RU2828261C2 - C17-, c20- and c21-substituted neuroactive steroids and methods of their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (1-A) or a pharmaceutically acceptable salt thereof, where: a) a compound of formula (1-A) is a compound of formula (1-A-1), where each R^Y4 is independently C₁-C₂₀ alkyl, cyano or halo; and e is either 0 or 2; or b) a compound of formula (1-A) is a compound of formula (1-A-3) wherein each R^Y1 is hydrogen, C₁-C₆ alkyl, or C₆ cycloalkyl; and each R^Y2 is independently C₁-C₆ alkyl, C₆ cycloalkyl, C₆ heterocyclyl having 1–4 heteroatoms, where each heteroatom is selected from N, O or S, C₆ aryl or C₆ heteroaryl having 1–4 heteroatoms, where each heteroatom is selected from N, O or S; and b= 0 or 1; or c) a compound of formula (1-A) is a compound of formula (1-A-5) wherein each R^Y3 is C₆ aryl or C₅-C₆ heteroaryl having 1–4 heteroatoms, where each heteroatom is selected from N, O or S; or two R^Y3 groups are joined together to form a 6-membered ring; c is 1, 2 or 3; and d is either 0, 1, or 2; and where R³ represents C₁-C₆ alkyl; R^X is independently either hydrogen or C₁-C₆ alkyl, R^Y is independently C₆ aryl, C₆ cycloalkyl, or C₆ heterocyclyl containing 1–4 heteroatoms, where each heteroatom is selected from N, O, or S; or R^X and R^Y are joined together to form a 6-membered heterocyclic ring; R¹⁹ is hydrogen or C₁-C₆ alkyl; R ⁵ is hydrogen; and represents a single bond. The invention also relates to a pharmaceutical composition with the ability to inhibit the function of the GABA receptor, based on these compounds.

EFFECT: obtaining new compounds and a pharmaceutical composition based on them which can be used in medicine in the treatment of cancer.

15 cl, 2 tbl, 108 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S.S.N. 62/360,813, filed July 11, 2016, U.S.S.N. 62/360,847, filed July 11, 2016, and U.S.S.N. 62/424,803, filed November 18, 2016, which are hereby incorporated by reference in their entireties.

LEVEL TECHNIQUES

Brain excitability is defined as the level of arousal of the animal, a continuum that ranges from coma to convulsions and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductivity of ions across neuronal membranes. At rest, the potential (or membrane voltage) of the neuronal membrane is approximately -70 mV, with the interior of the cell being negatively charged relative to the exterior of the cell. The potential (voltage) is the result of ionic (K ⁺ , Na ⁺ , Cl ^- , organic anions) equilibrium across the semipermeable membrane of the neuron. Neurotransmitters are stored in presynaptic vesicles and are released in response to neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine causes a depolarization of the membrane, for example, 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 to Na ⁺ ions. The reduced membrane potential stimulates neuronal excitability in the form of a postsynaptic action potential.

In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by GABA, a neurotransmitter. GABA has a strong effect on overall brain excitability because up to 40% of neurons in the brain use GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC, facilitating the flow of chloride ions down the electrochemical gradient of the GRC into the cell. Intracellular increases in the levels of this anion cause hyperpolarization of the transmembrane potential, which decreases the responsiveness of neurons to excitatory signals, i.e., decreases the excitability of neurons. In other words, the higher the concentration of chloride ions in a neuron, the lower the excitability of the brain and the level of arousal.

There is considerable literature indicating that the GRC is responsible for the manifestation of anxiety, seizure activity, and sedation. Thus, the therapeutically beneficial effects of GABA and drugs that act similarly to GABA or that facilitate the effects of GABA (e.g., the therapeutically useful barbiturates and benzodiazepines (BZ) such as Valium®) result from their interaction with specific regulatory sites on the GRC. The evidence to date indicates that in addition to the benzodiazepine and barbiturate binding site, the GRC contains at least one specific site for interaction with neuroactive steroids. See, e.g., Lan, N. C. et al., Neurochem. Res. (1991) 16:347-356.

Neuroactive steroids can be generated endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was discovered in 1986 (Majewska, MD et al., Science 232:1004–1007 (1986); Harrison, NL et al., J. Pharmacol. Exp. Ther. 241:346–353 (1987).

What is needed are new and improved neuroactive steroids that act as modulating agents for brain excitability and as agents for the prevention and treatment of diseases associated with the central nervous system. The compounds, compositions and methods described in the present application are directed to achieving this goal.

ESSENCE INVENTIONS

The compounds described herein act as GABA modulators in some embodiments, such as by acting on the GABA _A receptor in both a positive and negative manner. As modulators of central nervous system (CNS) excitability mediated by their ability to modulate the GABA _A receptor, such compounds are expected to have CNS activity.

In one aspect, a compound of formula ( I ) is provided:

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 ,- S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two the R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form carbocyclyl, heterocyclyl or -C(=O)-; R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; each of R ^17a and R ^17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 , or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In some embodiments, R ¹⁹ is hydrogen or alkyl. In some embodiments, R ¹⁹ is unsubstituted alkyl. In some embodiments, R ¹⁹ is substituted alkyl. In some embodiments, R ¹⁹ is -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH(CH ₃ ) ₂ .

In some embodiments, R ² is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ² is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ³ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ³ is methyl and ethyl (eg, substituted or unsubstituted alkyl).

In some embodiments, R ⁴ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁴ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁴ is hydrogen.

In some embodiments, represents a single bond, and R ⁵ represents hydrogen. In some embodiments, R ⁵ is absent, and represents a single or double bond, and if one represents a double bond, then the other represents a single bond.

In some embodiments, R ⁶ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁶ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁶ is hydrogen.

In some embodiments, R ⁷ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁷ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁷ is hydrogen.

In some embodiments, R ^11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , or R ^11a and R ^11b , together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ^11a and R ^11b, together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a and R ^11b are hydrogen.

