDA receptor. The compounds of the present invention include various combinations of these specified features to provide excellent NMDA modulators.

Connections

In one aspect, compounds according to formula (I) are provided:

and pharmaceutically acceptable salts thereof;

R ¹ represents a substituted or unsubstituted aliphatic group;

R ² is hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted cyclopropyl, or -OR ^A2 , where R ^A2 is hydrogen or substituted or unsubstituted alkyl;

R ^3a is hydrogen or -OR ^A3 , where R ^A3 is hydrogen or substituted or unsubstituted alkyl, and R ^3b is hydrogen; or R ^3a and R ^3b are linked to form an oxo (=O) group;

R ⁴ represents hydrogen, substituted or unsubstituted alkyl or halogen;

X is -C(R ^X ) ₂ - or -O-, where R ^X is hydrogen or fluorine, or one group of R ^X and R ^5b are linked to form a double bond;

each example of R ^5a and R ^5b is independently hydrogen or fluorine;

R ^6a represents a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, and a substituted and unsubstituted heteroaryl group wherein the non-hydrogen group is optionally replaced by fluorine; And

R ^6b represents hydrogen or a substituted or unsubstituted alkyl group, optionally substituted with fluorine;

denotes a single or double bond, with the proviso that if a single bond is present, then the hydrogen on _C5 is in alpha configuration;

and further provided that:

(1) at least one of R ^X , R ^5a and R ^5b is fluorine; or

(2) at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine; or

(3) R ^6a represents a non-hydrogen group containing two to ten carbon atoms.

In general, compounds described herein where the hydrogen at _C5 is in the beta configuration exhibit a loss of NMDA enhancement compared to compounds where the hydrogen at _C5 is alpha , or where the double bond is at _C5 - _C6 . Thus, a compound of formula (I) covers only compounds of formulas (IA) and (IB):

(IA)

(IB)

and pharmaceutically acceptable salts thereof.

Group R ¹

As defined throughout herein, R ¹ represents a substituted or unsubstituted aliphatic group, that is, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl.

In some embodiments, R ¹ is a substituted or unsubstituted alkyl, e.g., a substituted or unsubstituted C _1-6 alkyl, a substituted or unsubstituted C _1-2 alkyl, a substituted or unsubstituted C _2-3 alkyl, a substituted or unsubstituted C _3-4 alkyl , substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl. Examples of R ¹ C _1-6 alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), tert-butyl ( _C4 ), sec-butyl ( _C4 ), iso-butyl ( _C4 ), n-pentyl ( _C5 ), 3-pentanyl ( _C5 ), amyl ( _C5 ), neopentyl ( _C5 ), 3-methyl-2-butanyl ( _C5 ), tertiary amyl ( _C5 ), n-hexyl ( _C6 ), _C1-6 alkyl substituted 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10 or more fluorine groups (for example, -CF ₃ , -CH ₂ F, -CHF ₂ , difluoroethyl and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C _{1- 6} alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chlorine groups (for example, -CH ₂ Cl, -CHCl ₂ ), and C _1-6 alkyl substituted with alkoxy groups (for example, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ O-cyclopropyl). In some embodiments, R ¹ is a substituted alkyl, for example, R ¹ is alkyl, alkoxyalkyl, or aminoalkyl. In some embodiments, R ¹ is Me, Et, n-Pr, n-Bu, iso-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethylethyl, methoxymethyl, methoxyethyl or ethoxymethyl.

In some embodiments, R ¹ is unsubstituted C _1-3 alkyl, for example, R ¹ is -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH ₂ CH ₃ .

In some embodiments, R ¹ is alkyl substituted with one or more fluorine atoms; for example, R ¹ is -CH ₂ F, -CHF ₂ or -CF ₃ .

In some embodiments, R ¹ is alkyl substituted with one or more -OR ^A1 groups, where R ^A1 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R ¹ is -CH ₂ OR ^A1 , for example, where R ^A1 is hydrogen, -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH ₂ CH ₃ .

In some embodiments, R ¹ is substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-3 alkenyl, substituted or unsubstituted C _3-4 alkenyl, substituted or unsubstituted C _4-5 alkenyl or substituted or unsubstituted _C5-6 alkenyl. In some embodiments, R ¹ is ethenyl (C ₂ ), propenyl (C ₃ ), or butenyl (C ₄ ), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl. In some embodiments, R ¹ is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxy. In some embodiments, R ¹ is ethenyl.

In some embodiments, R ¹ is substituted or unsubstituted alkynyl, e.g., substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _2-3 alkynyl, substituted or unsubstituted C _3-4 alkynyl, substituted or unsubstituted C _4-5 alkynyl , or substituted or unsubstituted C _5-6 alkynyl. Examples of substituted or unsubstituted R ¹ alkynyl groups include, but are not limited to, ethynyl, propynyl or butynyl, unsubstituted or substituted alkyl, halogen, haloalkyl (eg, CF ₃ ), alkoxyalkyl, cycloalkyl (eg, cyclopropyl or cyclobutyl) or hydroxyl. In some embodiments, R ¹ is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, propynyl, fluoropropynyl, and chloroethynyl. In some embodiments, R ¹ is ethynyl (C ₂ ), propynyl (C ₃ ), or butynyl (C ₄ ), unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl. In some embodiments, R ¹ is ethynyl (C ₂ ), propynyl (C ₃ ), or butynyl (C ₄ ), substituted with substituted phenyl. In some embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halogen, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amido. In some embodiments, R ¹ is ethynyl (C ₂ ), propynyl (C ₃ ), or butynyl (C ₄ ), substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-thiazolyl, 1,2,4-thiazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl.

In some embodiments, R ¹ is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl. In some embodiments, R ¹ is ethynyl or propynyl substituted with substituted or unsubstituted aryl. In some embodiments, R ¹ is ethynyl or propynyl substituted with phenyl, unsubstituted or substituted halogen, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In some embodiments, R ¹ is ethynyl or propynyl substituted with a substituted or unsubstituted carbocyclyl. In some embodiments, R ^3a is ethynyl or propynyl substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R ¹ is ethynyl or propynyl substituted with substituted or unsubstituted heteroaryl. In some embodiments, R ¹ is ethynyl or propynyl substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. In some embodiments, R ¹ is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-thiazolyl, 1,2,4-thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In some embodiments, R ¹ is ethynyl or propynyl substituted with substituted or unsubstituted heterocyclyl. In some embodiments, R ¹ is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R ¹ is propynyl or butynyl substituted with hydroxyl or alkoxy. In some embodiments, R ¹ is propynyl or butynyl substituted with methoxy or ethoxy. In some embodiments, R ¹ is ethynyl or propynyl substituted with chlorine. In some embodiments, R ¹ is ethynyl or propynyl substituted with trifluoromethyl.

In some embodiments, R ¹ is a substituted or unsubstituted carbocyclyl, such as a substituted or unsubstituted C _3-6 carbocyclyl, a substituted or unsubstituted C _3-4 carbocyclyl, a substituted or unsubstituted C _4-5 carbocyclyl, or a substituted or unsubstituted C _5-6 carbocyclyl . In some embodiments, R ¹ is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

Groups R ² , R ^3a , R ^3b and R ⁴

As defined throughout herein, R ² is hydrogen, halogen, substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted cyclopropyl or -OR ^A2 , wherein R ^{A 2} is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is a halogen, such as fluorine, chlorine, bromine, or iodine. In some embodiments, R ² is fluorine or chlorine. In some embodiments, R ² is substituted or unsubstituted C _1-6 alkyl, e.g., substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _3-4 alkyl, substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl. In some embodiments, R ² is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ or cyclopropyl. In some embodiments, R ² is -OR ^A2 . In some embodiments, R ^A2 is hydrogen. In some embodiments, R ^A2 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _3-4 alkyl , substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl. In some embodiments, R ^A2 represents hydrogen, -CH ₃ , -CH ₂ CH ₃ or -CH ₂ CH ₂ CH ₃ , that is, represents R ² groups of the formula -OH, -OCH ₃ , -OCH ₂ CH ₃ , or -OCH ₂ CH ₂ CH ₃ . In some embodiments, R ² is a non-hydrogen substituent of the alpha configuration. In some embodiments, R ² is a non-hydrogen substituent of the beta configuration.

As defined throughout herein, R ^3a is hydrogen or -OR ^A3 , wherein R ^A3 is hydrogen or substituted or unsubstituted alkyl, and R ^3b is hydrogen; or R ^3a and R ^3b are linked to form an oxo (=O) group.

In some embodiments, R ^3a and R ^3b are both hydrogen.

In some embodiments, R ^3a and R ^3b are coupled to form an oxo (=O) group.

In some embodiments, R ^3a is -OR ^A3 and R ^3b is hydrogen. In some embodiments, wherein R ^3a is -OR ^A3 , R ^3a has an alpha or beta configuration. In some embodiments, wherein R ^3a is -OR ^A3 , R ^3a has an alpha configuration. In some embodiments, wherein R ^3a is -OR ^A3 , R ^3a has a beta configuration. In some embodiments, R ^A3 is hydrogen. In some embodiments, R ^A3 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _3-4 alkyl , substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl. In some embodiments, R ^A3 is hydrogen, -CH ₃ , -CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₃ , that is, represents a group R ^3a of the formula -OH, -OCH ₃ , -OCH ₂ CH ₃ or -OCH ₂ CH ₂ CH ₃ .

As defined throughout herein, R ⁴ is hydrogen, substituted or unsubstituted alkyl, or halogen. In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is a halogen, such as fluorine. In some embodiments, R ⁴ is a substituted or unsubstituted alkyl, e.g., a substituted or unsubstituted C _1-6 alkyl, a substituted or unsubstituted C _1-2 alkyl, a substituted or unsubstituted C _2-3 alkyl, a substituted or unsubstituted C _3-4 alkyl , substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl. In some embodiments, R ⁴ is C ₁ alkyl, such as -CH ₃ or -CF ₃ . In some embodiments, R ⁴ is hydrogen, -CH ₃ or -F. In some embodiments, when represents a single bond, R ⁴ represents a non-hydrogen substituent has an alpha configuration. In some embodiments, where represents a single bond, R ⁴ represents a non-hydrogen substituent has a beta configuration.

Group X, R ^5a , R ^5b , R ^6a and R ^6b

As defined throughout herein, X is -C(R ^X ) ₂ - or -O-, wherein R ^X is hydrogen or fluorine, or one group of R ^X and R ^5b are linked to form a double bond; R ^5a and R ^5b are each independently hydrogen or fluorine; R ^6a represents a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl and a substituted and unsubstituted heteroaryl group, wherein the non-hydrogen group is optionally substituted with fluorine; and R ^6b represents hydrogen or a substituted or unsubstituted alkyl group, optionally substituted with fluorine; with the proviso that: (1) at least one of R ^X , R ^5a and R ^5b is fluorine; or (2) at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine; or (3) R ^6a represents a non-hydrogen group containing from two to ten carbon atoms.

In some embodiments, X is -O-. In some embodiments, X is -CH ₂ -. In some embodiments, X is -CF ₂ -.

In some embodiments, at least one of R ^5a and R ^5b is hydrogen. In some embodiments, at least one of R ^5a and R ^5b is fluorine. In some embodiments, R ^5a and R ^5b are both hydrogen. In some embodiments, R ^5a and R ^5b are both fluorine. In some embodiments, R ^X and R ^5b are linked to form a double bond, such as a cis or trans double bond.

In some embodiments, R ^6a is a non-hydrogen group as defined herein that is not substituted with fluorine. In some embodiments, R ^6a is substituted or unsubstituted alkyl (eg, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ ), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl (eg , isopropanol). In some embodiments, R ^6a is a non-hydrogen group as defined herein that is substituted with fluorine.

In some embodiments, R ^6a is a non-hydrogen group as defined herein, and R ^6b is hydrogen. In some embodiments, R ^6a is a non-hydrogen group as defined herein, and R ^6b is a substituted or unsubstituted alkyl group, optionally substituted with fluorine. In some embodiments, R ^6b is an alkyl group that is not substituted with fluorine. In some embodiments, R ^6a is an alkyl group that is substituted with fluorine.

In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is a substituted or unsubstituted alkyl, e.g., a substituted or unsubstituted C _1-6 alkyl, a substituted or unsubstituted C _1-2 alkyl, a substituted or unsubstituted C _2-3 alkyl, a substituted or unsubstituted C _3-4 alkyl , substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl, optionally substituted with fluorine. In some embodiments, R ^6b is C ₁ alkyl, optionally substituted with fluorine, such as -CH ₃ or -CF ₃ .

In some embodiments, R ^6a is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C _1-6 alkyl, substituted or unsubstituted C _1-2 alkyl, substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _3-4 alkyl , substituted or unsubstituted C _4-5 alkyl or substituted or unsubstituted C _5-6 alkyl. Examples of R ^6a C _1-6 alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C ₁ ), substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), substituted or unsubstituted isopropyl ( C ₃ ), substituted or unsubstituted n-butyl (C ₄ ), substituted or unsubstituted tert-butyl (C ₄ ), substituted or unsubstituted sec-butyl (C ₄ ), substituted or unsubstituted iso-butyl (C ₄ ), substituted or unsubstituted n-pentyl ( _C5 ), substituted or unsubstituted 3-pentanyl ( _C5 ), substituted or unsubstituted amyl ( _C5 ), substituted or unsubstituted neopentyl ( _C5 ), substituted or unsubstituted 3-methyl-2-butanyl (C ₅ ), substituted or unsubstituted tertiary amyl ( _C5 ), substituted or unsubstituted n-hexyl ( _C6 ). In some embodiments, R ^6a is alkyl, as described above, substituted with one or more fluorine atoms, for example, 1, 2, 3, 4 or more fluorine atoms. In some embodiments, R ^6a is -CF ₃ , -CH ₂ F, -CHF ₂ , difluoroethyl, or 2,2,2-trifluoro-1,1-dimethylethyl. In some embodiments, R ^6a is alkyl, as described above, substituted with one or more -OR ^A6 groups, where R ^{A 6} is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 , for example, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ CH ₂ CH ₂ OCH ₃ .

In some embodiments, R ^6a is substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted C _2-6 alkenyl, substituted or unsubstituted C _2-3 alkenyl, substituted or unsubstituted C _3-4 alkenyl, substituted or unsubstituted C _4-5 alkenyl , or substituted or unsubstituted C _5-6 alkenyl, optionally substituted with fluorine. In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ).

In some embodiments, R ^6a is substituted or unsubstituted alkynyl, e.g., substituted or unsubstituted C _2-6 alkynyl, substituted or unsubstituted C _2-3 alkynyl, substituted or unsubstituted C _3-4 alkynyl, substituted or unsubstituted C _4-5 alkynyl or substituted or unsubstituted C _5-6 alkynyl, optionally substituted with fluorine. In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ).

In some embodiments, R ^6a is a substituted or unsubstituted carbocyclyl, e.g., a substituted or unsubstituted C _3-6 carbocyclyl, a substituted or unsubstituted C _3-4 carbocyclyl, a substituted or unsubstituted C _4-5 carbocyclyl, or a substituted or unsubstituted C _5-6 carbocyclyl, optionally substituted with fluorine. In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl.

In some embodiments, R ^6a is a substituted or unsubstituted heterocyclyl, such as a substituted or unsubstituted C _3-6 heterocyclyl, a substituted or unsubstituted C _3-4 heterocyclyl, a substituted or unsubstituted C _4-5 heterocyclyl, or a substituted or unsubstituted C _5-6 heterocyclyl, optionally substituted with fluorine.

In some embodiments, R ^6a is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl, optionally substituted with fluorine.

In some embodiments, R ^6a is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5-6 membered heteroaryl, optionally substituted with fluorine.

In some embodiments, R ^6a is a non-hydrogen group containing two to ten carbon atoms, such as two to nine, two to eight, two to seven, two to six, two to five, two to four or two to three carbon atoms, inclusive. For example, in some embodiments, R ^6a is substituted or unsubstituted C _2-3 alkyl, substituted or unsubstituted C _2-3 alkenyl, substituted or unsubstituted C _2-3 alkynyl, or substituted or unsubstituted C ₃ carbocyclyl.

In some embodiments, wherein at least one of R ^X , R ^5a and R ^5b is fluorine; or at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine; R ^6a is substituted or unsubstituted C _1-3 alkyl, substituted or unsubstituted C _1-3 alkenyl, substituted or unsubstituted C _1-3 alkynyl, or substituted or unsubstituted C ₃ carbocyclyl.

In some embodiments, R ^6a and R ^6b are the same group. In some embodiments, R ^6a and R ^6b are different groups and the carbon atom that is attached to R ^6a has an (S) or (R) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is -CF ₃ and R ^6b is hydrogen or C _1-4 alkyl. In some embodiments, R ^6a is a non-hydrogen group substituted with fluorine, and R ^6b is -CH ₃ . In some embodiments, R ^6a is substituted with one or more -OR ^A6 groups, where R ^A6 is hydrogen or substituted or unsubstituted alkyl. In some embodiments, R ^6a is substituted or unsubstituted C _2-4 alkyl, substituted or unsubstituted C _2-3 alkenyl, substituted or unsubstituted C _2-3 alkynyl, or substituted or unsubstituted C ₃ carbocyclyl, and R ^6b is -CH ₃ . In some embodiments, R ^6a is unsubstituted C _2-4 alkyl, unsubstituted C _2-3 alkenyl, or unsubstituted C _2-3 alkynyl, or unsubstituted C ₃ carbocyclyl, and R ^6b is -CH ₃ . In some embodiments, R ^6a is a non-hydrogen group substituted with fluorine, and R ^6b is -CH ₃ .

Various combinations of certain options

Various combinations of certain embodiments of the invention are proposed hereinafter.

For example, in some embodiments, when X is -CH ₂ -, and R ^5a and R ^5b are both hydrogen, a compound of formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof. In some embodiments, R ^6a is a non-hydrogen group containing from two to ten carbon atoms. In some embodiments, at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is methyl (C ₁ ), optionally substituted with one or more fluorine atoms, such as -CH ₃ or -CF ₃ . In some embodiments, R ^6a is substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), or substituted or unsubstituted isopropyl (C ₃ ). In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 . In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is -CH ₃ or -CF ₃ . In some embodiments denotes a single bond, and the hydrogen on _C5 is alpha . In some embodiments denotes a double bond. In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ² is hydrogen, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , cyclopropyl , fluorine or chlorine. In some embodiments, R ² is a non-hydrogen substituent of the alpha configuration. In some embodiments, R ² is a non-hydrogen substituent of the beta configuration. In some embodiments, R ^3a and R ^3b are both hydrogen. In some embodiments, R ^3a and R ^3b are coupled to form =O (oxo). In some embodiments, R ⁴ is hydrogen.

In some embodiments, when X is -CH ₂ -, and R ^5a and R ^5b are both fluorine, a compound of formula (Ib) is provided:

or a pharmaceutically acceptable salt thereof. In some embodiments, R ^6a is a non-hydrogen group containing from two to ten carbon atoms. In some embodiments, at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is methyl (C ₁ ), optionally substituted with one or more fluorine atoms, such as -CH ₃ or -CF ₃ . In some embodiments, R ^6a is substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), or substituted or unsubstituted isopropyl (C ₃ ). In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 . In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is -CH ₃ or -CF ₃ . In some embodiments denotes a single bond, and the hydrogen on _C5 is alpha . In some embodiments denotes a double bond. In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ² is hydrogen, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , cyclopropyl , fluorine or chlorine. In some embodiments, R ² is a non-hydrogen substituent of the alpha configuration. In some embodiments, R ² is a non-hydrogen substituent of the beta configuration. In some embodiments, R ^3a and R ^3b are both hydrogen. In some embodiments, R ^3a and R ^3b are coupled to form =O (oxo). In some embodiments, R ⁴ is hydrogen.

In some embodiments, when where X is -C(R ^X ) ₂ -, and one group of R ^X and R ^5b are linked to form a trans double bond, a compound of formula (IC) is provided:

or a pharmaceutically acceptable salt thereof. In some embodiments, R ^6a is a non-hydrogen group containing from two to ten carbon atoms. In some embodiments, at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is methyl (C ₁ ), optionally substituted with one or more fluorine atoms, such as -CH ₃ or -CF ₃ . In some embodiments, R ^6a is substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), or substituted or unsubstituted isopropyl (C ₃ ). In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 . In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is -CH ₃ or -CF ₃ . In some embodiments denotes a single bond, and the hydrogen on _C5 is alpha . In some embodiments denotes a double bond. In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ² is hydrogen, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , cyclopropyl , fluorine or chlorine. In some embodiments, R ² is a non-hydrogen substituent of the alpha configuration. In some embodiments, R ² is a non-hydrogen substituent of the beta configuration. In some embodiments, R ^3a and R ^3b are both hydrogen. In some embodiments, R ^3a and R ^3b are coupled to form =O (oxo). In some embodiments, R ⁴ is hydrogen.

In some embodiments, a compound of formula (I) is selected from a compound of formula (II):

or a pharmaceutically acceptable salt thereof. In some embodiments, R ^6a is a non-hydrogen group containing from two to ten carbon atoms. In some embodiments, at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is methyl (C ₁ ), optionally substituted with one or more fluorine atoms, such as -CH ₃ or -CF ₃ . In some embodiments, R ^6a is substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), or substituted or unsubstituted isopropyl (C ₃ ). In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 . In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is -CH ₃ or -CF ₃ . In some embodiments denotes a single bond, and the hydrogen on _C5 is alpha . In some embodiments denotes a double bond. In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ .

In some embodiments, a compound of formula (I) is selected from a compound of formula (II-A):

or a pharmaceutically acceptable salt thereof. In some embodiments, R ^6a is a non-hydrogen group containing from two to ten carbon atoms. In some embodiments, at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is methyl (C ₁ ), optionally substituted with one or more fluorine atoms, such as -CH ₃ or -CF ₃ . In some embodiments, R ^6a is substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), or substituted or unsubstituted isopropyl (C ₃ ). In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 . In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is -CH ₃ or -CF ₃ . In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ .

In some embodiments, a compound of formula (I) is selected from a compound of formula (II-B):

or a pharmaceutically acceptable salt thereof. In some embodiments, R ^6a is a non-hydrogen group containing from two to ten carbon atoms. In some embodiments, at least one of R ^6a and R ^6b is a non-hydrogen group substituted with fluorine. In some embodiments, the carbon atom that is attached to R ^6a has the (S) configuration. In some embodiments, the carbon atom that is attached to R ^6a has the (R) configuration. In some embodiments, R ^6a is methyl (C ₁ ), optionally substituted with one or more fluorine atoms, such as -CH ₃ or -CF ₃ . In some embodiments, R ^6a is substituted or unsubstituted ethyl (C ₂ ), substituted or unsubstituted n-propyl (C ₃ ), or substituted or unsubstituted isopropyl (C ₃ ). In some embodiments, R ^6a is -CH ₂ OR ^A6 , -CH ₂ CH ₂ OR ^A6 , or -CH ₂ CH ₂ CH ₂ OR ^A6 . In some embodiments, R ^6a is substituted or unsubstituted vinyl (C ₂ ) or substituted or unsubstituted allyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted ethynyl (C ₂ ) or substituted or unsubstituted propargyl (C ₃ ). In some embodiments, R ^6a is substituted or unsubstituted cyclopropyl. In some embodiments, R ^6b is hydrogen. In some embodiments, R ^6b is -CH ₃ or -CF ₃ . In some embodiments, R ¹ is -CH ₃ or -CH ₂ CH ₃ .

In some embodiments, the compound of formula (I) is selected from the group consisting of:

and their pharmaceutically acceptable salts.

Pharmaceutical compositions

In another aspect, the present invention relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I).

When used as pharmaceuticals, the compounds described herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared by a method well known in the pharmaceutical field and include at least one active compound.

In one embodiment, with respect to the pharmaceutical composition, the carrier is a carrier suitable for parenteral, oral or topical administration.

The present invention also relates to a compound of formula (I) or a pharmaceutical composition thereof for use as a pharmaceutical or drug.

Typically, the compounds described herein are administered in a therapeutically effective amount. The amount of compound actually administered will generally be determined by the attending physician, taking into account relevant factors including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the particular patient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions described herein can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of administration, the compounds described herein are preferably prepared in the form of injectable or oral compositions, or in the form of ointments, lotions or patches, all for transdermal administration.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions or powders. However, more often, to facilitate accurate dosing, the compositions are presented in unit dosage forms. The term "unit dosage forms" refers to physically discrete units suitable as single doses for humans and other mammals, each unit containing a specified amount of active substance calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled ampoules or syringes containing measured amounts of liquid compositions or, in the case of solid compositions, pills, tablets, capsules or the like. In such compositions, the compound is typically a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various excipients or carriers and processing aids used to produce desired dosage form.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, dyes, flavorings and the like. Solid forms may include, for example, any of the following ingredients or compounds with similar properties: a binder such as microcrystalline cellulose, tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

Injectable compositions are typically based on sterile injectable saline or phosphate-buffered saline or other injectable vehicles known in the art. Similar to the above, the active compound in such compositions is typically a minor component, the amount of which is typically from about 0.05 to 10% by weight, with the remainder of the composition being an injectable carrier and the like.

Transdermal compositions are typically prepared in the form of, for example, a topical ointment or cream containing the active ingredient(s) typically in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated into an ointment, the active ingredients will usually be combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredients may be formulated into a cream in, for example, an oil-in-water cream base. Such transdermal compositions are well known in the art and typically include additional ingredients to enhance the stability of skin penetration of the active ingredients or composition. All such known transdermal compositions and ingredients are included within the scope of the present invention.

The compounds described herein can also be administered using a transdermal drug delivery device. Accordingly, transdermal administration can be accomplished using a reservoir-type patch or one containing a porous membrane, or with various solid matrices.

The above-described components for orally administered, injectable or topically administered compositions are representative only. Other substances, as well as processing methods and the like, are set forth in Part 8 of Remington's PharmaCeutiCal SCienCes , 17th edition, 1985, MacK Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The above-described components for orally administered, injectable or topically administered compositions are representative only. Other substances, as well as processing methods and the like, are set forth in Part 8 of Remington's The SCienCe and PraCtiCe of PharmaCy , 21st edition, 2005, Publisher: LippinCott Williams & Wilkins, which is incorporated herein by reference.

Also, the compounds of the present invention can be administered in sustained release forms or sustained release drug delivery systems. Descriptions of typical sustained release agents can be found in Remington's PharmaCeutiCal SCienCes .

The present invention also relates to pharmaceutically acceptable compositions of a compound of formula (I). In one embodiment, the composition contains water. In another embodiment, the composition contains a cyclodextrin derivative. The most typical cyclodextrins are alpha , beta and gamma cyclodextrins, consisting of 6, 7 and 8 glucose residues linked by α-1,4 bonds, respectively, optionally containing one or more substituents on the linked sugar moieties, which include , but not limited to, methylated, hydroxyalkyl, acylated and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is a β-cyclodextrin sulfoalkyl ester, such as, for example, β-cyclodextrin sulfobutyl ether, also known as CAPTISOL®. See, for example, US Pat. No. 5,376,645. In some embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the composition includes hexapropyl-β-cyclodextrin (10-50% in water).

The present invention also relates to a pharmaceutically acceptable acid addition salt of a compound of formula (I). An acid that can be used to prepare a pharmaceutically acceptable salt is an acid that forms a non-toxic acid addition salt, that is, a salt containing pharmacologically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate , lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.

The following composition examples illustrate typical pharmaceutical compositions that can be prepared in accordance with the present invention. The present invention, however, is not limited to the following pharmaceutical compositions.

Exemplary Formulation 1 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2 - Capsules : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a starch diluent in a weight ratio of approximately 1:1. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

Typical Preparation 3 - Liquid : The compound of formula (I) or a pharmaceutically acceptable salt thereof (125 mg) may be added to sucrose (1.75 g) and xanthan gum (4 mg) and the resulting mixture may be mixed, strained 10 mesh US standard, and then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Sufficient water may then be added to give a total volume of 5 ml.

Exemplary Formulation 4 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

Exemplary Formulation 5 - Injection : The compound of formula (I) or a pharmaceutically acceptable salt thereof can be dissolved or suspended in buffered sterile saline injection to a concentration of approximately 5 mg/ml.

Exemplary Formulation 6 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. Add a small amount of magnesium stearate as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. Add a small amount of magnesium stearate as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 8 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 9 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. Add a small amount of magnesium stearate as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 10 - Tablets : The compound of formula (I) or a pharmaceutically acceptable salt thereof may be mixed as a dry powder with a dry gelatin vehicle in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

Injection dose levels range from about 0.1 mg/kg/hour, at least 10 mg/kg/hour, and are all administered over about 1 to about 120 hours, and in particular 24 to 96 hours. A prefilled bolus at a dose of about 0.1 mg/kg to about 10 mg/kg or greater may also be administered to achieve effective steady-state levels. It is suggested that the maximum total dose does not exceed approximately 2 g/day for a patient weighing 40 to 80 kg.

For the prevention and/or treatment of long-term chronic conditions, the duration of the drug regimen is typically extended to several months or years, making oral dosing preferable for reasons of tolerability and patient convenience. When administered orally, typical dosage regimens correspond to one to five, and in particular two to four, typically three oral doses per day. Using these dosing parameters, each dose contains from about 0.01 to about 20 mg/kg of the compound described herein, with preferred doses each containing from about 0.1 to about 10 mg/kg and, in particular, from about 1 to about 5 mg/kg.

Transdermal doses are typically selected to provide similar or lower blood levels than those achieved with injectable doses.

When used to prevent the occurrence of a CNS-related condition, the compounds described herein will be administered to a subject at risk of developing the condition, typically under the direction and supervision of a physician, at the dosages described above. Subjects at risk for developing a particular condition generally refer to subjects who have a family history of the condition, or subjects who, through genetic testing or research, have been identified as susceptible to developing the condition.

Methods of treatment and application

The compounds of formula (I) and their pharmaceutically acceptable salts, as defined herein, are generally intended to modulate the function of NMDA and therefore act as neuroactive steroids for the treatment and prevention of anxiety disorder-related conditions in a subject. Modulation, as used herein, refers to the inhibition or potentiation of NMDA receptor function. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can act as a negative allosteric modulator (NAM) of NMDA and inhibit NMDA receptor function. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof can act as positive allosteric modulators (PAMs) of NMDA and potentiate NMDA receptor function.

Typical CNS diseases associated with NMDA modulation include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer's disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder and dysthymic disorder), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), alcohol or drug use disorders , personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those associated with mutations, including those associated with mutations in the Shank protein group), neurodevelopmental disorders (including Rett syndrome), pain (including acute and chronic pain), epilepsy (including status epilepticus and monogenic forms of epilepsy, such as Dravet disease, tuberous sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington's disease and Parkinson's disease) and tinnitus. In some embodiments, a Compound of Formula (I) or a pharmaceutically acceptable salt thereof can be used to induce sedation or anesthesia. In some embodiments, a Compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative disorders, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, disorders, alcohol or drug use disorders, personality disorders, autism spectrum disorders, neurodevelopmental disorders, pain, epilepsy, stroke, traumatic brain injury, movement disorders and tinnitus.

In another aspect, the invention relates to a method of treating or preventing cerebral excitability in a subject suffering from or susceptible to a disease associated with cerebral excitability, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another pharmacologically active substance. The compounds described herein may be administered as a single active agent, or they may be administered in combination with other agents. Administration in combination can be accomplished in any manner apparent to one skilled in the art, including, for example, separate, sequential, and joint and alternate administration.

Examples

For a more complete understanding of the present invention, the following examples are presented. The synthetic examples and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods presented herein and should not be construed in any way as limiting the scope thereof.

Substances and methods

The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that where typical or preferred process conditions are given (i.e., reaction temperature, time, reactant molar ratios, solvents, pressures, etc.), other process conditions may also be used unless otherwise noted. Optimal reaction conditions may vary depending on the specific reagents or solvents used, but such conditions can be determined by one skilled in the art by routine selection of optimal parameters.

In addition, as will be apparent to those skilled in the art, commonly used protecting groups may be necessary to protect certain functional groups from unwanted interactions. The selection of the appropriate protecting group for a particular functional group, as well as the appropriate conditions for introducing and removing the protecting groups, are well known in the art. For example, numerous protecting groups and their introduction and removal are described by TW Greene and PGM Wuts, Protection Groups in Organic Synthesis , Second Edition, Wiley, New York, 1991, and references therein.

The compounds described herein can be isolated and purified by known standard methods. Such methods include, but are not limited to, recrystallization, column chromatography, HPLC or supercritical liquid chromatography (SFC). To describe the preparation of typical substituted biarylamides listed herein, the following detailed schemes are presented. The compounds described herein can be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Typical chiral columns available for use in the separation/purification of enantiomers/diastereomers described herein include, but are not limited to, ChiralPak® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD -H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

General method for performing supercritical fluid chromatography (SFC): SFC purification was performed using a Thar 200 preparative SFC chromatograph equipped with a Chiralpak AD-10 µM, 200x50 mm ID (inner diameter) column. Compounds were separated by eluting with mixtures of carbon dioxide and methanol or ethanol (eg, 20-35% methanol or ethanol and 0.1% ammonium hydroxide) at a flow rate of 55-200 ml/min, and monitored at 220 nm wavelength.

Individual pure isomers were obtained after chromatographic separation by SFC, yielding two isomers with a diastereomer ratio of ≥95:5 as determined by SFC.

The configuration of the steroid C-24 stereocenter of isomers 1-13 and 1-14 and 2-20 and 2-21 was determined by the Mosher method (Dale, J. A., Dull, D. L., and Mosher, H. S. (1969) J. Org. Chem. 34, 2543 ). The C-24 configuration of subsequent derivatives that use such intermediates, for example, 1-15 and 1-17, respectively, was determined.

For all other individual diastereomers for which the C-24 stereocenter was not determined by the Mosher method, the first eluting diastereomer obtained by the SFC method was approximately determined to be attached at C-24 in the (R) configuration, while the second eluting diastereomer obtained by the SFC method , was approximately defined as attached to C-24 in configuration (S). The determinations were not clearly confirmed by the Mosher method or other methods.

Example 1.

(a)

(b)

Obtaining connection 1-2 . To a solution of ketone 1-1 (50.0 g, 0.17 mol) and ethylene glycol (62 ml) in toluene (600 ml) was added p-toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture is refluxed overnight using a Dean-Stark fitting. The mixture was cooled to room temperature, diluted with ethyl acetate (500 ml), and washed with saturated aqueous sodium bicarbonate (300 ml x 2) and brine (300 ml x 2). The organic phase was dried over sodium sulfate and concentrated in vacuo to give crude product 1-2 (64.0 g, 100%), which was used directly in the next step without further purification. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.35 (d, J=5.6 Hz, 1H), 3.97-3.82 (m, 4H), 3.59-3.47 (m , 1H), 2.34-2.21 (m, 2H), 2.06-1.94 (m, 2H), 1.90-1.74 (m, 3H), 1.73-1.64 (m, 1H), 1.63-1.33 (m, 10H), 1.32-1.19 (m, 1H), 1.14-1.03 (m, 1H), 1.01 (s , 3H), 0.99-0.93 (m, 1H), 0.86 (s, 3H).

Obtaining connection 1-3 . To a solution of compound 1-2 (32 g, 96 mmol) in dry CH ₂ Cl ₂ (1200 ml) the Dess-Martin reagent (81 g, 192 mmol) was added portionwise at 0°C. The reaction mixture was then stirred at room temperature for 3 hours. TLC data (petroleum ether:ethyl acetate = 3:1) showed that the starting product was completely consumed. The mixture was quenched with a saturated aqueous solution of NaHCO ₃ /Na ₂ S ₂ O ₃ =1:3 (1 l). The organic phase was washed with brine (500 ml) and dried over Na ₂ SO ₄ and the solvent was evaporated to give crude product 1-3 (33.0 g, 100%), which was used directly in the next step without further purification. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.34 (d, J=5.2 Hz, 1H), 3.77-4.00 (m, 4H), 3.19-3.39 (m , 1H), 2.83 (dd, J=16.44, 2.13 Hz, 1H), 2.38-2.59 (m, 1H), 2.21-2.37 (m, 1H), 1.95-2.09 (m, 3H), 1.54-1.73 (m, 4H), 1.74-1.90 (m, 2H), 1.37-1.51 (m, 3H ), 1.21-1.34 (m, 2H), 1.19 (s, 3H), 0.98-1.12 (m, 1H), 0.83-0.93 (m, 3H).

Receiving MAD. To a solution of 2,6-di-tert-butyl-4-methylphenode (40 g, 180 mmol) in toluene (200 ml) was added a solution of AlMe3 (45 ml, 90 mmol, 2 M in hexane) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and used as a solution of MAD in toluene in the next step without any purification.

Obtaining connection 1-4 . To a solution of MAD (90 mmol, freshly prepared) in toluene (200 ml) was added dropwise a solution of compounds 1-3 (10 g, 30 mmol) in toluene (80 ml) at -78°C over a period of 1 hour. in a nitrogen atmosphere. The reaction mixture was then stirred for 30 min, a solution of CH ₃ MgBr (30 ml, 90 mmol, 1.0 M in toluene) was added dropwise at -78°C. The reaction mixture was heated to -40°C and stirred at this temperature for 3 hours. TLC data (petroleum ether:ethyl acetate = 3:1) showed that the starting product was completely consumed. The mixture was poured into a saturated aqueous NH ₄ Cl solution (200 ml) and extracted with EtOAC (150 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give compound 1-4 (4 g, 38% ) in the form of a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.30 (d, J=5.2 Hz, 1H), 3.75-4.04 (m, 4H), 2.42 (d, J=13 .6 Hz, 1H), 1.88-2.12 (m, 3H), 1.73-1.86 (m, 2H), 1.64-1.72 (m, 2H), 1.52- 1.63 (m, 4H), 1.35-1.51 (m, 4H), 1.19-1.32 (m, 1H), 1.12-1.18 (m, 1H), 1. 10 (s, 3H), 0.99-1.03 (m, 3H), 0.92-0.98 (m, 1H), 0.86 (s, 3H).