In some embodiments, each of ^R2 , ^R4 , ^R6 , ^R7 , ^R11a , and ^R11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, ^-ORA1 , ^-SRA1 , or -N(R ^A1 ) ₂ . In some embodiments, each of ^R2 , ^R4 , R6, R7, ^{R11a ,} and ^R11b is independently hydrogen, halogen, alkyl, or -ORA1. In some embodiments ^{, R2} , ^R4 , ^R6 , ^R7 , ^{R11a ,} and ^R11b are hydrogen.

In some embodiments, each of R ^17a and R ^17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen. In some embodiments, each of R ^17a and R ^17b is independently hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen.

In some embodiments, R ^17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -S(=O )R ^A2 or -SO ₂ R ^A2 . In some embodiments, R ^17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -S(=O)R ^A2 or -SO ₂ R ^A2 . In some embodiments, R ^17a is halogen, cyano, nitro, alkyl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ .

In one aspect, the present application provides a compound of formula ( II ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; R ³ is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., -CH ₃ ) or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or is hydrogen; and

represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or -OR ^A1 .

In some embodiments, R ¹⁹ is hydrogen. In some embodiments, R ¹⁹ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ¹⁹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ¹⁹ is -C( ^RC ) ₂ OR ^A1 . In some embodiments, R ¹⁹ is -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH(CH ₃ ) ₂ .

In some embodiments, R ² is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ² is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ³ is methyl and ethyl (eg, substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R ⁴ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁴ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁴ is hydrogen.

In some embodiments, represents a single bond, and R ⁵ represents hydrogen. In some embodiments, R ⁵ is absent, and represents a single or double bond, and if one represents a double bond, then the other represents a single bond.

In some embodiments, R ⁶ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁶ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁶ is hydrogen.

In some embodiments, R ⁷ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁷ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁷ is hydrogen.

In some embodiments, R ^11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , or R ^11a and R ^11b , together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ^11a and R ^11b, together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a and R ^11b are hydrogen.

In some embodiments, each of ^R2 , ^R4 , ^R6 , ^R7 , ^R11a , and ^R11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, ^-ORA1 , ^-SRA1 , or -N(R ^A1 ) ₂ . In some embodiments, each of ^R2 , ^R4 , R6, R7, ^R11a , and ^R11b is hydrogen, halogen, alkyl ^, or -ORA1. In some embodiments ^, each of ^R2 , ^R4 , ^R6 , ^R7 , ^{R11a ,} and ^R11b is hydrogen.

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-a ) or ( II-b ):

or

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-c ):

Where:

each of R ^21a and R ^21b independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 ; or R ^21a and R ^21b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; and n is an integer selected from 1, 2 and 3.

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-d ):

In one aspect, the present application provides a compound of formula ( III ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b, together with the carbon atom to which they are attached, form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; R ¹⁹ is unsubstituted alkyl; R ⁵ is absent or is hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In one aspect, the present application provides a compound of formula ( IV ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; Q is halogen, cyano, nitro, C-linked heterocyclyl, aryl, C-linked heteroaryl, -O-alkenyl, -O-alkynyl, -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 ; R ¹⁹ is -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl; R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In one aspect, the present application provides a compound of formula ( I ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 ,- S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group upon attachment to an oxygen atom, a sulfur protecting group upon attachment to a sulfur atom, a nitrogen protecting group upon attachment to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form carbocyclyl, heterocyclyl or -C(=O)-; R ³ is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; each of R ^17a and R ^17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 , or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In some embodiments, R ¹⁹ is hydrogen or alkyl. In some embodiments, R ¹⁹ is unsubstituted alkyl. In some embodiments, R ¹⁹ is substituted alkyl. In some embodiments, R ¹⁹ is -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH(CH ₃ ) ₂ .

In some embodiments, R ² is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ² is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ³ is alkyl (eg, substituted or unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ³ is methyl and ethyl (eg, substituted or unsubstituted alkyl).

In some embodiments, R ⁴ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁴ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁴ is hydrogen.

In some embodiments, represents a single bond, and R ⁵ represents hydrogen. In some embodiments, R ⁵ is absent, and represents a single or double bond, and if one represents a double bond, then the other represents a single bond.

In some embodiments, R ⁶ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁶ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁶ is hydrogen.

In some embodiments, R ⁷ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁷ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁷ is hydrogen.

In some embodiments, R ^11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , or R ^11a and R ^11b , together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ^11a and R ^11b, together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a and R ^11b are hydrogen.

In some embodiments, each of ^R2 , ^R4 , ^R6 , ^R7 , ^R11a , and ^R11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, ^-ORA1 , ^-SRA1 , or -N(R ^A1 ) ₂ . In some embodiments, each of ^R2 , ^R4 , R6, R7, ^{R11a ,} and ^R11b is independently hydrogen, halogen, alkyl, or -ORA1. In some embodiments ^{, R2} , ^R4 , ^R6 , ^R7 , ^{R11a ,} and ^R11b are hydrogen.

In some embodiments, each of R ^17a and R ^17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen. In some embodiments, each of R ^17a and R ^17b is independently hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen.

In some embodiments, R ^17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -S(=O )R ^A2 or -SO ₂ R ^A2 . In some embodiments, R ^17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -S(=O)R ^A2 or -SO ₂ R ^A2 . In some embodiments, R ^17a is halogen, cyano, nitro, alkyl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ .

In some embodiments, the connection is:

, , ,

, , ,

, ,

or a pharmaceutically acceptable salt of one of them.

In one aspect, the present application provides a compound of formula ( II ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; R ³ is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., -CH ₃ ) or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or is hydrogen; and

represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or -OR ^A1 .

In some embodiments, R ¹⁹ is hydrogen. In some embodiments, R ¹⁹ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ¹⁹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ¹⁹ is -C( ^RC ) ₂ OR ^A1 . In some embodiments, R ¹⁹ is -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH(CH ₃ ) ₂ .

In some embodiments, R ² is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ² is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ³ is methyl and ethyl (eg, substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R ⁴ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁴ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁴ is hydrogen.

In some embodiments, represents a single bond, and R ⁵ represents hydrogen. In some embodiments, R ⁵ is absent, and represents a single or double bond, and if one represents a double bond, then the other represents a single bond.