Obtaining connection 1-5 . To a solution of compound 1-4 (6.0 g, 17.3 mmol) in THF (200 ml) was added an aqueous solution of HCl (35 ml, 1 M) and acetone (35 ml). The reaction mixture was stirred for 20 minutes at room temperature. TLC data (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete. The reaction mixture was then diluted with EtOAC (200 ml), washed with saturated aqueous NaHCO ₃ (200 ml), dried over Na ₂ SO ₄ and evaporated at reduced temperature to give 1-5 (5.2 g, 99.2%). ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.27 (d, J=6.8 Hz, 1H), 2.45-2.35 (m, 2H), 2.09-1.84 (m , 4H), 1.82-1.57 (m, 6H), 1.50-1.35 (m, 4H), 1.26-1.08 (m, 4H), 1.05 (s, 3H ), 0.95 (s, 3H), 0.86 (s, 3H).

Obtaining connection 1-6 . To a solution of PH ₃ PEtBr (12.25 g, 33.00 mmol) in dry THF (15 ml) was added dropwise a solution of t-BuOK (3.70 g, 33.00 mmol) in dry THF (10 ml) in an atmosphere N ₂ at 0°C. The mixture was stirred at room temperature for 1.5 hours. Then, a solution of 1-5 (1.00 g, 3.31 mmol) in THF (10 ml) was added dropwise, and the resulting mixture was stirred at 70°C for 4 hours. TLC data (petroleum ether:ethyl acetate = 3:1) showed that the starting product was completely consumed. The reaction was quenched with saturated aqueous NH ₄ Cl (50 ml) and extracted with EtOAC (30 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1) to give 1-6 (900 mg, 90.9%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.32 (d, J=5.2 Hz, 1H), 5.15-5.12 (m, 1H), 2.44-2.30 (m , 3H), 2.29-2.21 (m, 1H), 2.05-1.97 (m, 2H), 1.81-1.45 (m, 14H), 1.30-1.15 (m, 3H), 1.12 (s, 3H), 1.02 (s, 3H), 0.95-1.01 (m, 1H), 0.90 (s, 3H).

Obtaining connection 1-7 . To a solution of compound 1-6 (1.00 g, 3.20 mmol) and methyl propiolate (0.67 g, 8.00 mmol) in dry CH ₂ Cl ₂ (15 ml), a solution of Et ₂ AlCl (12 .8 ml, 12.8 mmol, 1 M in toluene) with stirring at 0°C. The reaction mixture was then warmed to room temperature and stirred for 20 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that the starting product was completely consumed. The mixture was quenched with saturated aqueous NaHCO ₃ (30 ml) and extracted with CH ₂ Cl ₂ (30 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 1-7 (1.00 g, 78.7%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 6.97-6.91 (m, 1H) 5.82 (d, J=16 Hz, 1H), 5.42-5.41 (m, 1H) , 5.32 (d, J=5.2 Hz, 1H), 3.73 (s, 3H), 3.04-3.00 (m, 1H), 2.43 (d, J=12.8 Hz, 1H), 2.11-1.97 (m, 3H), 1.88-1.50 (m, 12H), 1.40-1.20 (m, 3H), 1.21-1, 26 (m, 1H), 1.18 (d, J=6.78 Hz, 3H), 1.12 (s, 3H), 1.04 (s, 3H), 0.82 (s, 3H).

Obtaining connection 1-8 . To a solution of compound 1-7 (1.75 g, 4.4 mmol) in dry THF (20 ml), was added dropwise at -78°C under nitrogen atmosphere DIBAL-H (1M in THF, 22 ml, 22. 0 mmol). The reaction mixture was heated to a temperature of 30°C and then stirred for 2 hours at a temperature of 30°C. The reaction was quenched by adding H ₂ O (2 ml), diluted with EtOAC (200 ml) and dried over anhydrous Na ₂ SO ₄ , filtered through a pad of celite, and the filter layer washed with EtOAC (50 ml x 3). The combined filtrates were concentrated in vacuo to give crude product 1-8 (1.6 g, 98%), which was used directly in the next step without further purification.

Obtaining connection 1-9 . A mixture of 1-8 (1.6 g, 4.3 mmol) and MnO2 (7.5 g, 86.0 mmol) in CH ₂ Cl ₂ (50 ml) was stirred at 30°C for 20 hours. The reaction mixture was filtered through a pad of celite, and the filter pad was washed with CH ₂ Cl ₂ (50 ml x 3). The combined filtrates were concentrated to dryness to give crude product 1-9 (1.3 g, 82%), which was used directly in the next step without purification, ¹ H NMR: (400 MHz, CDCl ₃ ) δ 9.54 (d, J =7.6 Hz, 1H), 6.84-6.78 (dd, J ₁ =15.6 Hz, J ₂ =7.6 Hz, 1H), 5.54-5.49 (dd, J ₁ =15.6 Hz, J ₂ =7.6 Hz, 1H), 5.45-5.44 (m, 1H), 5.32 (d, J=5.2 Hz, 1H), 3.19- 3.12 (m, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.14-2.08 (m, 1H), 2.00-1.52 (m, 13H) , 1.42-1.35 (m, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.12 (s, 3H), 1.05 (s, 3H), 0, 80 (s, 3H).

Obtaining connection 1-10 . To a suspension of 1-9 (600 mg, 1.63 mmol) and CsF (120 mg, 0.82 mmol) in toluene/THF (18 ml, 8/1) was added TMSCF ₃ (2.4 ml, 16.3 mmol ), and the mixture was stirred for 20 minutes at room temperature under a nitrogen atmosphere. TLC data (petroleum ether:ethyl acetate = 3/1) showed that the starting product was completely consumed. A solution of TBAF (6.8 ml, 1M in THF) was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with MTBE (200 ml), washed with saturated aqueous NaHCO ₃ (30 ml x 3) and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12/1) to give 1-10 (300 mg, 42%) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 5.97-5.91 (dd, J ₁ =15.6 Hz, J ₂ =7.6 Hz, 1H), 5.54-5.49 (dd , J ₁ =15.6 Hz, J ₂ =6.8 Hz, 1H), 5.42-5.38 (m, 1H), 5.30 (d, J = 5.2 Hz, 1H), 4 .44-4.36 (m, 1H), 2.97-2.94 (m, 1H), 2.42 (d, J=12.0 Hz, 1H), 2.01-1.98 (m , 2H), 1.88-1.64 (m, 6H), 1.40-1.32 (m, 3H), 1.26-1.21 (m, 2H), 1.17 (d, J =6.8 Hz, 3H), 1.12 (s, 3H), 1.05 (s, 3H), 1.00-0.95 (m, 2H), 0.79 (s, 3H).

Getting connection 1-11 . A mixture of 1-10 (40 mg, 0.09 mmol) and 5% Pd/C (10 mg) in EA (10 ml) was hydrogenated for 2 hours at 30°C under 1 atm of hydrogen. The reaction mixture was filtered through a pad of celite, and the filter pad was washed with EA (10 ml x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EA = 8/1) to give 1-11 (20 mg, 50%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.31 (d, J=5.2 Hz, 1H), 3.87-3.86 (m, 1H), 2.42 (d, J=12 .8 Hz, 1H), 2.15-2.12 (m, 1H), 2.05-1.96 (m, 3H), 1.86-1.41 (m, 16H), 1.38- 1.11 (m, 5H), 1.11 (s, 3H), 1.08-1.04 (m, 1H), 1.01 (s, 3H), 0.95 (d, J=6, 6 Hz, 3H), 0.69 (s, 3H).

Preparation of compounds 1-13 and 1-14 . 1-13 (120 mg, 40%) and 1-14 (120 mg, 40%) were obtained by SFC (supercritical fluid chromatography) purification starting from 1-10 (300 mg, 0.814 mmol). The configuration of 1-13 and 1-14 was confirmed by the Mosher method.

Obtaining connection 1-15 . A mixture of 1-13 (120 mg, 0.27 mmol) and 5% Pd/C (20 mg) in EtOAC (10 ml) was hydrogenated for 20 hours at room temperature under H ₂ (1 atm). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (10 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8/1) to give 1-15 (70 mg, 59%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.30 (d, J=5.2 Hz, 1H), 4.00-3.90 (m, 1H), 2.42 (d, J=13 .2 Hz, 1H), 2.02-1.29 (m, 18H), 1.28-1.08 (m, 6H), 1.03 (s, 3H), 1.02 (s, 3H) , 0.97 (d, J=6.8 Hz, 3H), 0.73 (s, 3H).

Obtaining connection 1-17 . A mixture of 1-14 (120 mg, 0.27 mmol) and 5% Pd/C (20 mg) in EtOAC (10 ml) was hydrogenated for 20 hours at room temperature under H ₂ (1 atm). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (10 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8/1) to give 1-17 (71 mg, 59%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.27 (d, J=5.6 Hz, 1H), 4.00-3.90 (m, 1H), 2.42 (d, J=13 .2 Hz, 1H), 2.03-1.28 (m, 19H), 1.25-1.03 (m, 5H), 1.03 (s, 3H), 1.02 (s, 3H) , 0.97 (d, J=6.4 Hz, 3H), 0.73 (s, 3H).

Example 2.

(a)

(b)

Getting 2-2 . To a solution of MAD (28.87 mmol, freshly prepared) in toluene (20 ml), a solution of 2-1 (4 g, 9.62 mmol) in toluene (20 ml) was added dropwise at -78°C over a period of time for 1 hour in a nitrogen atmosphere. The reaction mixture was then stirred for 30 min and a solution of EtMgBr (29 mL, 28.87 mmol, 1.0 M in toluene) was added dropwise at -78°C. The reaction mixture was heated to -40°C and stirred at this temperature for 3 hours. TLC data (petroleum ether:ethyl acetate = 3:1) showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (200 ml) and extracted with EtOAC (150 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give product 2-2 (2.0 g, 47.6%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.28 (d, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.45- 2.34 (m, 3H), 2.04-1.95 (m, 3H), 1.94-1.61 (m, 4H), 1.62-1.60 (m, 2H), 1. 53-1.26 (m, 10H), 1.19-1.01 (m, 4H), 1.10 (s, 3H), 0.98-0.90 (m, 4H), 0.85 ( t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Getting 2-3 . To a suspension of LiAlH ₄ (852.6 mg, 22.43 mmol) in THF (20 ml) was added 2-2 (2.0 g, 4.48 mmol) at a temperature of -78°C, then the solution was stirred at a temperature of -78 °C for 2 hours. The mixture was poured into a saturated aqueous NaOH solution (2 ml) and extracted with EtOAC (50 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to give product 2-3 (600 mg, 35%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 5.28 (d, J=5.2 Hz, 1H), 2.51-2.22 (m, 3H), 2.03-1.91 (m, 3H), 1.89-1.73 (m, 3H), 1.67-1.61 (m, 2H), 1.65-1.629 (m, 1H), 1.50-1.21 (m, 10H), 1.19-1.06 (m, 4H), 1.02 (s, 3H), 1.01-0.99 (m, 1H), 0. 98-0.93 (m, 4H), 0.87 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Getting 2-4 . To a mixture of 2-3 (0.3 g, 0.78 mmol) and CsF (0.06 g, 0.39 mmol) in toluene/THF (18 ml, 8/1) was added TMSCF ₃ (1.2 ml, 7.8 mmol), and the reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. TLC data (petroleum ether:ethyl acetate = 3/1) showed that the starting product was completely consumed. A solution of TBAF (7.8 mL, 7.8 mmol, 1M in THF) was added and the mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with tert-butyl methyl ether (30 ml), washed with saturated aqueous NaHCO ₃ solution (10 ml x 3) and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to give 2-4 (80 mg, 22%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.29 (d, J=5.2 Hz, 1H), 3.87-3.84 (m, 1H), 2.36 (d, J=13 .2 Hz, 1H), 2.05-1.95 (m, 3H), 1.86-1.61 (m, 6H), 1.54-1.06 (m, 17H), 1.03 ( s, 3H), 1.02-0.91 (m, 5H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Getting 2-5 and 2-6 . A mixture of 2-4 (0.07 g, 0.15 mmol) and 10% Pd/C (20 mg) in EtOAC (10 ml) was hydrogenated for 36 hours at 50°C under H ₂ (50 psi). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (20 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25/1) to give 2-5 (25 mg, 35.7%) and 2-6 (20 mg, 28.6%) as white powder. ^1H NMR (2-5): (400 MHz, CDCl ₃ ) δ 3.87-3.82 (m, 1H), 2.05-1.94 (m, 2H), 1.86-1.58 (m, 6H), 1.56-1.17 (m, 16H), 1.13-0.96 (m, 6H), 0.93 (d, J=6.8 Hz, 3H), 0. 88 (t, J=6.8 Hz, 3H), 0.86-0.84 (m, 1H), 0.83 (s, 3H), 0.67-0.61 (m, 4H). ^1H NMR (2-6): (400 MHz, CDCl ₃ ) δ 3.83-3.76 (m, 1H), 1.95-1.52 (m, 10H), 1.43-0.98 (m, 22H), 0.89 (s, 3H), 0.88-0.82 (m, 6H), 0.59 (s, 3H).

Receiving 2-14 . To a solution of MAD (91 mmol, freshly prepared) in toluene (200 ml) was added dropwise a solution of compound 2-13 (10 g, 30 mmol) in toluene (80 ml) at -78°C over a period of 1 hour. in a nitrogen atmosphere. The reaction mixture was then stirred for 30 min, and a solution of EtMgBr (91 mL, 91 mmol, 1.0 M THF) was added dropwise at -78°C. The reaction mixture was heated to -40°C and stirred at this temperature for 3 hours. TLC data (petroleum ether:ethyl acetate = 3:1) showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (200 ml) and extracted with EtOAC (150 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give compound 2-14 (4 g, 40% ) in the form of a white powder.

Receiving 2-15 . To a solution of 2-14 (4.0 g, 111 mmol) in THF (200 ml) was added aqueous HCl (35 ml, 1 M) and acetone (35 ml). the reaction mixture was stirred for 20 minutes at room temperature. TLC data (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete. The reaction mixture was then diluted with EtOAC (200 ml), washed with saturated aqueous NaHCO ₃ (200 ml), dried over Na ₂ SO ₄ and evaporated at reduced temperature to give 2-15 (3 g, 88%) as a white solid colors.

Receiving 2-16 . To a solution of PH ₃ PEtBr (15.8 g, 42.6 mmol) in dry THF (50 ml) was added dropwise a solution of t-BuOK (4.8 g, 42.6 mmol) in dry THF (20 ml) in an atmosphere N ₂ at 0°C. The mixture was stirred at room temperature for 1.5 hours. A solution of 2-15 (2.7 g, 8.5 mmol) in THF (20 ml) was then added dropwise and the resulting mixture was stirred at 80°C for 16 hours. TLC data (petroleum ether:ethyl acetate = 3:1) showed that the starting product was completely consumed. The reaction was quenched with saturated aqueous NH ₄ Cl (100 ml) and extracted with EtOAC (30 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1) to give 2-16 (1.8 g, 64%) as a white solid.

Receiving 2-17 . To a solution of compound 2-16 (1.8 g, 5.5 mmol) and methyl propiolate (1.1 g, 13.7 mmol) in dry CH ₂ Cl ₂ (20 ml) was added dropwise a solution of Et ₂ AlCl (22 ml , 22 mmol, 1M in toluene) with stirring at 0°C. The reaction mixture was then warmed to room temperature and stirred for 20 hours. TLC (petroleum ether:ethyl acetate = 5:1) showed that the starting product was completely consumed. The mixture was quenched with saturated aqueous NaHCO ₃ (30 ml) and extracted with CH ₂ Cl ₂ (30 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 2-17 (2.0 g, 88%) as a white powder. ^1H NMR: (300 MHz, CDCl ₃ ) δ 6.99-6.92 (m, 1H) 5.84 (d, J=10.5 Hz, 1H), 5.45-5.41 (m, 1H), 5.32 (d, J=5.2 Hz, 1H), 3.75 (s, 3H), 3.06-2.99 (m, 1H), 2.38 (d, J=12 .6 Hz, 1H), 2.14-1.67 (m, 10H), 1.54-1.25 (m, 7H), 1.21 (d, J=6.8 Hz, 3H), 1 .15 -0.99 (m, 5H), 0.87(t, J=7.2 Hz, 3H), 0.80 (s, 3H).

Receiving 2-18 . To a solution of compound 2-17 (2.2 g, 5.3 mmol) in dry THF (20 ml) at -78°C under nitrogen was added dropwise DIBAL-H (1M in THF, 27 ml, 27.0 mmol). The reaction mixture was heated to a temperature of 30°C and then stirred for 2 hours at a temperature of 30°C. The reaction was quenched by adding water (3 ml), diluted with EtOAC (200 ml) and dried over anhydrous Na ₂ SO ₄ , filtered through a pad of celite, and the filter layer was washed with EtOAC (50 ml x 3). The combined filtrates were concentrated in vacuo to give 1.9 g of crude product, which was used directly in the next step without further purification. A mixture of crude product (1.9 g, 4.9 mmol) and MnO2 (8.6 g, 98 mmol) in CH ₂ Cl ₂ (50 ml) was stirred at room temperature for 20 hours. The reaction mixture was filtered through a pad of celite, and the filter pad was washed with CH ₂ Cl ₂ (50 ml x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give 2-18 (1.5 g, 79%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 9.55-9.53 (m, 1H), 6.84-6.78 (m, 1H), 6.15-6.09 (m, 1H) , 5.45-5.41 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 3.15-3.14 (m, 1H), 2.36 (d, J =13.2 Hz, 1H), 2.10-2.03 (m, 3H), 1.90-1.60 (m, 9H), 1.59-1.27 (m, 7H), 1, 24 (d, J=6.8 Hz, 3H), 1.10-1.22 (m, 6H), 0.87-0.83 (m, 4H), 0.80 (s, 3H).

Receiving 2-19 . TMSCF ₃ (5.8 mL, 39.2 mmol), and the mixture was stirred for 20 hours at room temperature under a nitrogen atmosphere. TLC data (petroleum ether:ethyl acetate = 3/1) showed that the starting product was completely consumed. A solution of TBAF (39.2 mL, 39.2 mmol, 1M in THF) was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with MTBE (200 ml), washed with saturated NaHCO ₃ solution (30 ml x 3) and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25/1) to give 2-19 (0.65 g, 37%) as a white solid.

Getting 2-20 and 2-21 . 2-20 (210 mg, 32%) and 2-21 (210 mg, 32%) were obtained by SFC purification from 2-19 (650 mg, 1.44 mmol). The configuration of 2-20 and 2-21 was confirmed by the Mosher method. ¹ H NMR (2-20): (400 MHz, CDCl ₃ ) δ 5.92 (dd, J ₁ =15.6 Hz, J ₂ =7.2 Hz, 1H), 5.53 (dd, J ₁ =15.6 Hz, J ₂ =7.2 Hz, 1H), 5.40-5.37 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 4.43- 4.40 (m, 1H), 2.95-2.94 (m, 1H), 2.37 (d, J=13.6 Hz, 1H), 2.09-1.98 (m, 4H) , 1.87-1.18 (m, 18H), 1.16 (d, J=6.8 Hz, 3H), 1.12-0.97 (m, 6H), 0.85 (t, J =6.8 Hz, 3H), 0.78 (s, 3H). ¹ H NMR (2-21): (400 MHz, CDCl ₃ ) δ 5.95 (dd, J ₁ =15.6 Hz, J ₂ =7.2 Hz, 1H), 5.53 (dd, J ₁ =15.6 Hz, J ₂ =6.8 Hz, 1H), 5.39-5.36 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 4.44- 4.41 (m, 1H), 2.99-2.92 (m, 1H), 2.37 (d, J=13.2 Hz, 1H), 2.10-1.98 (m, 4H) , 1.87-1.25 (m, 18H), 1.16 (d, J=6.8 Hz, 3H), 1.09-0.99 (m, 6H), 0.85 (t, J =7.2 Hz, 3H), 0.80 (s, 3H).