In some embodiments, R ⁶ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁶ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁶ is hydrogen.

In some embodiments, R ⁷ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁷ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁷ is hydrogen.

In some embodiments, R ^11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , or R ^11a and R ^11b , together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ^11a and R ^11b, together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a and R ^11b are hydrogen.

In some embodiments, each of ^R2 , ^R4 , ^R6 , ^R7 , ^R11a , and ^R11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, ^-ORA1 , ^-SRA1 , or -N(R ^A1 ) ₂ . In some embodiments, each of ^R2 , ^R4 , R6, R7, ^R11a , and ^R11b is hydrogen, halogen, alkyl ^, or -ORA1. In some embodiments ^, each of ^R2 , ^R4 , ^R6 , ^R7 , ^{R11a ,} and ^R11b is hydrogen.

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-a ) or ( II-b ):

or

In some embodiments, the compound of formula ( I ) is a compound of formula ( II-c ):

Where:

each of R ^21a and R ^21b independently represents hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 ; or R ^21a and R ^21b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; and n is an integer selected from 1, 2 and 3.

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-d ):

In one aspect, the present application provides a compound of formula ( III-a ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b, together with the carbon atom to which they are attached, form a carbocyclyl, heterocyclyl or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; R ¹⁹ is unsubstituted alkyl; R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In one aspect, the present application provides a compound of formula ( III-b ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; Q is halogen, cyano, nitro, C-linked heterocyclyl, aryl, C-linked heteroaryl, -O-alkenyl, -O-alkynyl, -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 ; R ¹⁹ is -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl; R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In one aspect, the present application provides a compound of formula ( 1-A ):

or a pharmaceutically acceptable salt thereof, wherein: R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; each of R ^X and R ^Y independently is hydrogen, aryl or alkyl, or

R ^X and R ^Y are joined together to form a 3- to 10-membered heterocyclic ring; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or hydrogen; represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent; and a represents 0 or 1; provided that R ^X and R ^Y join together to form a 3- to 8-membered heterocyclic ring only when a represents 0.

In some embodiments, R ^X and R ^Y are not both hydrogen. In some embodiments, R ³ is alkyl. In some embodiments, R ¹⁹ is hydrogen.

In some embodiments, the compound is a compound of formula ( 1-A-1 )

where each R ^Y4 is independently alkyl, cyano or halogen; and e is 0, 1, 2, 3, 4 or 5.

In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F. In some embodiments, e is 3. In some embodiments, R ^X is hydrogen. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 3. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 2. In some embodiments, e is 1. In some embodiments, R ^Y4 is -F. In some embodiments, R ^Y4 is -F, and e is 1.

In some embodiments, the compound is a compound of formula ( 1-A-2 )

In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F. In some embodiments, e is 3. In some embodiments, R ^X is hydrogen. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 3. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 2. In some embodiments, e is 1. In some embodiments, R ^Y4 is -F.

In some embodiments, the compound is a compound of formula ( 1-A-3 )

where each of R ^Y1 and R ^Y2 is independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and b = 0, 1, 2, 3.

In some embodiments, R ^Y1 and R ^Y2 are both not -CH(CH ₃ ) ₂ .

In some embodiments, the compound is a compound of formula ( 1-A-4 )

In some embodiments, R ^Y1 is hydrogen, -CH ₃ or -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or cycloalkyl. In some embodiments, R ³ is -CH ₃ , -CF ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ . In some embodiments, R ^Y2 is heterocyclyl, aryl, or heteroaryl. In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents of: -CH ₃ , -CN, -F, -CF ₃ , or a combination thereof, or heteroaryl substituted with 0-5 substituents of: -CH ₃ , -CN, -F, -CF ₃ .

In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ , or R ^X is hydrogen, -CH ₃ , or -CH ₂ CH ₃ . In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ .

In some embodiments, the compound is a compound of formula ( 1-A-5 )

wherein each R ^Y3 is aryl or heteroaryl, or two R ^Y3 groups are joined together to form a 6-10 membered ring; c is 0, 1, 2, and 3; and d is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula ( 1-A-6 )

In some embodiments, if d is 2, then two R ^Y3 groups are joined together to form an aryl. In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ . In some embodiments, the compound is a compound of formula ( 1-A-7 ) or formula (1-A-8 )

In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ , or R ³ is -CH ₃ , -CF ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ .

In one aspect, the present application provides a compound of formula ( 2-A ),

or a pharmaceutically acceptable salt thereof, wherein R ³ is -CH ₃ , -CF ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ ; R ¹⁹ is hydrogen, -CH ₃ or -CH ₂ OR ^A1 , wherein R ^A1 is optionally substituted alkyl; R ³ is -CH ₃ , -CF ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ ; R ^17a is -NR ^A2 R ^A3 , -N(R1)C(O)R ^A2 , -N(R1)SO ₂ R ^A2 , -OR ^A3 , cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of R ^A2 and R ^A3 independently is hydrogen, carbocyclyl, heterocyclyl, aryl, heteroaryl or -OR ^A4 , wherein R ^A4 is hydrogen or alkyl; or R ^17A is , where A is oxazolyl or thiazolyl; R ^17b is hydrogen, hydroxyl, alkyl or alkoxy; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent; provided that: when R ^17a represents oxazolyl or , then R ^17b is not hydrogen, or when R ^17a is heterocyclyl, then R ¹⁹ is hydrogen, or when R ^17a is -OR ^A4 , then R ¹⁹ is hydrogen.

In some embodiments, R ^17a is -NR ^A2 R ^A3 , -N(R1)C(O)R ^A2 , -N(R1)SO ₂ R ^A2 . In some embodiments, R ^17a is aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R ¹⁹ is hydrogen. In some embodiments, R ^17a is heteroaryl. In some embodiments, R ^17a is heteroaryl and R ¹⁹ is hydrogen. In some embodiments, R ^17a is pyridyl, and R ¹⁹ is hydrogen.

In one aspect, the present application provides a compound of formula ( 3-A )

or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ is hydrogen or alkyl; R ^17a is nitro or alkoxy (e.g., -OCH ₃ ); each of R ² , R ⁴ , R ^11a or R ^11b independently is hydrogen, alkyl or alkoxy, or R ^11a and R ^11b are joined together to form oxo; represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent; and R ⁵ is absent or is hydrogen according to valence; provided that when R ² , R ^11a and R ^11b are hydrogen, then R ⁴ is alkyl, or when R ⁴ , R ^11a and R ^11b are hydrogen, then R ² is alkyl, or when R ⁴ is hydrogen, then R ² is -OH or alkoxy, R ^11a is hydrogen, and R ^11b is -OH or alkoxy, or R ² is -OH or alkoxy, and R ^11a and R ^11b are joined together to form oxo.

In some embodiments, R ⁴ is hydrogen, R ² is -OH or alkoxy, R ^11a is hydrogen, and R ^11b is -OH or alkoxy. In some embodiments, R ⁴ is hydrogen, R ² is -OH or alkoxy, and R ^11a and R ^11b are joined together to form oxo. In some embodiments, R ^17a is nitro. In some embodiments, R ^17a is alkoxy. In some embodiments, R ^17a is methoxy, and R ² is methyl.

In one aspect, the present application provides a compound as described in Table 1 or a pharmaceutically acceptable salt thereof.

In one aspect, the present application provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )), and a pharmaceutically acceptable excipient.

In one aspect, the present application provides a method of inducing sedation and/or anesthesia in a subject comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )), or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a method of administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein (e.g., a compound of Formula ( I ), Formula ( II ), Formula ( III ), or Formula ( IV ), Formula ( 1-A ), Formula ( 2-A ), or Formula ( 3-A )), wherein the subject becomes sedated and/or anesthetized within two hours of administration. In some embodiments, the subject becomes sedated and/or anesthetized within one hour of administration. In some embodiments, the subject becomes sedated and/or anesthetized immediately. In some embodiments, the compound is administered continuously.

In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

In some embodiments, the compound is administered in combination with another therapeutic agent.

In one aspect, the present application provides a method of treating a seizure in a subject comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a method of treating epilepsy or an epileptic condition in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a method of treating a neuroendocrine disorder or dysfunction in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a method of treating a neurodegenerative disease or disorder in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a method of treating a movement disorder or tremor in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a method of treating a mood disorder or anxiety disorder in a subject, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a method of treating disorders associated with GABA function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )).

In one aspect, the present application provides a kit comprising a solid composition comprising a compound described herein (e.g., a compound of formula ( I ), formula ( II ), formula ( III ), or formula ( IV ), formula ( 1-A ), formula ( 2-A ), or formula ( 3-A )) and a sterile diluent.

Thus, in another aspect, there are provided methods of treating CNS-related disorders in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula ( I ), Formula ( II ), Formula ( III ), or Formula ( IV ), Formula ( 1-A ), Formula ( 2-A ), or Formula ( 3-A )). In certain embodiments, the CNS-related disorders are selected from the group consisting of a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory disorder and/or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disorder, a chemical dependency disorder and/or withdrawal syndrome, and tinnitus. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, such as by continuous intravenous infusion.

In some embodiments, the subject is a subject suffering from Rett syndrome, fragile X syndrome, or Angelman syndrome.

Definitions

Chemicals definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are defined according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , 75th edition, inside front cover, and specific functional groups are generally defined as described in the present application. In addition, general principles of organic chemistry as well as specific functional moieties and reactivity are described in Thomas Sorrell, Organic Chemistry , 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 , ^3rd Edition, Cambridge University Press, Cambridge, 1987.

The isomers may 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 the preferred isomers may be prepared by asymmetric synthesis. See, e.g., 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 encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of different isomers.

The absolute configuration of an asymmetric center can be determined by methods known to those skilled in the art. In some cases, it is possible to determine the absolute configuration of an asymmetric center in a compound from the X-ray single crystal structure of the compound. In some cases, information about the absolute configuration of an asymmetric center can be obtained from the X-ray crystal structure of the compound to determine the absolute configuration of the corresponding asymmetric center in another compound obtained from the same or similar synthetic methods. In some cases, the absolute configuration of an asymmetric center can be determined experimentally by the nuclear Overhauser effect (NOE) method using nuclear magnetic resonance (NMR) spectroscopy.

In some embodiments, an asymmetric center with a known absolute configuration can be introduced into a compound with a chiral reagent, such as a chiral amine. In some embodiments, an asymmetric center with a known absolute configuration can be introduced into the compound by a reaction, such as reductive amination.

As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., is in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains greater than 75 wt.%, greater than 80 wt.%, greater than 85 wt.%, greater than 90 wt.%, greater than 91 wt.%, greater than 92 wt.%, greater than 93 wt.%, greater than 94 wt.%, greater than 95 wt.%, greater than 96 wt.%, greater than 97 wt.%, greater than 98 wt.%, greater than 98.5 wt.%, greater than 99 wt.%, greater than 99.2 wt.%, greater than 99.5 wt.%, greater than 99.6 wt.%, greater than 99.7 wt.%, greater than 99.8 wt.%, or greater than 99.9 wt.% of the enantiomer. In some embodiments, the mass is determined based on the total mass of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R compound. In some embodiments, the enantiomerically pure R compound in such compositions may, for example, comprise at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S compound. In some embodiments, the enantiomerically pure S-compound in such compositions may, for example, comprise at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be in a dosage form with little or no excipient or carrier.

In this application, the singular may be used to denote one or more than one (i.e., at least one) grammatical object. As an example, "analog" means one analog or more than one analog.

When a range of values is specified, such range includes each 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 given below and are useful in understanding the description and intended scope of the present invention.