Receiving 2-7 . A mixture of 2-20 (200 mg, 0.44 mmol) and 5% Pd/C (50 mg) in EtOAC (20 ml) was hydrogenated for 72 hours at 30°C under H ₂ (1 atm). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (10 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25/1) to give crude 2-7, which was purified by pre-HPLC to give 2-7 (64 mg, 52%) as a white powder. ¹ H NMR (2-7): (400 MHz, CDCl ₃ ) δ 5.29 (d, J=4.8 Hz, 1H), 3.90-3.80 (m, 1H), 2.36 ( d, J=13.6 Hz, 1H), 2.05-1.60 (m, 11H), 1.53-1.06 (m, 15H), 1.03 (s, 3H), 1.02 -0.89 (m, 5H), 0.85 (t, J ₁ =14.8 Hz, J ₂ =7.2 Hz, 3H), 0.69 (s, 3H).

Receiving 2-8 . A mixture of 2-21 (200 mg, 0.44 mmol) and 5% Pd/C (50 mg) in EtOAC (20 ml) was hydrogenated for 72 hours at 30°C under H ₂ (1 atm). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (10 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25/1) to give 2-8 (105 mg, 52%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.29 (d, J=4.8 Hz, 1H), 3.86-3.83 (m, 1H), 2.36 (d, J=13 .2 Hz, 1H), 2.05-1.95 (m, 4H), 1.86-1.60 (m, 7H), 1.54-1.08 (m, 15H), 1.03 ( s, 3H), 1.01-0.90 (m, 5H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Getting 2-10 and 2-12 . A mixture of 2-8 (30 mg, 0.067 mmol) and 10% Pd/C (10 mg) in EtOAC (10 ml) was hydrogenated for 20 hours at 50°C under H ₂ (50 psi). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (20 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 25/1) to give 2-10 (11 mg, 37%) and 2-12 (7 mg, 23%) as a white powder. ^1H NMR (2-10): (400 MHz, CDCl ₃ ) δ 3.85-3.82 (m, 1H), 2.04-1.93 (m, 2H), 1.84-1.59 (m, 6H), 1.56-1.20 (m, 14H), 1.14-0.96 (m, 7H), 0.93 (d, J=6.8 Hz, 3H), 0. 88-0.84 (m, 4H), 0.83 (s, 3H) 0.67-0.61 (m, 4H). ^1H NMR (2-12): (400 MHz, CDCl ₃ ) δ 3.89-3.80 (m, 1H), 2.08-1.93 (m, 2H), 1.91 -1.66 (m, 6H), 1.52-1.01 (m, 23H), 0.97 (s, 3H), 0.95-0.90 (m, 6H), 0.66 (s, 3H).

Example 3.

Getting 3-2 . To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene/THF (20 ml, 8/1) was added TMSCF ₃ (1.53 ml, 10.35 mmol) and the mixture was stirred for 20 minutes at room temperature under nitrogen atmosphere. TLC data (petroleum ether:ethyl acetate = 3/1) showed that the starting product was completely consumed. A solution of TBAF (6.8 ml, 1M in THF) was added and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with MTBE (200 ml), washed with saturated aqueous NaHCO ₃ (30 ml x 3) and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to give 3-2 (220 mg, 46%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.31 (d, J=2.0 Hz, 1H), 2.44-2.41 (m, 1H), 2.04-1.96 (m , 3H), 1.81-1.67 (m, 5H), 1.65-1.39 (m, 11H), 1.34-1.32 (m, 3H), 1.31-1.25 (m, 1H), 1.21-1.10 (m, 3H), 1.12-0.98 (m, 4H), 0.96 (s, 3H), 0.98-0.90 (m , 4H), 0.68 (s, 3H.).

Getting 3-3 and 3-4 . Pd/C (20 mg) was added to a solution of compound 3-2 (220 mg, 0.569 mmol) in EtOAC (10 mL), then the mixture was stirred under hydrogen atmosphere (50 psi) at 50°C overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to give pure product 3-3 (100 mg, 38.5%) and 3-4 (51 mg, 19.3%) in in the form of a white powder. ^1H NMR (3-3): (400 MHz, CDCl ₃ ) δ 2.01-1.95 (m, 1H), 1.89-1.75 (m, 2H), 1.69-1.55 (m, 9H), 1.52-1.43 (m, 5H), 1.32-1.28 (m, 4H), 1.27-1.20 (m, 7H), 1.17-1 .08 (m, 4H), 1.06-0.96 (m, 3H), 0.96-0.91 (m, 3H), 0.80 (s, 3H), 0.68-0.49 (m, 4H). ^1H NMR (3-4): (400 MHz, CDCl ₃ ) δ 2.01-1.95 (m, 1H), 1.89-1.67 (m, 5H), 1.66-1.60 (m, 2H), 1.63-1.36 (m, 8H), 1.35-1.31 (m, 4H), 1.29-1.24 (m, 4H), 1.22 (s , 3H), 1.28-1.06 (m, 6H), 0.96 (s, 3H), 0.95-0.92 (m, 3H), 0.68 (s, 3H).

Getting 3-5 and 3-6 . Compound 3-2 (1.2 g, 2.63 mmol) was separated by SFC to give product 3-5 (400 mg) and 3-6 (400 mg) as a white powder (total yield: 66.7%) . ¹ H NMR (3-5): (400 MHz, CDCl ₃ ) δ 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40 (m, 1H), 2.08- 1.95 (m, 3H), 1.90-0.90 (m, 35H), 0.70 (s, 3H). ¹ H NMR (3-6): (400 MHz, CDCl ₃ ) δ 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40 (m, 1H), 2.08- 1.95 (m, 3H), 1.90-0.92 (m, 35H), 0.70 (s, 3H).

Receiving 3-7 . To a solution of compound 3-6 (300 mg, 0.66 mmol) in EtOAC (8 ml) was added Pd/C (10%, 200 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 24 hours. The suspension was filtered through a celite pad and the filter pad was washed with EtOAC (50 ml x 2). The combined filtrates were concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 3-7 (142 mg, 47%) as a white solid. ^1H NMR: (3-7) (400 MHz, CDCl ₃ ) δ 1.96-1.92 (m, 1H), 1.90-1.75 (m, 1H), 1.70-1.57 (m, 5H), 1.55-1.35 (m, 6H), 1.30-1.20 (m, 12H), 1.20-1.06 (m, 12H), 1.19-0 .81 (m, 11H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). ^1H NMR: (3-7A) (400 MHz, CDCl ₃ ) δ 1.96-1.92 (m, 1H), 1.90-1.75 (m, 3H), 1.70-1.57 (m, 2H), 1.55-1.25 (m, 13H), 1.21-1.00 (m, 15H), 0.96-0.86 (m, 8H), 0.65 (s , 3H).

Getting 3-8 . To a solution of compound 3-5 (300 mg, 0.66 mmol) in EtOAC (8 ml) was added Pd/C (10%, 200 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 24 hours. The suspension was filtered through a celite pad and the filter pad was washed with EtOAC (50 ml x 2). The combined filtrates were concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 3-8 (141.6 mg, 47%) as a white solid. ^1H NMR: (3-8) (400 MHz, CDCl ₃ ) δ 1.96-1.92 (m, 1H), 1.90-1.70 (m, 2H), 1.69-1.57 (m, 5H), 1.55-1.20 (m, 18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m , 4H). ^1H NMR: (3-8A) (400 MHz, CDCl ₃ ) δ 1.97-1.70 (m, 6H), 1.70-1.57 (m, 2H), 1.50-1.30 (m, 13H), 1.25-1.05 (m, 15H), 1.00-0.86 (m, 7H), 0.65 (s, 3H).

Example 4.

(a)

(b)

(With)

Getting connection 4-2 . HATU (46.3 g, 121.8 mmol), DIPEA (45.9 g, 355.2 mmol) were added to a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL) at room temperature. The mixture was stirred for 1 hour and N,O-dimethylhydroxylamine hydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred at room temperature for an additional 6 hours. The reaction mixture was concentrated, poured into water, extracted with EtOAC, washed with water, dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 3:1) to give the desired product 4-2 (24 g, 57%) as a white solid. ¹ H NMR: (300 MHz, CDCl ₃ ) δ: ppm 5.25 (d, J=5.2 Hz, 1H), 3.59 (s, 3H), 3.46-3.37 (m, 1H), 3.07 (s, 3H), 2.70 (s, 1H), 2.40-2.09 (m, 4H), 1.92-1.63 (m, 6H), 1.44-1.33 (m, 6H), 1.29-1 .15 (m, 3H), 1.11-0.93 (m, 5H), 0.90 (s, 3H), 0.85 (d, J=6.4 Hz, 3H), 0.82- 0.78 (m, 1H), 0.58 (s, 3H).

Obtaining connection 4-3 . To a solution of compound 4-2 (14 g, 33.52 mmol, 1.0 eq.) in dry CH ₂ Cl ₂ (600 ml) at a temperature of 0°C, Dess-Martin reagent (28 g, 67.04 mmol, 2.0 eq.). The reaction mixture was then stirred at room temperature for 6.5 hours. TLC data (PE:EA=3:1) showed that the starting product was completely consumed. The mixture was quenched with a saturated aqueous solution of NaHCO ₃ /Na ₂ S ₂ O ₃ =1:3 (800 ml). The organic phase was washed with brine (500 ml) and dried over Na ₂ SO ₄ and the solvent was evaporated to give crude product 4-3 (14.0 g, 100%), which was used directly in the next step without further purification.

Getting connection 4-4 . To a solution of MAD (101 mmol, 3.0 eq.) in toluene, freshly prepared by adding a solution of Me ₃ Al (50.5 ml, 101.00 mmol, 2 M in hexane) to a stirred solution of 2,6-di-tert- butyl 4-methyl phenode (44.4 g, 202 mmol) in toluene (200 ml), followed by stirring for 1 hour at room temperature, a solution of 4-3 (14.0 g, 33.7 mmol, 1 .0 eq.) in toluene (10 ml) at -78°C in a nitrogen atmosphere. The reaction mixture was then stirred for 30 min and a solution of MeMgBr (33.7 mL, 101 mmol, 3.0 eq, 3M in ether) was added dropwise at -78°C. The reaction mixture was heated to a temperature of 25°C and stirred at this temperature for 12 hours. TLC data (PE:EA = 3:1) showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (200 ml) and extracted with EtOAC (200 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA=3:1) to give pure title compound (7.5 g, 52%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.30 (d, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.50- 2.30 (m, 3H), 2.05-1.70 (m, 7H), 1.52-1.30 (m, 9H), 1.20-0.90 (m, 15H), 0. 68 (s, 3H).

Obtaining connection 4-5 . To a solution of compound 4-4 (7.5 g, 17.4 mmol, 1.0 eq.) in THF (150 mL) was added dropwise a solution of MeMgBr (29 mL, 87 mmol, 5.0 eq., 3 M in THF ) at room temperature for 30 min in a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 12 hours. TLC (PE:EA = 1:1) showed that the starting product was completely consumed. The mixture was poured into a saturated aqueous NH ₄ Cl solution (200 ml) and extracted with EtOAC (150 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 4:1) to give product 4-5 (5.2 g, 77%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.30 (d, J=5.2 Hz, 1H), 2.50-2.30 (m, 3H), 2.14 (s, 3H) 2 .03-1.93 (m, 3H), 1.87-1.68 (m, 4H), 1.60-1.18 (m, 12H), 1.12 (s, 3H), 1.11 -1.03 (m, 1H), 1.01 (s, 3H),1.00-0.94 (m, 1H), 0.91 (d, J=6.4 Hz, 3H), 0, 68 (s, 3H).

Getting 4-6 . To a solution of compound 4-5 (300 mg, 0.777 mmol, 1.0 eq.) in toluene (5 ml) was added dropwise a solution of EtMgBr (4.5 ml, 4.5 mmol, 6.0 eq., 1 M in THF ) at room temperature for 10 min in a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 12 hours. TLC (PE:EA = 3:1) showed that the starting product was completely consumed. The mixture was poured into a saturated aqueous NH ₄ Cl solution (20 ml) and extracted with EtOAC (50 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 8:1) to give product 4-6 (200 mg, 62%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.23 (d, J=5.6 Hz, 1H), 2.40-2.30 (m, 1H), 2.00-1.55 (m , 7H), 1.50-1.98 (m, 25H), 0.95 (s, 3H), 0.94-0.80 (m, 8H), 0.62 (s, 3H).

Getting 4-7 and 4-8 . To a solution of compound 4-6 (175 mg, 0.42 mmol) in EtOAC (10 ml) was added 10% Pd/C (40 mg) under argon. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 50°C overnight. The suspension was filtered through a celite pad and the filter pad was washed with EA (20 ml x 3). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: PE:EA = 8:1) to give 4-7 (84 mg, 48%) and 4-8 (25 mg, 14%) in the form of a white powder. ^1H NMR (4-7): (400 MHz, CDCl ₃ ) δ 1.98-1.92 (m, 1H), 1.87-1.78 (m, 1H), 1.70-1.60 (m, 2H), 1.58-1.20 (m, 21H), 1.20-0.97 (m, 11H), 0.95-0.82 (m, 7H), 0.80 (s , 3H), 0.70-0.61 (m, 4H). ^1H NMR (4-8): (400 MHz, CDCl ₃ ) δ 2.00-1.78 (m, 4H), 1.68-1.63 (m, 1H), 1.57-1.55 (m, 1H), 1.53 -1.35 (m, 10H), 1.32 -1.12 (m, 16H), 1.11 -0.99 (m, 5H), 0.97 (s , 3H), 0.95-0.83 (m, 6H), 0.67 (s, 3H).

Getting 4-9 . To a solution of compound 10-12B (80 mg, 0.193 mmol) in EtOAC (20 ml) was added 10% Pd/C (20 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 12 hours. The mixture was filtered through a celite pad and the filter pad was washed with EtOAC (5 mL x 2). The combined filtrates were concentrated to dryness to give the product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1 to 10:1) to give 4-9 (40 mg, 50%) as a white powder . ^1H NMR (4-9): (400 MHz, CDCl ₃ ) δ 2.02-1.93 (m, 1H), 1.92-1.80 (m, 1H), 1.70-0.85 (m, 41H), 0.82 (s, 3H), 0.67 (s, 3H).

Getting 4-10 . To a solution of compound 10-12A (80 mg, 0.193 mmol) in EtOAC (20 ml) was added 10% Pd/C (20 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 48 hours. The mixture was filtered through a celite pad and the filter pad was washed with EtOAC (5 mL x 2). The combined filtrates were concentrated to dryness to give the product, which was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 12:1 to 10:1) to give 4-10 (40 mg, 50%) as a white powder . ^1H NMR (4-10): (400 MHz, CDCl ₃ ) δ 2.02-1.93 (m, 1H), 1.92-1.80 (m, 1H), 1.70-0.85 (m, 41H), 0.82 (s, 3H), 0.67 (s, 3H).

Getting 4-11 and 4-12 . 4-11 (100 mg, 15.38%) and 4-12 (90 mg, 13.85%) were obtained by SFC purification from 4-6 (600 mg, 1.55 mmol). ¹ H NMR (isomer 1): (400 MHz, CDCl ₃ ) δ 5.30 (m, 1H), 2.43-2.40 (d, J=12.4 Hz, 1H), 2.14-1 .99 (m, 3H), 1.96-1.68 (m, 3H), 1.68-1.52 (m, 5H), 1.51-1.24 (m, 13H), 1.19 -1.09 (m, 8H), 1.02 (s, 3H), 0.96-0.93 (m, 3H), 0.93-0.87 (m, 3H), 0.69 (s , 3H). ¹ H NMR (isomer 2): (400 MHz, CDCl ₃ ) δ 5.30 (m, 1H), 2.44-2.40 (d, J=14 Hz, 1H), 2.17-1.96 (m, 3H), 1.96-1.67 (m, 3H), 1.67-1.18 (m, 18H), 1.16-1.09 (m, 8H), 1.06 (s , 3H), 0.96-0.93 (m, 3H), 0.93-0.87 (m, 3H), 0.69 (s, 3H).

Example 5.

Preparation of compound 5-2 . To a solution of 5-1 (200 mg, 0.52 mmol) in toluene (5 ml) at -78°C, n-PrMgBr (1.3 ml, 2 M in THF, 2.6 mmol) was added dropwise. The mixture was gradually warmed to room temperature and stirred for 6 hours. The reaction mixture was quenched with an aqueous solution of NH ₄ Cl and extracted with EtOAC. The organic layer was dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: PE:EA = 15:1) to give 5-2 (130 mg, 58%) as a white solid. ¹ H NMR: (300 MHz, CDCl ₃ ) δ: ppm 5.30 (d, J=4.8 Hz, 1H), 2.48-2.38 (m, 1H), 2.02-1.95 (m, 3H), 1.88-1.66 ( m, 3H), 1.63-1.52 (m, 5H), 1.52-1.46 (m, 4H), 1.43-1.41 (m, 1H), 1.41-1. 35 (m, 4H), 1.30-1.22 (m, 3H), 1.20-1.14 (m, 4H), 1.13-1.08 (m, 4H), 1.03 ( s, 3H), 0.95-0.90 (m, 3H), 0.90-0.87 (m, 3H), 0.87-0.85 (m, 1H) 0.68 (s, 3H ).

Getting 5-3 and 5-4 . To a solution of compound 5-2 (400 mg, 0.93 mmol) in EtOAC (20 ml) was added 10% Pd/C (100 mg). The mixture was then stirred under a hydrogen atmosphere (50 psi) at 50°C overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give pure products 5-3 (150 mg, 37.3%) and 5-4 (27 mg, 6.7%) in in the form of a white powder. ^1H NMR (5-3): (300 MHz, CDCl ₃ ) δ 1.97-1.94 (m, 1H), 1.93-1.77 (m, 1H), 1.67-1.62 (m, 3H), 1.56-1.51 (m, 6H), 1.47-1.30 (m, 11H), 1.24 (s, 6H), 1.20 (s, 1H), 1.13 (s, 5H), 1.09-0.99 (m, 4H), 0.94-0.90 (m, 6H), 0.80 (s, 3H), 0.65 (s, 3H). ^1H NMR (5-4): (300 MHz, CDCl ₃ ) δ 1.98-1.94 (m, 2H), 1.91-1.78 (m, 5H), 1.65-1.51 (m, 5H), 1.47-1.46 (m, 3H), 1.38-1.35 (m, 9H), 1.32-1.30 (m, 2H), 1.25 (s , 3H), 1.22 (s, 6H), 1.16-1.10 (m, 4H), 1.06-1.04 (m, 4H), 0.98-0.94 (m, 4H ), 0.92-0.89 (m, 6H), 0.86-0.83 (m, 1H), 0.64 (s, 3H).