"Alkyl" refers to a radical of a saturated hydrocarbon group with a straight or branched chain having from 1 to 20 carbon atoms ("C _1-20 alkyl"). In some embodiments, the alkyl group has from 1 to 12 carbon atoms ("C _1-12 alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("C _1-8 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C _1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group has 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 (C ₄ ), iso-butyl (C ₄ ), n-pentyl (C ₅ ), 3-pentanyl (C ₅ ), amyl (C ₅ ), neopentyl (C ₅ ), 3-methyl-2-butanyl (C ₅ ), tertiary amyl (C ₅ ) and n-hexyl (C ₆ ). Further examples of alkyl groups include n-heptyl (C ₇ ), n-octyl (C ₈ ), etc. Unless otherwise specified, each alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, from 1 to 5 substituents, from 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C _1-10 alkyl (e.g., -CH ₃ ). In certain embodiments, the alkyl group is substituted C _1-10 alkyl. Common abbreviations for alkyl groups 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 ).

"Alkenyl" refers to a straight or branched chain hydrocarbon group radical having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C _2-20 alkenyl"). In some embodiments, an alkenyl group has from 2 to 10 carbon atoms ("C _2-10 alkenyl"). In some embodiments, an alkenyl group has from 2 to 8 carbon atoms ("C _2-8 alkenyl"). In some embodiments, an alkenyl group has from 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, an alkenyl group has from 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, an alkenyl group has from 2 to 4 carbon atoms ("C _2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C _2-3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ("C ₂ alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C _2-4 alkenyl groups include ethenyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and the like. Examples of _C2-6 alkenyl groups include the above-described _C2-4 alkenyl groups, as well as pentenyl ( _C5 ), pentadienyl ( _C5 ), hexenyl ( _C6 ), and the like. Further examples of alkenyl include heptenyl ( _C7 ), octenyl ( _C8 ), octatrienyl ( _C8 ), and the like. Unless otherwise specified, each alkenyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl"), with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is an unsubstituted _C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted _C2-10 alkenyl.

"Alkynyl" refers to a straight or branched chain hydrocarbon group radical having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C _2-20 alkynyl"). In some embodiments, an alkynyl group has from 2 to 10 carbon atoms ("C _2-10 alkynyl"). In some embodiments, an alkynyl group has from 2 to 8 carbon atoms ("C _2-8 alkynyl"). In some embodiments, an alkynyl group has from 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, an alkynyl group has from 2 to 5 carbon atoms ("C _2-5 alkynyl"). In some embodiments, an alkynyl group has from 2 to 4 carbon atoms ("C _2-4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C _2-3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C ₂ alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 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 ), and the like. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkynyl groups, as well as pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Additional examples of alkynyl include heptynyl ( _C7 ), octynyl ( _C8 ), and the like. Unless otherwise specified, each alkynyl group is independently optionally substituted, e.g., unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl"), with one or more substituents; e.g., 1-5 substituents, 1-3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is an unsubstituted _C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted _C2-10 alkynyl.

"Aryl" refers to a radical of a monocyclic or polycyclic (e.g. , bicyclic or tricyclic) 4n+2 aromatic ring system (e.g. , having 6, 10, or 14 π electrons shared within the cyclic matrix) having 6-14 ring carbon atoms and zero heteroatoms provided within the aromatic ring system (" _C6-14aryl "). In some embodiments, an aryl group has six ring carbon atoms (" _C6aryl "; e.g. , phenyl). In some embodiments, an aryl group has ten ring carbon atoms (" _C10aryl "; e.g. , naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (" _C14aryl "; e.g. , anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to denote the number of carbon atoms in the aryl ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each aryl group is independently optionally substituted, such as unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl"), with one or more substituents. In certain embodiments, the aryl group is unsubstituted C _6-14 aryl. In certain embodiments, the aryl group is substituted C _6-14 aryl.

In certain embodiments, the aryl group is substituted with one or more groups selected from halogen, _C1 - _C8 alkyl, C1 _{- C8} haloalkyl, cyano, hydroxy, _C1 - _C8 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- to 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, SO-alkyl, SO ₂ -alkyl, S-aryl, SO-aryl, SO ₂ -aryl; or R ⁵⁶ and R ⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated) containing from 5 to 8 atoms and optionally containing one or more heteroatoms selected from the group N, O or S. R ⁶⁰ and R ⁶¹ independently represent 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 heterocyclic group include the following:

wherein 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.

"Halo" or "halogen," independently or as part of another substituent, means, unless otherwise specified, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. The term "halide," alone or as part of another substituent, refers to a fluorine, chlorine, bromine, or iodine atom. In certain embodiments, the halogen group is either fluorine or chlorine.

"Haloalkyl" and "haloalkoxy" may include alkyl and alkoxy structures that are substituted with one or more halogen groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl groups and haloalkoxy groups, respectively, in which the halogen is fluorine.

"Hydroxy" or "hydroxyl", independently or as part of another substituent, means, unless otherwise specified, the group -OH.

"Hydroxyalkyl" may include alkyl structures that are substituted with one or more hydroxyl groups.

"Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g. , having 6 or 10p electrons shared within the cyclic matrix) having ring carbon atoms and 1-4 ring heteroatoms provided within the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, according to valence. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or more rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclic or heterocyclic groups in which the point of attachment is on the heteroaryl ring, and in such cases, the number of carbon atoms continues to denote the number of carbon atoms in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups in which the point of attachment is on either the aryl or heteroaryl ring, and in such cases, the number of ring members means 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 (e.g. , indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, e.g. , either on the ring bearing the heteroatom (e.g. , 2-indolyl) or on the ring that does not contain the heteroatom (e.g. , 5-indolyl).

In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having carbon ring atoms and 1-4 ring heteroatoms provided within the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having carbon ring atoms and 1-4 ring heteroatoms provided within the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having carbon ring atoms and 1-4 ring heteroatoms provided within the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, a 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each heteroaryl group is independently optionally substituted, such as unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl"), with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, thiazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Examples of 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 formulas:

,

wherein 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.

"Carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms ("C _3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group has from 3 to 8 ring carbon atoms ("C _3-8 carbocyclyl"). In some embodiments, the carbocyclic group has from 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, the carbocyclic group has from 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, the carbocyclic group has from 5 to 10 ring carbon atoms ("C _5-10 carbocyclyl"). Examples of _C3-6 carbocyclic groups include, without limitation, cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl (C6), cyclohexenyl ( _{C6 )} , cyclohexadienyl ( _C6 ), and the like. Examples of _C3-8 carbocyclic groups include, but are not limited to, the above-mentioned _C3-6 carbocyclic groups, as well as cycloheptyl ( _C7 ), cycloheptenyl ( _C7 ), cycloheptadienyl ( _C7 ), cycloheptatrienyl ( _C7 ), cyclooctyl ( _C8 ), cyclooctenyl ( _C8 ), bicyclo[2.2.1]heptanyl ( _C7 ), bicyclo[2.2.2]octanyl ( _C8 ), and the like. Examples of _C3-10 carbocyclic groups include, but are not limited to, the above-described _C3-8 carbocyclic groups, as well as cyclononyl ( _C9 ), cyclononenyl ( _C9 ), cyclodecyl ( _C10 ), cyclodecenyl ( _C10 ), octahydro- 1H- indenyl ( _C9 ), decahydronaphthalenyl ( _C10 ), spiro[4.5]decanyl ( _C10 ), and the like. As shown in the above examples, in certain embodiments, the carbocyclic group is either a monocyclic system ("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 in which a carbocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups in which the point of attachment is on the carbocyclic ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the carbocyclic ring system. Unless otherwise specified, each carbocyclic group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl"), with one or more substituents. In certain embodiments, the carbocyclic group is an unsubstituted C _3-10 carbocyclyl. In certain embodiments, the carbocyclic group is a substituted C _3-10 carbocyclyl.

In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclic group having 3 to 10 ring carbon atoms ("C _3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C _3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C _5-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 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 _C3-6 cycloalkyl groups include the aforementioned _C5-6 cycloalkyl groups, as well as cyclopropyl ( _C3 ) and cyclobutyl ( _C4 ). Examples of _C3-8 cycloalkyl groups include the aforementioned _C3-6 cycloalkyl groups, as well as cycloheptyl ( _C7 ) and cyclooctyl ( _C8 ). Unless otherwise specified, each cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is unsubstituted _C3-10 cycloalkyl. In certain embodiments, a cycloalkyl group is substituted _C3-10 cycloalkyl.

"Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In heterocyclic groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, according to valence. The heterocyclic 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. Heterocyclic bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein a heterocyclic ring, as defined above, is fused to one or more carbocyclic groups, the point of attachment being on either the carbocyclic or heterocyclic ring, or a ring system wherein a heterocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, the point of attachment being on the heterocyclic ring, in which cases, the number of ring members continues to denote the number of ring members in the heterocyclic ring system. Unless otherwise specified, each heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl"), with one or more substituents. In certain embodiments, the heterocyclic group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

In some embodiments, the heterocyclic group is a 5- to 10-membered non-aromatic ring system having carbon ring atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclic group is a 5- to 8-membered non-aromatic ring system having carbon ring atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclic group is a 5- to 6-membered non-aromatic ring system having carbon ring atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

Examples of 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Examples of 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclic 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 heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Examples of 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperadinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Examples of 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxaline. Examples of 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Examples of 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of 5-membered heterocyclic groups fused to a _C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, zoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Examples of 6-membered heterocyclic 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, etc.

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

wherein 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 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. These heterocyclic rings may optionally be substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl ( e.g. 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 provides, for example, lactam and urea derivatives.

"Acyl" refers to the radical -C(O) ^R20 , where ^R20 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 described herein. "Alkanoyl" is an acyl group where ^R20 is a group that is not hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O) _CH3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O) _CH2Ph ), -C(O) _{-C1 -C8} alkyl, -C(O)-( _CH2 ) _t ( _{C6 -C10} aryl), -C(O)-( _CH2 ) _t (5-10 membered heteroaryl), -C(O)-( _CH2 ) _t ( _C3 - _C10 cycloalkyl), and -C(O)-( _CH2 ) _t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, ^R21 is _C1 - _C8 alkyl substituted with halogen or hydroxy; or _C3 - _C10 cycloalkyl, 4-10 membered heterocyclyl, _C6 - _C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _C1 - _C4 haloalkyl, unsubstituted _C1 - _C4 hydroxyalkyl or unsubstituted _C1 - _C4 haloalkoxy, or hydroxy.

"Acylamino" refers to the radical -NR ²² C(O)R ²³ , wherein each R ²² and each 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. Examples of "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethylcarbonylamino, benzoylamino, and benzylcarbonylamino. Specific examples of "acylamino" groups are ^-NR24C (O) _-C1 - _C8 alkyl, ^-NR24C (O)-( _CH2 ) _t ( _C6 - _C10 aryl), ^-NR24C (O)-( _CH2 ) _t (5-10 membered heteroaryl), ^-NR24C (O)-( _CH2 ) _t ( _C3 - _C10 cycloalkyl), and ^-NR24C (O)-( _CH2 ) _t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and each ^R24 is independently hydrogen or _C1 - _C8 alkyl. In certain embodiments, ^R25 is H, _C1 - _C8 alkyl substituted with halogen or hydroxy; _C3 - _C10 cycloalkyl, 4-10 membered heterocyclyl, _C6 - _C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _C1 - _C4 haloalkyl, unsubstituted _C1 - _C4 hydroxyalkyl or unsubstituted _C1 - _C4 haloalkoxy or hydroxy; and ^R26 is H, _C1 - _C8 alkyl substituted with halogen or hydroxy; _C3 - _C10 cycloalkyl, 4-10 membered heterocyclyl, _C6 - _C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _C1 - _C4 haloalkyl, unsubstituted _C1 - _C4 hydroxyalkyl or unsubstituted _C1 - _C4 haloalkoxy or hydroxy; provided that at least one of ^R25 and ^R26 is not H.