Getting 5-5 and 5-6 . To a solution of compound 5-1 (1500 mg, 3.88 mmol) in dry THF (30 mL), a solution of n-PrMgBr (11.6 mL, 23.3 mmol) was added dropwise at 0°C. The mixture was stirred at 40°C for 16 hours. TLC data (PE/EtOAC = 2/1) indicated that the reaction was complete. To quench the reaction, a saturated aqueous solution of NH ₄ Cl (5 ml) was slowly added. The resulting solution was partitioned between EtOAC (30 ml x 3) and H ₂ O (30 ml). The combined organic layers were concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC = 10/1 to give a mixture of the diastereoisomer pair (1.1 g) as a white powder. A pair of diastereoisomers were separated by prep-SFC to give 5-6 (380 mg, 22.8%) as a white solid and 5-5 (385 mg, 23.1%) as a white solid. ¹ H NMR (5-5): (400 MHz, CDCl ₃ ) δ 5.31-5.30(m, 1H), 2.44-2.41(d, 1H, J=12.8 Hz), 2.01-1.96 (m, 3H), 1.86-1.69 (m, 3H),1.58-1.25 (m, 16H), 1.14-1.08 (m, 11H ), 1.06-0.99 (m, 4H), 0.94-0.91 (m, 6H), 0.68 (s, 3H). ¹ H NMR (5-6): (400 MHz, CDCl ₃ ) δ 5.31-5.30(m, 1H,), 2.44-2.41(d, 1H, J=12.4 Hz) , 2.02-1.96 (m, 3H), 1.87-1.68 (m, 3H), 1.57-1.25 (m, 16H), 1.18-1.08 (m, 10H), 1.02-0.99(m, 4H), 0.94-0.91(m, 6H), 0.68 (s, 3H).

Getting 5-8 . A mixture of 5-6 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAC (30 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (50 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC = 20/1 to give 5-8 (111.3 mg, 55.4%) as a white solid. ¹ H NMR (5-8) (400 MHz, CDCl ₃ ), δ (ppm) 1.97-1.94 (d, 1H, J=12.0 Hz), 1.83-1.78 (m, 1H), 1.65-1.61 (m, 3H), 1.50-1.24 (m, 20H), 1.13-1.00 (m, 11H), 0.94-0 .85 (m, 7H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). ¹ H NMR (5-8A) (400 MHz, CDCl ₃ ), δ (ppm) 1.98-1.95 (d, 1H, J=11.2 Hz), 1.88-1.80 (m, 3H), 1.65-1.60 (m, 1H), 1.51-1.47 (m, 1H), 1.40-1.31 (m, 12H), 1.28-1 .20(m, 8H), 1.16-1.01 (m, 11H), 0.96-0.80 (m, 10H), 0.65 (s, 3H).

Receiving 5-7 . A mixture of 5-5 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAC (30 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (50 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC=20/1 to give 5-7 (118.5 mg, 59.0%) as a white solid. ¹ H NMR (5-7) (400 MHz, CDCl ₃ ), δ (ppm) 1.97-1.94 (d, 1H, J=12.8 Hz), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 3H), 1.51-1.24 (m, 20H), 1.13-1.00 (m, 11H), 0.94-0 .85 (m, 7H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). ¹ H NMR (5-7A) (400 MHz, CDCl ₃ ), δ (ppm) 1.98-1.95 (d, 1H, J=11.2 Hz), 1.88-1.79 (m, 3H), 1.65-1.59 (m, 1H), 1.52-1.47 (m, 1H), 1.41-1.31 (m, 11H), 1.27-1 .22 (m, 9H), 1.13-1.11 (m, 7H), 1.06-1.01 (m, 4H), 0.96-0.90 (m, 10H), 0.65 (c, 3H).

Example 6.

(a)

(b)

(With)

(d)

Getting 6-2 . To a solution of 6-1 (150 mg, 0.39 mmol) in THF (4 mL) was added allylmagnesium bromide (2.34 mL, 2.34 mmol, 1M in ether) at -78°C. The reaction mixture was then warmed to room temperature and stirred for 12 hours. The mixture was quenched with NH ₄ Cl solution (20 ml) and extracted with EtOAC (10 ml x 2). The organic phase was dried with Na ₂ SO ₄ and purified by silica gel column chromatography (eluent: PE:EA=10:1) to give 6-2 (100 mg, 59%). ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.89-5.82 (m, 1H), 5.31 (d, J=5.2 Hz, 2H), 5.15-5.09 (m , 2H), 2.43-2.40 (m, 1H), 2.22-2.20 (d, J=7.6 Hz, 2H), 2.04-1.96 (m, 3H), 1.95-1.57 (m, 3H), 1.54-1.24 (m, 12H), 1.19-1.11 (m, 5H), 1.09-1.05 (m, 6H ), 1.03 (s, 3H), 0.98-0.92 (m, 5H), 0.68 (s, 3H).

Getting 6-3 . To a solution of 9-BBN (3.2 ml, 1.6 mmol, 2M in THF) at 0°C was added dropwise a solution of 6-2 (70 mg, 0.16 mmol) in THF (2 ml). The reaction mixture was heated at 60°C and stirred for 12 hours. The mixture was cooled to 0°C and an aqueous solution of NaOH (10%) (2 ml) was added, then H ₂ O ₂ (30%, 1 ml). The mixture was stirred for 2 hours at 0°C and then extracted with EtOAC. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 2:1) to give 6-3 (30 mg, 42%) as a white solid. ^1H NMR: (300 MHz, CDCl ₃ ) δ: 5.30 (d, J=5.2 Hz, 1H), 3.68-3.65 (m, 2H), 2.43-2.39 ( m, 1H), 2.03-1.80 (m, 6H), 1.79-1.62 (m, 6H), 1.47-1.36 (m, 5H), 1.32-1. 25 (m, 7H), 1.17-1.13 (m, 4H), 1.11-1.07 (m, 6H), 10.5-0.98 (m, 4H), 0.94- 0.90 (m, 5H), 0.68 (s, 3H).

Getting 6-4 and 6-5 . A mixture of 6-1 (1.0 g, 2.59 mmol) and 10% Pd/C (140 mg) in EtOAC (30 ml) was hydrogenated for 16 hours at 50°C under H ₂ (50 psi). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (20 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give 6-4 (500 mg, 49.5%) and 6-5 (200 mg, 19.8%) as a solid white substances.

Getting 6-6 . C3H5MgBr (1.1 mL, 1.08 mmol) was added dropwise to a solution of 6-4 (70 mg, _0.18 mmol) in dry THF (2 mL) at -78°C under _N2 atmosphere _. . The mixture was gradually warmed to room temperature and stirred for 12 hours. The reaction was quenched with aqueous NH ₄ Cl and extracted with EtOAC. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to obtain pure product 6-6 (40 mg, 51.9%) as a white powder. ¹ H NMR: (300 MHz, CDCl ₃ ) δ: ppm 5.92-5.79 (m, 1H), 5.15 (d, J=4.2 Hz, 1H), 5.11 (d, J=13.2 Hz, 1H), 2.21 (d , J=7.5 Hz, 2H), 1.97-1.75 (m, 5H), 1.67-1.34 (m, 19H), 1.30-0.94 (m, 11H), 0.91 (d, J=6.3 Hz, 3H), 0.80 (s, 3H), 0.69-0.61 (m, 4H).

Getting 6-7 and 6-8 . Compound 6-2 (400 mg, 0.849 mmol) was separated by SFC to obtain 6-7 (96 mg) and 6-8 (162 mg) as a white powder (overall yield: 65%). ¹ H NMR (6-7) (400 MHz, CDCl ₃ ), δ 5.90-5.81 (m, 1H), 5.31 (d, J=5.2 Hz, 1H), 5.20- 5.09 (m, 2H), 2.45-2.35 (m, 1H), 2.25-2.15 (m, 2H), 2.04-0.90 (m, 36H), 0. 68 (s, 3H). ¹ H NMR (6-8) (400 MHz, CDCl ₃ ), δ 5.90-5.80 (m, 1H), 5.31 (d, J=5.2 Hz, 1H), 5.21- 5.09 (m, 2H), 2.45-2.34 (m, 1H), 2.25-2.15 (m, 2H), 2.04-0.89 (m, 36H), 0. 68 (s, 3H).

Getting 6-6-Bz . BzCl (64.4 mg, 0.46 mmol) was added dropwise to a solution of 6-6 (100 mg, 0.23 mmol) in pyridine (3 mL) at room temperature. The reaction mixture was then stirred at 40°C for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was quenched with water and extracted with EtOAC. The combined organic phase was washed with 1M HCl (30 ml) and brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 6-8-Bz (60 mg, 48%) as a white solid.

Getting 6-11-Bz . Compound 6-6-Bz (60 mg, 0.11 mmol) was separated by SFC to give 6-11-Bz (40 mg, 66%) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.99-7.98 (d, J=7.2 Hz, 2H), 7.53-7.49 (t, J=7.2 Hz, 1H ), 7.42-7.38 (t, J=7.2 Hz, 2H), 2.22-2.20 (d, J=7.6 Hz, 2H), 1.98-1.57 ( m, 11H), 1.54-1.26 (m, 16H), 1.15 (s, 3H), 1.12-1.10 (m, 6H), 0.92-0.91 (d, J=6.0 Hz, 3H), 0.80 (s, 3H), 0.64-0.60 (m, 4H).

Preparation 6-11 To a solution of compound 6-11-Bz (40 mg, 0.075 mmol) in a solvent mixture of THF (2 ml) and MeOH (1 ml) was added a solution of LiOH (90 mg, 3.75 mmol) in H ₂ O (1 ml). The mixture was stirred at 40°C for 3 days. TLC data showed that the starting product was completely consumed. The reaction mixture was washed with brine and extracted with EtOAC. The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 6-11 (23 mg, 71%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.86-5.84 (m, 1H), 5.13-5.09 (m, 2H), 2.21-2.19 (d, J= 7.6 Hz, 2H), 1.84-1.25 (m, 19H), 1.24 (s, 3H), 1.14 (s, 3H), 1.13-1.09 (m, 7H ), 0.91-0.90 (d, J=6.8 Hz, 3H), 0.80 (s, 3H), 0.64-0.60 (m, 4H).

Example 7.

(a)

(b)

Preparation of compound 7-2 . To a solution of 7-1 (193 mg, 0.5 mmol, 1.0 eq.) in dry THF (3 ml), at -78°C, n-BuLi (1.6 ml, 4 mmol, 8 ,0 eq.). The resulting mixture was stirred at this temperature for 0.5 hour and then allowed to warm to room temperature and stirred at this temperature for an additional 18 hour. TLC data (PE/EA = 5/1) indicated that the reaction was complete. The mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAC (10 ml x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE:EA = 20:1) to give product 7-2 (85 mg, 38.6%) as a white powder. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 5.31 (d, J=5.2 Hz, 1H), 2.41 (d, J=13.2 Hz, 1H), 2.10-1, 95 (m, 3H), 1.94-1.62 (m, 42H), 1.52-1.22 (m, 17H), 1.22-1.20 (m, 1H), 1.15 ( s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 1.04-1.00 (m, 3H), 1.00-0.85 (m, 9H), 0 .67 (s, 3H).

Preparation of compound 7-3 . A mixture of 7-2 (100 mg, 2.59 mmol) and 10% Pd/C (140 mg) in EtOAC (30 ml) was hydrogenated for 16 hours at 50°C under H ₂ (50 psi). The reaction mixture was filtered through a pad of celite and the filter pad was washed with EtOAC (20 mL x 3). The combined filtrates were concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15:1) to give 7-3 (35 mg, 35%) and 7-3A (19 mg, 19%) as a white powder. ^1H NMR (7-3): (400 MHz, CDCl ₃ ) δ 2.02-1.92 (m, 1H), 1.90-1.77 (m, 1H), 1.70-1.38 (m, 14H), 1.36-1.29 (m, 6H), 1.28-1.20 (m, 8H), 1.20-1.08 (m, 6H), 1.07- 0.96 (m, 4H), 0.96-0.84 (m, 7H), 0.82 (s, 3H), 0.70-0.60 (m, 4H).

^1H NMR (7-3A): (400 MHz, CDCl ₃ ) δ 1.98-1.80 (m, 4H), 1.67-1.48 (m, 6H), 1.45-1.33 (m, 9H), 1.32-1.23 (m, 10H), 1.22-1.18 (m, 4H), 1.17-1.10 (m, 6H), 1.10- 0.97(m, 4H), 0.94(s, 3H), 0.93-0.87(m, 6H), 0.64(s, 3H).

Preparation of 7-4 and 7-5 To a solution of compound 7-1 (1.5 g, 3.88 mmol) in dry THF (15 ml) at -78°C, n-BuLi (12.5 ml, 31 mmol, 2.5 M in THF). The resulting mixture was stirred at this temperature for 0.5 hour and then allowed to warm to room temperature and stirred at this temperature for an additional 18 hour. TLC data (PE/EA = 5/1) indicated that the reaction was complete. The mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAC (30 ml x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE:EA = 20:1) to give 7-2 (800 mg, 46.4%) as a white powder, which was separated by SFC to give 7-4 (207 mg) and 7-5 (360 mg) in the form of white powder. ¹ H NMR (7-4): (400 MHz, CDCl ₃ ) δ 5.38-5.29 (m, 1H), 2.44 (d, 1H, J=12.5 Hz), 2.04- 1.69 (m, 6H), 1.57-1.25 (m, 18H), 1.20-0.89 (m, 23H), 0.70 (s, 3H). ¹ H NMR (7-5): (400 MHz, CDCl ₃ ) δ 5.32 (s, 1H), 2.44 (d, 1H, J=12.3 Hz), 2.08-1.68 ( m, 6H), 2.55-1.25 (m, 17H), 2.22-0.85 (m, 24H), 0.70 (s, 3H).

Getting 7-6 . Pd/C (100 mg) was added to a solution of 7-4 (0.17 g, 0.38 mmol) in 15 mL EtOH, then the reaction mixture was stirred under hydrogen (50 psi) at 50°C for 24 hours. The resulting solution was filtered and concentrated. The product was purified by silica gel column chromatography, eluting (PE:EA=20:1) to give 7-6 (40 mg, yield: 23.42%) as a white solid. ¹ H NMR(7-6) (400 MHz, CDCl ₃ ), δ 1.97-1.94 (m, 1H), 1.88-1.76 (m, 1H), 1.71-1, 59 (m, 3H), 1.56-1.23 (m, 21H), 1.23-0.86 (m, 19H), 0.81 (s, 3H), 0.65 (s, 3H) .

Getting 7-7 . Pd/C (200 mg) was added to a solution of 7-5 (0.23 g, 0.52 mmol) in 15 mL EtOH, then the reaction mixture was stirred under hydrogen (50 psi) at 50°C for 24 hours. The resulting solution was filtered and concentrated. The product was purified by silica gel column chromatography, eluting (PE:EA=20:1) to give 7-7 (70 mg, yield: 30.3%) as a white solid. ¹ H NMR(7-7) (400 MHz, CDCl ₃ ), δ (ppm) 1.99-1.92 (m, 1H,), 1.88-1.78 (m, 1H), 1.70-1.52 (m, 6H), 1.46-1.20 (m, 21H), 1.18-0.87 (m, 20H), 0.81 (s, 3H), 0. 65 (s, 3H).

Example 8.

(a)

(b)

Getting 8-2 . To a solution of compound 8-1 (100 mg, 0.25 mmol) in toluene (8 mL), a solution of iso-PrMgBr (1.5 mL, 1.5 mmol, 1 M in THF) was added dropwise at room temperature over 10 min. in a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (20 ml) and extracted with EtOAC (50 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 8:1) to give product 8-2 (66 mg, 59.46%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.30 (d, J=5.2 Hz, 1H), 2.43-2.40 (m, 1H), 2.04-1.55 (m , 3H), 1.88-1.66 (m, 5H), 1.58-1.13 (m, 15H), 1.11 (s, 3H), 1.08 (s, 3H), 1. 01 (s, 3H), 0.96-0.90 (m, 6H), 0.90-0.86 (m, 3H), 0.68 (s, 3H).

Getting 8-3 and 8-4 . To a solution of compound 8-2 (60 mg, 0.14 mmol) in EtOAC (15 ml) was added 10% Pd/C (20 mg) under argon. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (50 psi) at 50°C overnight. The suspension was filtered through a celite pad and the filter pad was washed with EA (20 ml x 3). The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give 8-3 (27 mg, 45%) and 8-4 (9 mg, 15% ) in the form of a white powder. ^1H NMR (8-3): (400 MHz, CDCl ₃ ) δ 1.97-1.94 (m, 1H), 1.85-1.78 (m, 2H), 1.74-1.42 (m, 12H), 1.48-1.20 (m, 12H), 1.18-1.09 (m, 3H), 1.07 (s, 3H), 1.02-0.98 (m , 2H), 0.93-0.88 (m, 6H), 0.88-0.86 (m, 3H), 0.80 (s, 3H), 0.63 (s, 3H). ^1H NMR (8-4): (400 MHz, CDCl ₃ ) δ 1.98-1.95 (m, 1H), 1.89-1.79 (m, 3H), 1.75-1.54 (m, 7H), 1.48-1.24 (m, 16H), 1.23 (s, 3H), 1.19-1.11 (m, 4H), 1.08 (s, 4H), 0.95 (s, 3H), 0.94-0.88 (m, 6H), 0.88-0.86 (m, 3H), 0.63 (s, 3H).

Getting 8-7 and 8-8 . To a solution of compound 8-1 (1500 mg, 3.88 mmol) in dry THF (30 ml) at 0°C, a solution of iso-PrMgCl (11.6 ml, 23.3 mmol) was added dropwise. The mixture was stirred at 40°C for 16 hours. TLC data (PE/EtOAC = 2/1) indicated that the reaction was complete. To quench the reaction, a saturated aqueous solution of NH ₄ Cl (5 ml) was slowly added. The resulting solution was partitioned between EtOAC (30 ml x 3) and H ₂ O (30 ml). The combined organic layers were concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC=10/1 to give a mixture of the diastereoisomer pair (800 mg) as a white powder. The diastereoisomer pair was separated by prep-SFC to give 8-8 (317 mg, 19.0%) and 8-7 (250 mg, 15.0%) as a white solid. ¹ H NMR (8-8): (400 MHz, CDCl ₃ ) δ 5.30 (s, 1H), 2.42 (d, J=12.4 Hz, 1H), 2.01-1.99 ( m, 3H), 1.89-1.65 (m, 4H), 1.59-1.58 (m, 1H), 1.51-1.26 (m, 9H), 1.20-1. 05 (m, 12H), 1.04-0.99 (m, 4H), 0.94-0.88 (m, 10H), 0.68 (s, 3H). ¹ H NMR (8-7): (400 MHz, CDCl ₃ ) δ 5.30 (d, J=3.6 Hz, 1H), 2.42 (d, J=12.4 Hz, 1H), 2 .00-1.97 (m, 3H), 1.89-1.68 (m, 4H), 1.58-1.25 (m, 10H), 1.19-1.08 (m, 10H) , 1.03-0.98 (m, 4H), 0.95-0.88 (m, 10H), 0.68 (s, 3H).