"Acyloxy" refers to the radical -OC(O) ^R27 , wherein ^R27 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. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In certain embodiments, ^R28 is _C1 - _C8 alkyl substituted with halogen or hydroxy; C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, arylalkyl, 5-10 membered 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, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having from 1 to 6 carbon atoms. Additional alkoxy groups have from 1 to 4 carbon atoms.

In certain embodiments, R ²⁹ is a group that has 1 or more substituents, such as 1 to 5 substituents, and in particular 1 to 3 substituents, in particular 1 substituent selected from the group consisting of amino, substituted amino, C ₆ -C ₁₀ aryl, aryloxy, carboxyl, cyano, C ₃ -C ₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, 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, without limitation, -O-( _CH2 ) _t ( _C6 - _C10 aryl), -O-( _CH2 ) _t (5-10 membered heteroaryl), -O-( _CH2 ) _t ( _C3 - _C10 cycloalkyl), and -O-( _CH2 ) _t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present may themselves be substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _C1 - _C4 haloalkyl, unsubstituted _C1 - _C4 hydroxyalkyl, or unsubstituted _C1 - _C4 haloalkoxy or hydroxy. Specific examples of "substituted alkoxy" groups are _-OCF3 , _-OCH2CF3 , _{-OCH2Ph , -OCH2 - cyclopropyl} , _{-OCH2CH2OH ,} and _-OCH2CH2NMe2 .

"Amino" refers to the radical -NH ₂ .

"Oxo" refers to =O.

"Substituted amino" refers to an amino group of the formula -N( ^R38 ) ₂ , wherein ^R38 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 ^R38 is not hydrogen. In certain embodiments, each ^R38 is independently selected from hydrogen, _C1 - _C8 alkyl, _C3 - _C8 alkenyl, _C3 - _C8 alkynyl, _C6 - _C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or _C3 - _C10 cycloalkyl; or C ₁ -C ₈ alkyl substituted with halogen or hydroxy; C ₃ -C ₈ alkenyl substituted with halogen or hydroxy; _C3 - _C8 alkynyl substituted with halogen or hydroxy, or -( _CH2 ) _t ( _C6 - _C10 aryl), -( _CH2 ) _t (5-10 membered heteroaryl), -( _CH2 ) _t ( _C3 - _C10 cycloalkyl) or -( _CH2 ) _t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _{C1-C4 haloalkyl} , unsubstituted _C1 - _C4 hydroxyalkyl or unsubstituted _C1 - _C4 haloalkoxy or hydroxy; or both ^R38 groups are joined to form an alkylene group.

Examples of "substituted amino" groups include, without limitation, -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 membered heterocyclyl), wherein t is an integer from 0 to 4, such as 1 or 2, each R ³⁹ independently represents hydrogen or C ₁ -C ₈ alkyl; and any alkyl group present may itself be substituted with halogen, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocyclic groups present may themselves be substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _C1 - _C4 haloalkyl, unsubstituted _C1 - _C4 hydroxyalkyl or unsubstituted _C1 - _C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups, as described 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 a -C(O)N( ^R62 ) ₂ radical, wherein each ^R62 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, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one of ^R62 is not hydrogen. In certain embodiments, ^R62 is selected from H, _C1 - _C8 alkyl, _C3 - _C10 cycloalkyl, 4-10 membered heterocyclyl, _C6 - _C10 aryl, and 5-10 membered heteroaryl; or _C1 - _C8 alkyl substituted with halogen or hydroxy; or _C3 - _C10 cycloalkyl, 4-10 membered heterocyclyl, _C6 - _C10 aryl or 5-10 membered heteroaryl, each of which is substituted with unsubstituted _C1 - _C4 alkyl, halogen, unsubstituted _C1 - _C4 alkoxy, unsubstituted _C1 - _C4 haloalkyl, unsubstituted _C1 - _C4 hydroxyalkyl or unsubstituted _C1 - _C4 haloalkoxy or hydroxy; provided that at least one ^R62 is not H.

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

"Cyano" refers to the radical -CN.

"Nitro" refers to the radical -NO ₂ .

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

"Nitrogen-containing heterocyclic" group means a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 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.

The alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups described herein are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclic, a "substituted" or "unsubstituted" heterocyclic, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, e.g., a substituent that, when substituted, results in the formation of a stable compound, e.g., a compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more replaceable positions in the group, and if more than one position is substituted in any given structure, the substituent at each position is the same or different. The term "substituted" includes substitution with all permissible substituents on organic compounds, any of the substituents described herein, that result in the formation of a stable compound. The present invention includes any and all such combinations that result in a stable compound. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent described herein that match the valences 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, _-NO2 , _-N3 , -SO2H _, -SO3H, -OH, ^-ORaa , -ON( ^Rbb ) ₂ , -N( ^Rbb ) ₂ , -N( ^Rbb ) ₃ ⁺ _X- , -N( ^ORcc ) ^Rbb , -SH, ^-SRaa , ^-SSRcc , -C(=O) ^Raa , _-CO2H , -CHO, -C ^{( ORcc )} ₂ , _-CO2Raa , ^-OC (=O) ^Raa , -OCO2Raa, -C(= _O )N( ^Rbb ) ₂ , -OC(=O)N( ^Rbb ) ₂ , ^{-NRbbC (} ₌ ^O ) ^Raa , -NRbbCO2Raa , -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, C _3-10 carbocyclyl, 3-14-membered heterocyclyl, C _6-14 aryl and 5-14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted 0, 1, 2, 3, 4 or 5 groups R ^dd ;

each 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 joined to form a 3-14-membered heterocyclic 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 R ^dd groups;

each 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 are joined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl independently substituted by 0, 1, 2, 3, 4 or 5 R ^dd groups;

each R ^cc 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 5-14-membered heteroaryl, or two R ^cc groups are joined to form a 3-14-membered heterocyclic 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 R ^dd groups;

each 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, wherein each alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

each 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 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 5-10 membered heteroaryl, or two R ^ff groups are joined to form a 3-14 membered heterocyclic 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 R ^gg groups; and

each R ^gg independently represents a 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; where X is the counterion.