Getting 8-6 . A mixture of 8-8 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAC (30 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (50 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC=20/1 to give 8-6 (85.9 mg, 42.8%) as a white solid and 8-6A (17 .6 mg, 8.8%) as a white solid. ¹ H NMR (8-6) (400 MHz, CDCl ₃ ), δ (ppm) 1.97-1.94 (d, 1H, J=12.8 Hz), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 3H), 1.54-1.45 (m, 3H), 1.36-1.19 (m, 13H), 1.16-0 .96 (m, 12H), 0.92-0.87 (m, 10H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). ¹ H NMR (8-6A) (400 MHz, CDCl ₃ ), δ (ppm) 1.98-1.95 (d, 1H, J=10.8 Hz), 1.88-1.79 (m, 3H), 1.71-1.59 (m, 3H), 1.53-1.48 (m, 2H), 1.42-1.31 (m, 6H), 1.27-0 .96 (m, 20H), 0.92-0.87 (m, 12H), 0.80 (s, 3H), 0.64 (s, 3H).

Getting 8-5 . A mixture of 8-7 (150 mg, 0.348 mmol, 1.0 eq.) and Pd/C (75 mg, cat.) in EtOAC (20 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (50 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC=20/1 to give 8-5 (89.0 mg, 44.3%) as a white solid and 8-5A (4 .6 mg, 2.3%) as a white solid. ¹ H NMR (8-5) (400 MHz, CDCl ₃ ), δ (ppm) 1.97-1.94 (d, 1H, J=12.8 Hz), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 3H), 1.54-1.45 (m, 3H), 1.36-1.19 (m, 13H), 1.16-0 .96 (m, 12H), 0.92-0.87 (m, 10H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). ¹ H NMR (8-5A) (400 MHz, CDCl ₃ ), δ (ppm) 1.98-1.95 (d, 1H, J=10.8 Hz), 1.91-1.79 (m, 3H), 1.72-1.64 (m, 2H), 1.54-1.50 (m, 1H), 1.46-1.00 (m, 28H), 0.96-0 .87 (m, 12H), 0.64 (s, 3H).

Example 9.

Getting 9-2 . To a solution of compound 9-1 (100 mg, 0.25 mmol) in THF (2 ml) was added dropwise a solution of cyclopropylmagnesium bromide (2.5 ml, 2.5 mmol, 1M in THF) at room temperature over 10 min under atmosphere nitrogen. The reaction mixture was then stirred at room temperature for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (20 ml) and extracted with EtOAC (50 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give product 9-2 (33 mg, 30%) as a white powder. ¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.31 (d, J=5.2 Hz, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.08-1 .93 (m, 3H), 1.90-1.65 (m, 3H), 1.62-1.27 (m, 13H), 1.22-1.08 (m, 11H), 1.01 (s, 3H), 1.00-0.85 (m, 6H), 0.68 (s, 3H), 0.40-0.25 (m, 4H).

Getting 9-3 and 9-4 . Compound 9-2 (200 mg, 0.46 mmol) was separated by SFC to give 9-3 (90 mg) and 9-4 (100 mg) as a white solid (overall yield: 95%). ^1H NMR: (9-3) (400 MHz, CDCl ₃ ) δ 5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.02-1.99 (m, 3H), 1.95-1.60 (m, 3H), 1.50-1.25 (m, 9H), 1.20-1.05 (m, 11H), 1.02-0 .93 (m, 11H), 0.68 (s, 3H), 0.35-0.28 (m, 4H). ^1H NMR: (9-4) (400 MHz, CDCl ₃ ) δ 5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.02-1.95 (m, 3H), 1.93-1.60 (m, 3H), 1.50-1.25 (m, 10H), 1.20-1.05 (m, 11H), 1.02-0 .93 (m, 11H), 0.68 (s, 3H), 0.36-0.24 (m, 4H).

Getting 9-7 . To a solution of compound 9-3 (100 mg, 0.23 mmol) in EtOAC (8 ml) under N ₂ was added Pd/C (10%, 200 mg). The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 24 hours. The suspension was filtered through a celite pad and the filter pad was washed with EtOAC (30 ml x 2). The combined filtrates were concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 9-7 (27.8 mg, 27.8%) as a white solid. ^1H NMR: (9-7) (400 MHz, CDCl ₃ ) δ 1.97-1.94 (m, 1H), 1.90-1.80 (m, 1H), 1.64-1.57 (m, 3H), 1.54-1.30 (m, 7H), 1.28-0.85 (m, 25H), 0.80 (s, 3H), 0.65-0.60 ( m, 4H), 0.36-0.33 (m, 4H). ^1H NMR: (9-7A) (400 MHz, CDCl ₃ ) δ 1.95-1.83 (m, 4H), 1.70-1.57 (m, 1H), 1.45-1.11 (m, 22H), 1.05-0.85 (m, 17H), 0.65 (s, 3H), 0.36-0.34 (m, 4H).

Getting 9-8 . To a solution of compound 9-4 (100 mg, 0.23 mmol) in EtOAC (8 ml) was added Pd/C (10%, 200 mg) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 24 hours. The suspension was filtered through a celite pad and the filter pad was washed with EtOAC (30 ml x 2). The combined filtrates were concentrated to dryness to give a crude product which was purified by HPLC to give 9-8 (18.3 mg, 18%) as a white solid. ^1H NMR: (9-8) (400 MHz, CDCl ₃ ) δ 1.97-1.94 (m, 1H), 1.90-1.80 (m, 1H), 1.60-1.57 (m, 3H), 1.54-1.20 (m, 16H), 1.19-0.82 (m, 16H), 0.80 (s, 3H), 0.65-0.60 (m , 4H), 0.36-0.28 (m, 4H).

Example 10.

(a)

(b)

(With)

(d)

(e)

(f)

(g)

(h)

(i)

Getting 10-2 . To a solution of compound 10-1 (100 mg, 0.25 mmol) in toluene (8 ml) at room temperature, a solution of ethynylmagnesium bromide (4 ml, 2.0 mmol, 0.5 M in THF). The reaction mixture was then stirred at 50°C overnight. TLC data showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (10 ml) and extracted with EtOAC (25 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give product 10-2 (80 mg, 74.98%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.30 (d, J=5.2 Hz, 1H), 2.43-2.40 (m, 2H), 2.06-1.81 (m , 5H), 1.80-1.67 (m, 3H), 1.67-1.59 (m, 2H), 1.49 (s, 3H), 1.48-1.42 (m, 2H ), 1.40-1.24 (m, 4H), 1.20-1.13 (m, 2H), 1.10 (s, 3H), 0.96-0.92 (m, 3H), 0.69 (s, 3H).

Getting 10-3 and 10-4 . Compound 10-2 (350 mg, 0.849 mmol) was separated by SFC to obtain 10-3 (82 mg) and 10-4 (94 mg) as a white powder (total yield: 50%). ¹ H NMR (10-3) (400 MHz, CDCl ₃ ), δ 5.29 (d, J=5.2 Hz, 1H), 2.43-2.40 (m, 2H), 2.05- 0.95 (m, 38H), 0.68 (s, 3H). ¹ H NMR (10-4) (400 MHz, CDCl ₃ ), δ 5.29 (d, J=5.2 Hz, 1H), 2.43-2.40 (m, 2H), 2.05- 0.95 (m, 38H), 0.68 (s, 3H).

Getting 10-5 . To a solution of compound 10-1 (3.0 g, 7.76 mmol) in a solvent mixture of EtOAC (20 mL) and EtOH (10 mL) was added Pd/C (33%, 1.0 g) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was then stirred under H ₂ (50 psi) at 50°C for 6 days. The suspension was filtered through a celite pad and the filter pad was washed with EtOAC (100 ml x 3). The combined filtrates were concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 10-5 (1.7 g, 56%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 2.48-2.44 (m, 1H), 2.43-2.40 (m, 1H), 2.13 (s, 3H), 1.95 -1.25 (m, 20H), 1.23 (s, 3H), 1.22-1.00 (m, 8H), 0.90-0.88 (d, J=6.4 Hz, 3H ), 0.80 (s, 3H), 0.63-0.60 (m, 4H).

Getting 10-6 . To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 ml) at 0°C under N ₂ was added dropwise ethynylmagnesium bromide (28.2 ml, 14.1 mmol). The reaction mixture was then stirred at room temperature for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was quenched with saturated aqueous NH ₄ Cl (80 ml) and extracted with EtOAC. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 10-6 (380 mg, 64%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 2.42 (s, 1H), 1.97-1.48 (m, 14H), 1.47 (s, 3H), 1.29-1.26 (m, 7H), 1.24 (s, 3H), 1.23-0.94 (m, 7H), 0.93-0.92 (d, J=6.4 Hz, 3H), 0. 80 (s, 3H), 0.65-0.62 (m, 4H).

Getting 10-6-Bz . BzCl (168 mg, 1.2 mmol) was added dropwise to a solution of 10-6 (250 mg, 0.60 mmol) in pyridine (3 ml) at room temperature. The reaction mixture was then stirred at 45°C for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAC. The combined organic phase was washed with 1M HCl (20 ml) and brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 10-6-Bz (200 mg, 64%) as a white solid.

Preparation of 10-8-Bz and 10-9-Bz Compound 10-6-Bz (200 mg, 0.39 mmol) was separated by SFC to give 10-8-Bz (80 mg, 40%) and 10-9- Bz (70 mg, 35%) as a white solid. ^1H NMR: (10-8-Bz) (400 MHz, CDCl ₃ ) δ 7.99-7.98 (d, J=7.6 Hz, 2H), 7.51-7.49 (d, J =7.2 Hz, 1H), 7.42-7.38 (t, J=7.2 Hz, 2H), 2.42 (s, 1H), 2.05-1.68 (m, 8H) , 1.65 (s, 3H), 1.60-1.49 (m, 7H), 1.48 (s, 3H), 1.45-1.11 (m, 16H), 0.94-0 .92 (d, J=6.4 Hz, 3H), 0.87 (s, 3H), 0.66-0.62 (m, 4H). ^1H NMR: (10-9-Bz) (400 MHz, CDCl ₃ ) δ 7.99-7.98 (d, J=7.6 Hz, 2H), 7.51-7.49 (d, J =7.2 Hz, 1H), 7.42-7.38 (t, J=7.6 Hz, 2H), 2.43 (s, 1H), 2.05-1.67 (m, 8H) , 1.65 (s, 3H), 1.60-1.48 (m, 5H), 1.47 (s, 3H), 1.45-1.20 (m, 11H), 1.19-0 .95 (m, 9H), 0.94-0.92 (d, J=6.8 Hz), 0.87 (s, 3H), 0.66-0.62 (m, 4H).

Getting 10-8 . To a solution of compound 10-8-Bz (80 mg, 0.15 mmol) in a mixture of solvents of THF (3 ml) and MeOH (1.5 ml) was added a solution of LiOH (180 mg, 7.5 mmol) in H ₂ O (1.5 ml). The mixture was stirred at 40°C for 3 days. TLC data showed that the starting product was completely consumed. The reaction mixture was washed with brine and extracted with EtOAC. The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-8 (57 mg, 92%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 2.42 (s, 1H), 1.93-1.49 (m, 11H), 1.48 (s, 3H), 1.35-1.20 (m, 16H), 1.19-0.94 (m, 5H), 0.93-0.92 (d, J=6.4 Hz, 3H), 0.80 (s, 3H), 0. 65-0.62 (m, 4H).

Getting 10-9 . To a solution of compound 10-9-Bz (70 mg, 0.14 mmol) in a mixture of solvents of THF (3 ml) and MeOH (1.5 ml) was added a solution of LiOH (168 mg, 7.0 mmol) in H ₂ O (1.5 ml). The mixture was stirred at 40°C for 3 days. TLC data showed that the starting product was completely consumed. The reaction mixture was washed with brine and extracted with EtOAC. The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-9 (53 mg, 91%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 2.42 (s, 1H), 1.93-1.49 (m, 11H), 1.48 (s, 3H), 1.29-0.94 (m, 21H), 0.93-0.92 (d, J=6.4 Hz, 3H), 0.80 (s, 3H), 0.65-0.62 (m, 4H).

Getting 10-7 . To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 ml) was added vinyl magnesium bromide (9.87 ml, 9.87 mmol) dropwise at 0°C under N ₂ atmosphere. The reaction mixture was then stirred at room temperature for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was quenched with saturated aqueous NH ₄ Cl (30 ml) and extracted with EtOAC. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 10-7 (300 mg, 51%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.93-5.86 (m, 1H), 5.20-5.16 (d, J=17.6 Hz, 1H), 5.05-5 .02 (d, J=10.8 Hz, 1H), 1.96-193 (m, 1H), 1.60-1.57 (m, 4H), 1.51-1.20 (m, 20H ), 1.19-1.00 (m, 8H), 0.91-0.89 (d, J=6 Hz, 3H), 0.80 (s, 3H), 0.64-0.60 ( m, 4H).

Getting 10-7-Bz . BzCl (150 mg, 1.06 mmol) was added dropwise to a solution of 10-7 (220 mg, 0.53 mmol) in pyridine (3 ml) at room temperature. The reaction mixture was then stirred at 40°C for 12 hours. TLC data showed that the starting product was completely consumed. The mixture was quenched with saturated aqueous solution and extracted with EtOAC. The combined organic phase was washed with 1M HCl (30 ml) and brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 80:1) to give 10-7-Bz (150 mg, 54%) as a white solid.

Obtaining 10-10-Bz and 10-11-Bz . Compound 10-7-Bz (190 mg, 0.37 mmol) was separated by SFC to give 10-10-Bz (75 mg, 39%) and 10-11-Bz (70 mg, 37%) as a solid white. ^1H NMR: (10-10-Bz) (400 MHz, CDCl ₃ ) δ 7.99-7.97 (d, J=7.2 Hz, 1H), 7.51-7.49 (d, J =7.6 Hz, 1H), 7.42-7.38 (t, J=8.0 Hz, 2H), 5.93-5.86 (dd, J ₁ =11.2 Hz, J ₂ = 17.2.1H), 5.21-5.16 (d, J=17.6 Hz, 1H), 5.05-5.02 (d, J=10.4 Hz, 1H), 2.05 -1.75 (m, 8H), 1.65-1.27 (m, 19H), 1.26 (s, 3H), 1.25-0.93 (m, 10H), 0.91 -0.90 (d, 6.0 Hz, 3H), 0.86 (s, 3H), 0.70-0.64 (m, 4H) ¹ H NMR: (10-11-Bz) (400 MHz , CDCl ₃ ) δ 7.99-7.97 (d, J=7.2 Hz, 1H), 7.51-7.49 (d, J=7.6 Hz, 1H), 7.42-7 .38 (t, J=8.0 Hz, 2H), 5.93-5.86 (dd, J ₁ =10.8 Hz, J ₂ =17.6, 1H), 5.20-5.16 (d, J=17.2 Hz, 1H), 5.05-5.02 (d, J=10.4 Hz, 1H), 2.05-1.75 (m, 8H), 1.65- 1.27 (m, 10H), 1.26 (s, 3H), 1.25-0.93 (m, 10H), 0.91-0.90 (d, 6.4 Hz, 3H) , 0.86 (s, 3H), 0.70-0.64 (m, 4H).

Getting 10-10 . To a solution of compound 10-10-Bz (75 mg, 0.14 mmol) in a mixture of solvents of THF (3 ml) and MeOH (1.5 ml) was added a solution of LiOH (168 mg, 7.0 mmol) in H ₂ O (1.5 ml). The mixture was stirred at 40°C for 3 days. TLC data showed that the starting product was completely consumed. The reaction mixture was washed with brine and extracted with EtOAC. The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-10 (55 mg, 94%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 1.96-1.92 (m, 1H), 1.90-1.70 (m, 2H), 1.69-1.57 (m, 5H) , 1.55-1.20 (m, 18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H).

Getting 10-11-Bz . To a solution of compound 10-11-Bz (70 mg, 0.13 mmol) in a solvent mixture of THF (3 ml) and MeOH (1.5 ml) was added a solution of LiOH (168 mg, 7.0 mmol) in H ₂ O (1.5 ml). The mixture was stirred at 40°C for 3 days. TLC data showed that the starting product was completely consumed. The reaction mixture was washed with brine and extracted with EtOAC. The combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1) to give 10-11 (49 mg, 91%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 1.96-1.92 (m, 1H), 1.90-1.70 (m, 2H), 1.69-1.57 (m, 5H) , 1.55-1.20 (m, 18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H).

Receiving 10-22 and 10-23 . To a solution of 10-14 (550 mg, 1.27 mmol) in THF (10 ml) was added NaH (254 mg, 6.36 mmol) at 0°C, and stirred at the same temperature for 30 minutes. CH ₃ I (127 mg, 0.770 mmol) was then added dropwise to the mixture. The progress of the reaction was monitored by TLC. After 1 hour, 127 mg CH ₃ I was added in two portions. After stirring at room temperature for 1.5 hours, the reaction mixture was quenched with aqueous NH ₄ Cl (20 ml), extracted with EtOAC (20 ml x 3), dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1) to give 10-14 as a white powder. The diastereoisomer pairs (340 mg) were separated by prep-SFC to give 10-22 (130 mg, 22.9%) as a white powder and 10-23 (135 mg, 23.8%) as a white powder. ^1H NMR (10-22): (400 MHz, CDCl ₃ ) δ 5.30 (s, 1H), 3.65-3.53 (m, 2H), 3.35 (s, 3H), 3, 04 (broad, 1H), 2.44-2.40 (d, 1H, J=13.6 Hz), 2.02-1.95 (m, 3H), 1.86-1.64 (m , 5H), 1.62-1.58 (m, 1H), 1.52-1.23 (m, 9H), 1.17-1.05 (m, 11H), 1.04-0.98 (m, 4H), 0.95-0.93 (d, 4H, J=6.8 Hz), 0.68 (s, 3H). ¹ H NMR (10-23): (400 MHz, CDCl ₃ ) δ 5.30 (s, 1H), 3.61 (t, 2H, J=6.0 Hz), 3.35 (s, 3H) , 3.04 (broad, 1H), 2.44-2.40 (d, 1H, J=12.8 Hz), 2.02-1.95 (m, 3H), 1.86-1, 64 (m, 5H), 1.57-1.25 (m, 12H), 1.16-0.93 (m, 17H), 0.68 (s, 3H).

Receipt 10-17 . A mixture of 10-22 (100 mg, 0.224 mmol) and Pd/C (50 mg, cat.) in EtOAC (10 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (40 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC = 15/1 to give 10-17 (68.4 mg, 68.1%) as a white solid. ¹ H NMR (10-17) (400 MHz, CDCl ₃ ), δ 3.62-3.58 (m, 2H), 3.35 (s, 3H), 3.07 (br, 1H), 1 .97-1.93 (d, 1H, J=12.8 Hz), 1.83-1.74 (m, 2H), 1.69-1.55 (m, 5H), 1.50-1 .43 (m, 3H), 1.37-1.23 (m, 12H), 1.16-0.97 (m, 10H), 0.93-0.91 (d, 1H, J=6, 0 Hz), 0.80(s, 3H), 0.68-0.64 (m, 3H).

Receipt 10-19 . A mixture of 10-23 (100 mg, 0.224 mmol) and Pd/C (50 mg, cat.) in EtOAC (10 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (40 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC = 15/1 to give 10-19 (68.6 mg, 68.3%) as a white solid. ¹ H NMR (10-19) (400 MHz, CDCl ₃ ), δ 3.60 (t, 2H, J=6.0 Hz), 3.35 (s, 3H), 3.07 (br, 1H ), 1.97-1.94 (d, 1H, J=12.8 Hz), 1.81-1.57 (m, 6H), 1.54-1.43 (m, 4H), 1, 36-1.22 (m, 12H), 1.16-0.97 (m, 10H), 0.92-0.91 (d, 1H, J=6.0 Hz), 0.80 (s, 3H), 0.68-0.61 (m, 3H).

Getting 10-7 . Lindlar catalyst (24 mg) was added to a solution of 10-6 (60 mg, 0.14 mmol) in EtOAC (2 mL). The mixture was then stirred under a hydrogen atmosphere (1 atm) at room temperature for 1.5 hours. The mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to give pure product 10-7 (26 mg, 43.0%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.93-5.85 (m, 1H), 5.20-5.16 (d, J=17.2 Hz, 1H), 5.05-5 .02 (d, J=10.8 Hz, 1H), 1.96-1.93 (m, 1H), 1.79-1.67 (m, 1H), 1.66-1.57 (m , 4H), 1.55-1.36 (m, 11H), 1.35-1.27 (m, 9H), 1.26-0.97 (m, 8H), 0.96-0.89 (m, 3H), 0.81 (s, 3H), 0.68-0.62 (m, 4H).

Obtaining connection 10-12 . To a solution of 10-1 (50 mg, 0.13 mmol) in THF (2 ml), at -50°C, a solution of vinylmagnesium bromide (1 mmol, 1M in THF, 1 ml) was added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 hours. TLC data (petroleum ether:ethyl acetate = 3:1) indicated that the reaction was complete, the reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 ml) and then extracted with EtOAC (10 ml x 3). The combined organic layer was washed with brine (10 mL x 2), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 15/1) to give 10-12 (27 mg, 54%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.94-5.86 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 5.19 (d, J=17 .2 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.01-1.95 (m, 3H ), 1.80-1.61 (m, 4H), 1.56-1.37 (m, 10H), 1.27 (s, 3H), 1.18-1.13 (m, 3H), 1.11 (s, 3H), 1.10-1.04 (m, 3H), 1.01 (s, 3H), 1.00-0.95 (m, 2H), 0.92 (d, J=6.4 Hz, 3H), 0.67 (s, 3H).

Receiving 10-12A and 10-12B . Compound 10-12 (350 mg, 0.84 mmol) was separated by SFC to give 10-12A (160 mg) and 10-12B (110 mg) as a white solid (overall yield: 77%). ¹ H NMR (10-12-A): (400 MHz, CDCl ₃ ) δ 5.94-5.86 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 5, 19 (d, J=17.2 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 2.50-2.40 (m, 1H), 2.05-0.85 (m, 36H), 0.67 (s, 3H). ¹ H NMR (10-12-B): (400 MHz, CDCl ₃ ) δ 5.94-5.86 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 5, 19 (d, J=17.2 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 2.50-2.40 (m, 1H), 2.05-0.85 (m, 36H), 0.67 (s, 3H).

Obtaining connection 10-13 . To a solution of 10-12 (500 mg, 1.21 mmol) in THF (5 ml) at 0°C under an inert N ₂ atmosphere, 9-BBN (24.2 ml, 12.1 mmol) was gradually added. The mixture was stirred at 60°C for 16 hours. Then the reaction mixture was cooled to a temperature of 0°C, and a 10% aqueous solution of NaOH (10 ml), 30% H ₂ O ₂ (5 ml) was added. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with aqueous Na ₂ S ₂ O ₃ (10 ml), extracted with EtOAC (10 ml x 3), dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by pre-HPLC to give 10-13 (100 mg, 19.2%) as a white solid, ¹ H NMR: (300 MHz, CD ₃ OD) δ 5.32 (d, J= 5.2 Hz, 1H), 3.70 (d, J=6.4 Hz, 2H), 2.51-2.35 (m, 1H), 2.14-1.84 (m, 4H), 1.82-1.26 (m, 16H), 1.24-1.10 (m, 7H), 1.08-1.00 (m, 7H), 1.00-0.93 (m, 4H ), 0.73 (s, 3H).

Obtaining connection 10-14 . To a solution of 10-13 (50 mg, 0.11 mmol) in THF (5 ml) was added NaH (13.2 mg, 0.55 mmol) at 0°C, and stirred at the same temperature for 30 minutes. CH ₃ I (78 mg, 0.55 mmol) was then added dropwise to the mixture. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NH ₄ Cl (10 ml), extracted with EtOAC (10 ml x 3), dried over Na ₂ SO ₄ and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 10-14 (13 mg, 25.2%) as a white powder. ^1H NMR: (300 MHz, CDCl ₃ ) δ 5.23 (d, J=5.2 Hz, 1H), 3.54 (d, J=6.4 Hz, 2H), 3.29 (s, 3H), 2.38-2.34 (m, 1H), 1.95-1.88 (m, 3H), 1.74-1.58 (m, 5H), 1.52-1.19 ( m, 14H), 1.10 (s, 3H), 1.09-1.05 (m, 1H), 1.04 (s, 3H), 1.02-0.94 (m, 2H), 0 .91 (s, 3H), 0.87 (d, J=6.4 Hz, 3H), 0.61 (s, 3H).

Getting 10-20 and 10-21 . Crude product 10-13 was washed with EtOAC (30 ml) which gave the diastereoisomer pairs (900 mg, 53.9%) as a white solid. The mixture (400 mg) was separated by SFC to give 10-20 (30 mg, 4.0%) as a white solid and 10-21 (68 mg, 9.2%) as a white solid. ^1H NMR (10-20): (400 MHz, methanol-d4) δ 5.28 (s, 1H), 3.69 (t, 2H, J=7.2 Hz), 2.42-2.39 (d, 1H, J=11.6 Hz), 2.04-1.90 (m, 5H), 1.78-1.28 (m, 17H), 1.17-1.02 (m, 12H ), 0.95-0.93 (d, 4H, J=6.8 Hz), 0.71 (s, 3H). ^1H NMR (10-21): (400 MHz, methanol-d4) δ 5.28 (s, 1H), 3.68 (t, 2H, J=7.2 Hz), 2.42-2.39 (d, 1H, J=11.6 Hz), 2.04-1.90 (m, 5H), 1.78-1.28 (m, 16H), 1.18-0.98 (m, 13H ), 0.95-0.93 (d, 4H, J=7.0 Hz), 0.71 (s, 3H).

Receipt 10-16 . A mixture of 10-20 (20 mg, 0.046 mmol) and Pd/C (20 mg, cat.) in EtOAC (5 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (50 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC = 5/1 to give 10-16 (7.6 mg, 39.3%) as a white solid. ¹ H NMR (10-16) (400 MHz, methanol-d4), δ 3.70 (t, 2H, J=7.2 Hz), 2.01-1.98 (d, 1H, J=12, 4 Hz), 1.93-1.82 (m, 1H), 1.72-1.57 (m, 5H), 1.53-1.39 (m, 5H), 1.35-0.99 (m, 22H), 0.96-0.94 (d, 4H, J=6.4 Hz), 0.84 (s, 3H), 0.70-0.66 (m, 4H).

Receipt 10-18 . A mixture of 10-21 (40 mg, 0.092 mmol, 1.0 eq.) and Pd/C (20 mg, cat.) in EtOAC (5 ml) was hydrogenated with hydrogen at 50 psi for 48 hours at 50°C. The reaction mixture was filtered through a pad of celite. The filter layer was washed with EtOAC (50 ml). The filtrate was concentrated in vacuo and the residue was purified on a silica gel column eluting with PE/EtOAC = 5/1 to give 10-18 (12.9 mg, 32.1%) as a white solid. ¹ H NMR (10-18) (400 MHz, methanol-d4), δ 3.68 (t, 2H, J=7.2 Hz), 1.99-1.96 (d, 1H, J=12, 4 Hz), 1.92-1.82 (m, 1H), 1.68-1.58 (m, 5H), 1.52-1.41 (m, 5H), 1.37-0.97 (m, 22H), 0.94-0.92 (d, 4H, J=6.4 Hz), 0.82 (s, 3H), 0.67-0.65 (m, 4H).

Example 11.

(a)

(b)

(With)

Preparation of compound 11-2 . To a solution of crude 11-1 (30 g, 77 mmol) in dichloromethane (200 mL) was added imidazole (10.4 g, 154 mmol) and tert-butylchlorodimethylsilane (13.8 g, 92 mmol). The mixture was then stirred at 15°C for 16 hours. The mixture was washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 150:1 to 80:1) to give crude product 11-2 (38 g, 98%) as a white solid.

Preparation of compound 11-3 . To a solution of diisopropylamine (34.3 g, 340 mmol) in THF (1 L) was added butyllithium (136 ml, 340 mmol, 2.5 M in hexane) under a nitrogen atmosphere at -78°C. The mixture was then stirred at -78°C for 10 minutes and then at 25°C for 10 minutes and finally at -78°C for 10 minutes. A solution of crude compound 11-2 (34 g, 68 mmol) in THF (100 ml) was then added and stirred for 1 hour at -78°C. Triethyl phosphite (22.6 g, 136 mmol) was then added to the mixture, which was then stirred under oxygen for 3 hours at -78°C and then at 25°C for 16 hours. Ammonium chloride (aq) was then added to the mixture. The organic layer was separated, purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give crude product 11-3 (10 g, 28%) as a yellow solid.

Preparation of compound 11-4 . To a solution of crude 11-3 (10 g, 19 mmol) in dichloromethane (100 ml) was added Dess-Martin reagent (16 g, 38 mmol) at 0°C under nitrogen atmosphere. The mixture was then stirred at 30°C for 3 hours. A mixed solution of sodium bicarbonate and sodium thiosulfate in water was then added to the mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo to give crude 11-4 (5.9 g, 59%) as a white solid.

Preparation of compound 11-5 . Hydrogen chloride (aq, 6 mL, 6 mmol, 1M) was added to a solution of crude 11-4 (5.9 g, 11 mmol) in THF (60 mL). The mixture was stirred at 15°C for 16 hours. Sodium bicarbonate (aq) was then added to the mixture. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo to give crude 11-5 (3.2 g, yield: 70%) as a white solid.

Preparation of compound 11-6 . To a solution of crude 11-5 (3.2 g, 7.9 mmol) in pyridine (50 ml), acetyl chloride (1.5 g, 19 mmol) was added dropwise at 0°C as monitored by TLC until the reaction was complete . Then water was added to the mixture and concentrated in vacuo. Water was added to the residue and dichloromethane was extracted. The organic layer was dried over anhydrous sodium sulfate, purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:1) to give crude 11-6 (2.8 g, 79%) as a white solid.

Preparation of connection 11-7 . To a solution of crude 11-6 (2.8 g, 6.3 mmol) in dichloromethane (10 ml) at 0°C, diethylaminosulfur trifluoride (8 g, 50 mmol) was added dropwise. The mixture was then stirred for 16 hours at 30°C. The mixture was then added to sodium bicarbonate (aq). The organic layer was separated, dried over anhydrous sodium sulfate, purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100:1 to 33:1) to give crude 11-7 (2 g, 68%) as white solid.

Preparation of connection 11-8 . To a solution of crude 11-7 (2 g, 4.2 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (900 mg, 21 mmol) in water (10 mL) and then methanol (5 mL) was added. The mixture was then stirred at 30°C for 16 hours. The mixture was then concentrated in vacuo. Water was added to the residue and filtered. The solid was washed with water, dried in vacuo to give 11-8 (1.5 g, 85%) as a white solid. ^1H NMR: (400 MHz, methanol-d4) δ 5.34 (d, J=5.2 Hz, 1H), 3.45-3.35 (m, 1H), 2.30-2.10 ( m, 3H), 2.10-1.68 (m, 7H), 1.68-1.44 (m, 6H), 1.35-1.28 (m, 2H), 1.28-1. 12 (m, 3H), 1.12-0.98 (m, 8H), 0.74 (s, 3H).

Obtaining connection 11-9 . Hydrogen chloride (5 mL, 4M in methanol) was added to a solution of 11-8 (1 g, 2.4 mmol) in methanol (15 mL). The mixture was stirred at 30°C for 15 minutes. Sodium bicarbonate (aq) was added until pH = 7. The mixture was then concentrated in vacuo. Water was added to the residue, extracted with ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 5:1) to give 11 -9 (970 mg, 93%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.34 (d, J=5.2 Hz, 1H), 3.87 (s, 3H), 3.60-3.48 (m, 1H), 2.32-2.15 (m, 2H), 2.10-1.95 (m, 2H), 1.95-1.70 (m, 5H), 1.65-1.40 (m, 8H ), 1.30-0.90 (m, 13H), 0.70 (s, 3H).

Getting connection 11-10 . To a solution of 11-9 (0.97 g, 2.3 mmol) in dichloromethane (50 ml) was added Dess-Martin reagent (2.3 g, 5.4 mmol) at 0°C under nitrogen atmosphere. The mixture was then stirred at 30°C for 3 hours. A mixed solution of sodium bicarbonate and sodium thiosulfate in water was then added to the mixture. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated in vacuo to give crude compound 11-10 (1 g, 100%) as a yellow oil.

Obtaining compounds 11-11 and 11-12 . To a solution of butylated hydroxytoluene (3.1 g, 14.2 mmol) in toluene (20 ml) was added Me ₃ Al (3.6 ml, 7.2 mmol, 2M in toluene) at 15°C. The mixture was then stirred at 15°C for 30 minutes. A solution of 11-11 (0.9 g, 2.4 mmol) in toluene (5 ml) was added at -78°C. The mixture was then stirred at -78°C for 1 hour. Methyl magnesium bromide (2.4 ml, 7.2 mmol, 3M in ether) was then added at -78°C. The mixture was then stirred at -78°C for 1 hour. Ammonium chloride (aq) was then added to the mixture and filtered. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1 to 10:1) to give 240 mg of crude 11-11 (yield: 28 %) and 210 mg crude 11-12 (yield: 25%). ^1H NMR (400 MHz, CDCl ₃ ): δ 5.33-5.25 (m, 1H), 3.87 (s, 3H), 2.50-0.75 (m, 33H), 0.70 (c, 3H). ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.35-5.27 (m, 1H), 2.50-2.37 (m, 1H), 2.32 (s, 3H), 2.20 -0.75 (m, 32H), 0.70 (s, 3H).

Obtaining connection 11-13 . Sodium borohydride (100 mg, 2.6 mmol) was added to a solution of 11-12 (70 mg, 0.16 mmol) in ethanol (2 ml) at 15°C. The mixture was stirred for 30 minutes at a temperature of 15°C. Ammonium chloride (aq) was then added to the mixture and concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 8:1) to give 11-13 (40 mg, 57% ) in the form of a white solid. ^1H NMR: (400 MHz, methanol-d4) δ 5.35-5.28 (m, 1H), 3.88-3.68 (m, 1H), 2.49-2.37 (m, 1H ), 2.18-1.22 (m, 20H), 1.19 (d, J=6.0 Hz, 3H), 1.18-1.14 (m, 1H), 1.11-1, 08 (m, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 1.02-0.95 (m, 1H), 0.76 (s, 3H).

Preparation of compounds 11-15 and 11-16 . The diastereomeric mixture 11-13 (30 mg, 0.071 mmol) was separated by SFC to obtain 11-15 (12.2 mg) and 11-16 (14.7 mg) as a white powder (overall yield: 90%). ¹ H NMR (11-15): (400 MHz, MeOD) δ 5.32 (d, J=5.2 Hz, 1H), 3.85-3.72 (m, 1H), 2.50-2 .40 (m, 1H), 2.20-1.57 (m, 11H), 1.52-0.85 (m, 23H), 0.78 (s, 3H). ¹ H NMR (11-16): (400 MHz, MeOD) δ 5.32 (d, J=5.2 Hz, 1H), 3.85-3.72 (m, 1H), 2.50-2 .40 (m, 1H), 2.20-1.45 (m, 15H), 1.40-0.85 (m, 20H), 0.78 (s, 3H).

Obtaining connection 11-19 . To a solution of 11-12 (70 mg, 0.16 mmol) in THF (2 ml) at -78°C was added methylmagnesium bromide (1 ml, 3 mmol, 3M in ether). The mixture was stirred at 15°C for 30 minutes. Ammonium chloride (aq) was then added to the mixture and concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 8:1) to give 11-19 (39 mg, 55% ) in the form of a white solid. ^1H NMR: (400 MHz, methanol-d4) δ 5.33-5.28 (m, 1H), 2.48-2.38 (m, 1H), 2.12-1.70 (m, 17H ), 1.23 (s, 6H), 1.20-1.12 (m, 3H), 1.10 (d, J=6.4 Hz, 3H), 1.06 (s, 3H), 1 .04 (s, 3H), 1.03-0.91 (m, 2H), 0.76 (s, 3H).

Example 12: Preparation of intermediate 0-9

Getting 0-2 . To a solution of compound 0-1 (100 g, 255 mmol, 1.0 eq.) in dry MeOH (500 ml) was added concentrated H ₂ SO ₄ (14 ml). The mixture was refluxed overnight and then cooled to room temperature. The mixture was quenched with saturated aqueous NaHCO ₃ (0.5 L) and then evaporated to remove MeOH. The remaining mixture was extracted with EtOAC (300 ml x 3). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ and evaporated to give the product (100 g crude, 96%) as an off-white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 4.09-4.02 (m, 1H), 3.66 (s, 3H), 3.63-3.58 (m, 1H), 2.39 -2.31 (m, 1H), 2.25-2.15 (m, 1H), 1.97-1.91 (m, 1H), 1.91-1.55 (m, 10H), 1 .52-1.02 (m, 14H), 0.95-0.88 (m, 6H), 0.62 (s, 3H).

Receiving 0-3 . To a solution of compound 0-2 (250 g, 615 mmol, 1.0 eq.) in dry pyridine (0.8 L) was added a solution of TsCl (352 g, 1844 mmol, 3.0 eq.) in dry pyridine (200 ml ). The mixture was stirred at room temperature for 18 hours. Gradually crushed ice was added to the mixture and the precipitated solid was filtered, washed with aqueous 10% HCl (400 ml x 3) and water (400 ml x 2) and then evaporated to dryness, giving the crude product (500 g, crude) as off-white powder, which was directly used in the next step.

Receiving 0-4 . A mixture of compound 0-3 (250 g crude), CH ₃ COOK (24 g, 245 mmol, 0.77 eq.), water (150 ml) and DMF (900 ml) was heated at reflux for 24 hours. The solution was cooled to room temperature, and crushed ice was gradually added to it. The precipitated solid was filtered and washed with water (100 ml x 2). The crude solid was purified by a silica gel column (PE/EtOAC = 8/1) to give compound 0-4 (40 g, 34.3% yield over two steps) as a white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 5.32-5.38 (m, 1H), 3.66 (s, 3H), 3.47-3.57 (m, 1H), 2.16- 2.41 (m, 4H), 1.93-2.04 (m, 2H), 1.74-1.92 (m, 4H), 1.30-1.59 (m, 9H), 0. 90-1.19 (m, 12H), 0.68 (s, 3H).

Getting 0-5. To a solution of compound 0-4 (33 g, 85 mmol, 1.0 eq.) in dry CH ₂ Cl ₂ (700 ml) at a temperature of 0°C, the Dess-Martin reagent (72 g, 170 mmol, 2, 0 eq.). The reaction mixture was then stirred at room temperature for 1 hour. TLC data (PE:EA=3:1) showed that the starting product was completely consumed. The reaction mixture was quenched with a saturated aqueous solution of NaHCO ₃ /Na ₂ S ₂ O ₃ =1:3 (250 ml). The organic phase was washed with brine (200 ml×2) and dried over Na ₂ SO ₄ and the solvent was evaporated to give the desired product (35 g, crude), which was used in the next step without further purification.

Receiving 0-6 . To a solution of MAD (0.42 mol, 3.0 eq.) in toluene, freshly prepared by adding a solution of Me ₃ Al (210 ml, 0.42 mmol, 2 M in hexane) to a stirred solution of 2,6-di-tert-butyl -4-methylphenol (185 g, 0.84 mol) in toluene (200 ml), followed by stirring for 1 hour at room temperature, a solution of compound 0-5 (54 g, 0.14 mol, 1.0 eq.) in toluene (200 ml) at -78°C in a nitrogen atmosphere. The reaction mixture was then stirred for 30 min, a solution of MeMgBr (140 ml, 0.42 mol, 3.0 eq, 3M in ether) was added dropwise at -78°C. The reaction mixture was heated to -40°C and stirred at this temperature for 3 hours. TLC data (PE:EA = 3:1) showed that the starting product was completely consumed. The mixture was poured into saturated aqueous NH ₄ Cl (100 ml) and extracted with EtOAC (300 ml x 2). The combined organic phases were dried over Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The crude product was purified by silica gel chromatography eluting with PE:EA=10:1 to give pure title compound (30 g, 53%) as a white powder. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.31-5.29 (m, 1H), 3.66 (s, 3H), 2.39-2.33 (m, 2H), 2.24 -2.22 (m, 1H), 1.99-1.95 (m, 3H), 1.85-1.68 (m, 4H), 1.59-1.40 (m, 8H), 1 .31-1.26 (m, 2H), 1.17-1.01 (m, 11H), 0.93-0.91 (m, 4H), 0.67 (s, 3H).

Receiving 0-7 . To a solution of compound 0-6 (30.0 g, 74.51 mmol) in THF/H ₂ O (800 ml, 1/1) was added LiOH·H ₂ O (17.51 g, 417.28 mmol). The reaction mixture was stirred at room temperature for 18 hours. TLC data (PE/EA=2/1) showed that compound 0-6 was completely consumed. The mixture was concentrated in vacuo, diluted with water (2 L), and then acidified to pH=4 with 1M aqueous HCl. The precipitate that formed was collected by filtration and dried in vacuo to give product 0-7 (33 g, crude) as an off-white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.31-5.30 (m, 1H), 2.44-2.36 (m, 2H), 2.29-2.24 (m, 1H) , 2.01-1.95 (m, 3H), 1.87-1.71 (m, 5H), 1.61-1.56 (m, 2H), 1.50-1.32 (m, 8H), 1.17-1.09 (m, 7H), 1.01 (s, 3H), 0.95-0.93 (m, 4H), 0.68 (s, 3H).

Receiving 0-8 . Mixture of compound 0-7 (32.0 g, 82.35 mmol), N,O-dimethylhydroxylamine (16.07 g, 164.70 mmol), HATU (37.57 g, 98.82 mmol) and Et ₃ N (46.0 ml, 329.40 mmol) in 500 ml anhydrous CH ₂ Cl ₂ was stirred for 18 hours at room temperature. TLC data showed that the reaction was complete. CH ₂ Cl ₂ was then added to the mixture, and the resulting solution was washed with water, 1 N aqueous HCl, saturated aqueous NaHCO ₃ and saturated saline, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, purified on silica gel (PE: EtOAC = from 10:1 to 3:1) to give title compound 0-8 (17.0 g, yield: 47.8%) as an off-white solid ¹ H NMR: (400 MHz, CDCl ₃ ) δ 5.31 -5.29 (m, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 3.03 (s, 2H), 2.47-2.29 (m, 3H), 2.04-1.68 (m, 7H), 1.60-1.43 (m, 7H), 1.38-1.30 (m, 2H), 1.20-1.08 (m, 6H ), 1.03-0.91 (m, 8H), 0.68 (s, 3H).

Obtaining key intermediate 0-9 . To a solution of compound 0-8 (17.0 g, 39.38 mmol) in 300 ml anhydrous THF was added dropwise MeMgBr (65.6 ml, 196.92 mmol, 3M in ether) under N ₂ atmosphere at 0°C . After the addition was complete, the reaction mixture was stirred for 2 hours at room temperature. TLC data showed that the reaction was complete. Then at a temperature of 0°C, a saturated aqueous solution of NH ₄ Cl was slowly added, then the mixture was poured into water, extracted with EtOAC (2 * 200 ml), the organic layers were washed with saturated saline, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated, purified on silica gel (PE: EtOAC = 20:1 to 6:1) to give the title compound 0-9 (11.0 g, yield: 72%) as a white solid. ^1H NMR: (400 MHz, CDCl ₃ ) δ 5.31-5.30 (m, 1H), 2.50-2.30 (m, 3H), 2.17 (s, 2H), 2.14 (s, 3H), 2.02-1.94 (m, 3H), 1.88-1.67 (m, 4H), 1.61-1.58 (m, 1H), 1.56-1 .49 (m, 5H), 1.47-1.41 (m, 2H), 1.31-1.11 (m, 7H), 1.08-0.91 (m, 8H), 0.68 (c, 3H).

Research methods

The compounds of the present invention can be evaluated using various in vitro and in vivo studies described in the literature; examples of them are described below.

The following examples are presented to illustrate the biological activity of the compounds, pharmaceutical compositions and methods described herein and in any way should not be construed as limiting its scope.

NMDA potentiation

NMDA potentiation was assessed by local whole-cell voltage clamping of mammalian cells that express NMDA receptors or by using the two-electrode voltage clamp (TEVC) method in Xenopus laevis oocytes expressing NMDA receptors.

Method of local potential clamping on a whole cell of mammalian cells

The whole cell local voltage clamp method was used to study the effects of compounds (0.1 mm and 1.0 mm) on the NMDA receptor (GRIN ₁ /GRIN ₂ A subunits) expressed in HEK cells. The NMDA/glycine peak and steady-state currents were recorded from stably transfected cells expressing the NMDA receptor, and the modulating effects of the study drugs on these currents were examined. The results are shown in Table 1.

Cells were stably transfected with human GRIN1 (variant NR1-3). These cells were transiently transfected (LipofeCtamine ^™ ) with GRIN ₂ A cDNA and CD8 antigen cDNA (pLeu). Approximately 24-72 hours after transfection, 1 μl of Dynabeads M-45 CD8 was added to determine successful cell transfection (Jurman et al., BioteChniques (1994) 17:876-881). Cells were passaged until 50-80% confluence. Cells were plated on poly-L-lysine-coated coverslips covered with complete culture medium in 35 mm culture dishes. The fused cell clusters were electrically connected (PritChett et al., SCienCe (1988), 242:1306-8). Because reactions in distant cells do not sufficiently capture the potential and because of uncertainty about the degree of connectivity (Verdoorn et al., Neuron (1990), 4: 919-28) cells were cultured at a density that allowed individual cells to be examined (without visible connections to neighboring cells) . Cells were incubated at 37°C in a humidified atmosphere with 5% CO ₂ (relative humidity approximately 95%). Cells were continuously maintained and passaged in sterile culture flasks containing a 1:1 mixture of Dulbecco's modified Eagle's medium and F-12 nutrient mixture (D-MEM/F-12 1x, liquid, with L-glutamine) supplemented with 9% fetal bovine serum. and 0.9% penicillin/streptomycin solution. Complete medium was supplemented with 3.0 μg/ml puromycin.

Whole cell currents were measured using HEKA EPC-10 amplifiers using PatChMaster software. Cell culture dishes for recordings were mounted on a microscope dish holder and continuously perfused (1 ml/min) with a “wash solution” (NaCl 137 mM, KCl 4 mM, CaCl ₂ 1.8 mM, MgCl ₂ 1 mM, HEPES 10 mM, D-glucose 10 mM, pH (NaOH) 7.4). All solutions applied to cells, including the solution filled into the pipette, were kept at room temperature (19°C-30°C). After forming a gigaohm contact between the contact electrodes and transfected individual HEK 293 cells (pipette resistance range: 2.5 MΩ - 6.0 MΩ; contact resistance range: >1 GΩ), the cell membrane, transverse to the pipette tip, was disrupted to allow electrode access to the inside of the cell (whole cell configuration). At this point, the wash solution was switched to "NMDA wash solution" (NaCl 137 mM, KCl 4 mM, CaCl ₂ 2.8 mM, HEPES 10 mM, D-glucose 10 mM, Cremophor 0.02%, pH (NaOH) 7 ,4). NMDA inward currents were measured by injecting 30 μM NMDA (and 5.0 μM glycine) into cells with voltage clamp (2 injections) for 5 sec. The cells were measured at a resting potential of -80 mV. For the analysis of test substances, NMDA receptors were stimulated with 30 μM NMDA and 5.0 μM glycine after sequential preincubation of increasing concentrations of the test substance. The duration of pre-incubation was 30 seconds. The stimulation duration was 5 seconds. The test substances were dissolved in DMSO to obtain 0.1 mM and 1 mM stock solutions. The test substances were diluted to 0.1 µM and 1 µM in “NMDA wash solution”. Both concentrations of the test substances were tested on each cell. Similar concentrations were applied at least three times or until steady-state current amplitude was reached. Each day, one cell was probed with 50 μM PREGS (positive control), using a similar application protocol to determine successful transfection of cells with NMDA receptors.

In Table 1, "A" means 10-75% potentiation, "B" means >75%-150% potentiation, and "C" means >150-250% potentiation; and “D means potentiation >250%.

Oocytes

A two-electrode voltage clamp (TEVC) technique was used to study the effects of compounds (10 μM) on the NMDA receptor (GRIN1/GRIN ₂ A) expressed in Xenopus oocytes. The glutamate/glycine peak and steady-state currents were recorded from oocytes expressing the NMDA receptor, and the modulatory effects of the study drugs on these currents were examined. The results are shown in Table 2.

Ovaries were collected from heavily anesthetized female Xenopus laevis by cooling to 4°C and immersing in tricaine methanesulfonate (MS-222 at 150 mg/L) in sodium bicarbonate (300 mg/L). After anesthesia, the animal was decapitated under anesthesia and the spinal cord was destroyed in accordance with the animal rights regulations of the canton of Geneva. A small part of the ovary was separated for direct processing, while the remaining part was placed at a temperature of 4 ° C in a sterile Barth solution containing, in mM: NaCl 88, KCl 1, NaHCO ₃ 2.4, HEPES 10, MgSO ₄ 7H ₂ O 0 .82, Ca(NO ₃ ) ₂ 4H ₂ O 0.33, CaCl ₂ 6H ₂ O 0.41, at pH 7.4, and with the addition of 20 μg/ml kanamycin, 100 units/ml penicillin and 100 μg /ml streptomycin. All recordings were performed at a temperature of 18°C, and the cells were perfused with a medium containing, in mM: NaCl 82.5, KCl 2.5, HEPES 5, CaCl ₂ 2H ₂ O, CaCl ₂ 6H ₂ O 1, pH 7, 4.

Oocytes were injected with both cDNAs encoding the human GRIN ₁ and GRIN ₂ A subunits using an in-house automated injection device (Hogg et al., J. Neurosci. Methods , (2008) 169: 65-75), and receptor expression was assessed electrophysiologically. in at least two days. The cDNA injection ratio for GRIN1 and GRIN ₂ A was 1:1. Electrophysiological data recording was performed using an automated process equipped with standard TEVCs, and data were recorded and analyzed using proprietary data acquisition and processing software running Matlab (Mathworks InC.). The membrane potential in oocytes was maintained at −80 mV throughout the experiments. To study the effects of in-house compounds, currents were induced by applying 3 μM glutamate and 10 μM glycine for 10 seconds. Then, before treatment with the test substance at a concentration of 10 μM for 120 sec, the oocytes were washed for 90 sec. Thereafter, they were immediately re-treated with 3 μM glutamate and 10 μM glycine for 10 seconds. Potentiation of both peak current and steady-state current was assessed. Statistical analysis data were processed using ExCel (MiCrosoft) or Matlab (Mathworks InC.) software. To obtain mean measurements with standard deviations, all experiments were performed using at least three cells.

Glutamate was prepared as a concentrated stock solution (10 ^-1 M) in water and then diluted in vehicle to obtain the desired analytical concentration. Glycine was prepared as a stock solution at 1 M in water. The compounds were prepared as a stock solution (10 ^-2 M) in DMSO and then diluted in vehicle to obtain the desired analytical concentration. The residual amount of DMSO did not exceed a concentration of 1%, a concentration that has not been shown to have an effect on the functioning of Xenopus oocytes.

In Table 2, "A" means 10-50% potentiation, "B" means >50%-100% potentiation, and "C" means >100% potentiation.

As shown in Table 1, compounds containing a beta hydrogen at C ₅ are less preferred than compounds containing either an alpha hydrogen at C ₅ or a double bond between C ₅ -C ₆ due to reduced NMDA receptor potentiation. This is illustrated by comparing control compound 5 with compounds 4-6 and 4-7. Removal of the methyl at C ₂₁ also results in a significant reduction in NMDA potentiation, for example, control compound 4 has a fivefold reduction in potentiation compared to control compound 3, measured at a concentration of 0.1 μM. Therefore, the compounds in this sample carry both a methyl group at _C21 and either a double bond between _C5 - _C6 or an alpha hydrogen at _C5 . In addition, during the study, the compounds in this sample showed increased potency and limited maximal potentiation of the NMDA receptor up to a compound concentration of 1 μM (eg, control compound 2 compared to 4-6 and 1-11). Such properties are expected to limit the risk of inducing glutamate-mediated neurotoxicity compared to compounds that achieve greater maximal potentiation of the NMDA receptor.

Other embodiments

In the claims, the use of singular means one object or more than one object, unless otherwise indicated or otherwise follows from the context. Claims or specifications that include an "or" between one or more group members are considered to be

executed if one, more than one or all members of the group are present in, used in, or otherwise related to the product or process, unless the contrary is stated or the context otherwise requires. The invention includes embodiments in which only one group member is present in, used in, or related to a given product or process. The invention includes embodiments in which more than one or all members of the group are present in, used in, or related to a given product or process.

In addition, the invention covers all variations, combinations and permutations in which one or more limitations, elements, conditions, descriptive terms from one or more listed claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that depends on the same primary claim. Where elements are represented as enumerations, for example in Markush group format, each subgroup of elements is also described, and any element(s) may be removed from the group. It should be understood that, in general, when an invention or aspects of an invention are referred to as containing specific elements and/or features, certain embodiments of the invention or aspects of the invention are, or consist essentially of, such elements and/or features. For purposes of simplicity, these embodiments have not been specifically stated herein in literal terms in every case. It should also be noted that the terms “comprising” and “comprising” are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, limits are included. In addition, it should be understood that, unless specifically stated or otherwise obvious from the context and understood by any person of ordinary skill in the art, values that are expressed as a range may imply any specific value or subgroup within the stated range in various embodiments of the invention, up to a tenth of an integer lower limit of the range, unless the context clearly indicates otherwise.

This application relates to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the included references and this description, the description must be relied upon. Moreover, any specific embodiment of the present invention that is prior art may be excluded from any one or more claims. Since such variations are considered to be known to any person skilled in the art, they may be excluded even if the exclusion is not specifically stated herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether related to prior art or not.

Those skilled in the art will have identified, or will be able to determine, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not limited to the above description, but rather is defined in the accompanying claims. Those skilled in the art will appreciate that various changes and modifications to the present disclosure may be made without departing from the spirit or scope of the present invention as defined in the following claims.

Claims (90)

1. A connection selected from the group consisting of: and their pharmaceutically acceptable salts. 2. A compound according to claim 1, selected from the group consisting of: and their pharmaceutically acceptable salts. 3. A compound according to claim 1, selected from the group consisting of: and their pharmaceutically acceptable salts. 4. A compound according to claim 1, selected from the group consisting of: and their pharmaceutically acceptable salts. 5. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: b. A compound according to claim 1, selected from the group consisting of: and their pharmaceutically acceptable salts. 7. A compound according to claim 1, selected from the group consisting of: 8. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 9. A compound according to claim 1, selected from the group consisting of: 10. The compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 11. A compound according to claim 1, selected from the group consisting of: 12. The compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 13. A compound according to claim 1, selected from the group consisting of: 14. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 15. A compound according to claim 1, selected from the group consisting of: 16. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 17. A compound according to claim 1, selected from the group consisting of: 18. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 19. A compound according to claim 1, selected from the group consisting of: 20. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 21. A compound according to claim 1, selected from the group consisting of: 22. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 23. The compound according to claim 1, selected from the group consisting of: 24. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 25. A compound according to claim 1, selected from the group consisting of: 26. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 27. The compound according to claim 1, selected from the group consisting of: 28. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 29. The compound according to claim 1, selected from the group consisting of: 30. A compound according to claim 1, which is a pharmaceutically acceptable salt of a compound selected from the group consisting of: 31. Pharmaceutical composition for positive allosteric modulation of NDMA receptor activity, containing an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims. 1-30 and a pharmaceutically acceptable carrier. 32. A method of treating a CNS disease mediated by positive allosteric modulation of NDMA receptor activity in a subject in need of such treatment, comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims. 1-30 or the pharmaceutical composition according to claim 31. 33. The method of claim 32, wherein the CNS disease mediated by positive allosteric modulation of NDMA receptor activity is selected from the group consisting of adjustment disorder, anxiety disorder (including obsessive-compulsive disorder, post-traumatic stress disorder and social phobia), cognitive disorder (including Alzheimer's disease and other forms of dementia), dissociative disorder, eating disorder, mood disorder (including depression, bipolar disorder and dysthymic disorder), schizophrenia or other psychotic disorder (including schizoaffective disorder), sleep disorder (including insomnia), sleep disorder alcohol or drug use, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorder (including those associated with mutations, including those associated with mutations in the Shank protein group), neurodevelopmental disorders (including Rett syndrome, complex tuberous sclerosis (TSC), pain (including acute and chronic pain), encephalopathy due to a medical condition (including hepatic encephalopathy and anti-NMDA receptor encephalitis), seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet disease), stroke, traumatic brain injury, movement disorder (including Huntington's disease and Parkinson's disease) and tinnitus. 34. The method of claim 33, wherein the CNS disease mediated by positive allosteric modulation of NDMA receptor activity is Alzheimer's disease. 35. The method of claim 33, wherein the CNS disease mediated by positive allosteric modulation of NDMA receptor activity is Parkinson's disease. 36. The method of claim 33, wherein the CNS disease mediated by positive allosteric modulation of NDMA receptor activity is Huttington's disease. 37. The method of claim 33, wherein the CNS disease mediated by positive allosteric modulation of NDMA receptor activity is hepatic encephalopathy or anti-NMDA receptor encephalitis.