A "counterion" or "anionic counterion" is a negatively charged group bonded to a cationic quaternary amino group while maintaining electron neutrality. Examples of counterions include halide ions (e.g. , F- ^{, Cl-} , Br- ^{, I-} ), NO3- _, ^ClO4- , _OH- , ^{H2PO4- ,} HSO4-), sulfonate ions ₍ e.g. , methanesulfonate, trifluoromethanesulfonate ^, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene- ₁ -sulfonic acid _- 5-sulfonate, ethane-1-sulfonic ^acid -2-sulfonate, etc.), and carboxylate ions (e.g. , acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

Nitrogen atoms can be substituted or unsubstituted according to valence and include primary, secondary, tertiary and quaternary nitrogen atoms. Examples of nitrogen atom 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) _2N ( ^Rcc ) ₂ , -P(=O)( ^NRcc ) 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 membered heteroaryl, or two ^Rcc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclic 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 ^Rdd groups, and wherein ^Raa , ^Rbb , ^Rcc and ^Rdd are defined higher.

In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amine protecting groups include, but are not limited to, -OH, -OR ^aa , -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)OR ^aa , -C(=O)N(R ^cc ) ₂ , -S(=O) ₂ R ^aa , -C(=NR ^cc )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 , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclic group, _C6-14 aryl and 5-14 membered heteroaryl group, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 ^Rdd groups, and wherein ^Raa , ^Rbb , ^Rcc and ^Rdd are as defined above. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

Examples of amino protecting groups include, but are not limited to, amide groups ( e.g. , -C(=O) ^Raa ), which include, but are not limited to, formamide and acetamide; carbamate groups (e.g. , -C(=O) ^ORaa ), which include, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc), t ^- butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g. , -S(=O) _2Raa ), which include, but are not limited to, p- toluenesulfonamide (Ts), methanesulfonamide (Ms), and N- [2-(trimethylsilyl)ethoxy]methylamine (SEM).

In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O)R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) _3, -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ and -P(=O)(NR ^bb ) ₂ , where R ^aa , R ^bb and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

Examples of oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), tri-isopropylsilyl (TIPS), t -butyldimethylsilyl (TBDMS), t -butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R ^aa , -N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O)R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) _3, -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ and -P(=O)( ^NRbb ) ₂ , where ^Raa , ^Rbb and ^Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

These and other examples of substituents are described in more detail in the detailed description, examples, and claims. The above lists of examples of substituents are not intended to limit the invention in any way.

Other definitions

As used herein, the term "modulation" refers to the suppression or enhancement of GABA receptor function. A "modulator" (e.g. , a modulator compound) can be, for example, a GABA receptor agonist, partial agonist, antagonist, or partial antagonist.

"Pharmaceutically acceptable" means approved or deserving of approval by a federal or state regulatory agency or the like in countries other than the United States of America, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and particularly in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that exhibits the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be adducts of inorganic or organic acids and adducts of a base. In particular, such salts include: (1) acid adducts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed by organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed either by replacing an acidic proton present in the parent compound with a metal ion, for example , an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or by forming coordinate bonds with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. The salts further include, for example, sodium, potassium, calcium, magnesium, ammonium, tetra-alkylammonium, etc.; and, if the compound contains basic functional groups, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of the acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetra-alkylammonium, etc. See, e.g. , Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

"Solvate" refers to forms of a compound that are associated with a solvent or water (called a "hydrate"), typically by a solvolysis reaction. This physical association involves the binding of hydrogen. Common solvents include water, ethanol, acetic acid, and the like. The compounds of the invention can be obtained, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, a solvate can be isolated, such as by incorporation of one or more solvent molecules into the crystal lattice of a crystalline solid. "Solvate" includes both solution phase and insoluble solvates. Exemplary solvates include hydrates, ethanolates, and methanolates.

"Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms, or in the arrangement of their atoms in space, are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are not mirror images superimposed on each other are called "enantiomers." When a compound has an asymmetric center, such as being bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). A chiral compound can exist as either an individual enantiomer or as a mixture of both. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

"Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and that differ by the shift of hydrogen atoms and electrons. Thus, two structures can be in equilibrium by the shift of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with either acid or base. Another example of tautomers are the ac- and nitro- forms of phenylnitromethane, which are formed similarly upon treatment with acid or base. Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of the compound of interest.

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

Disease, disorder and condition are used interchangeably in this application.

As used in this application, and unless otherwise specified, the terms "treat," "treating," and "treatment" include an action performed when a subject is suffering from a specified disease, disorder, or condition that reduces the severity of the disease, disorder, or condition or delays the development or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and also include an action performed before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to initiate a desired biological effect, such as to treat a CNS-related disorder, to induce anesthesia or sedation. As will be appreciated by those skilled in the art, an effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disorder being treated, the route of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses 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 benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, used alone or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of a disease, disorder, or compound. The term "therapeutically effective amount" may include an amount that improves the overall therapeutic condition, reduces or avoids the manifestation of symptoms or factors of the 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 an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with that disease, disorder, or condition, or to prevent a recurrence. 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 benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves the overall prophylactic condition or enhances the prophylactic effectiveness of another prophylactic agent.

DETAILED DESCRIPTION CERTAIN OPTIONS IMPLEMENTATIONS INVENTIONS

Provided herein are compounds (e.g., a compound of formula ( I )), pharmaceutical compositions, and methods of using them for treating a disease or disorder as disclosed herein.

Connections

The compounds described herein are generally intended to modulate GABA function and therefore act as neuroactive steroids for the treatment and prevention of CNS conditions in a subject. Modulation, as used herein, refers to the suppression or enhancement of GABA receptor function. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutic agents for the prevention and/or treatment of CNS conditions in mammals, including humans and non-human mammals. Thus, as noted above, the present invention includes and encompasses such methods of treatment, as well as compounds used in such methods, and the use of such compounds for the preparation of medicaments useful in such methods.

In one aspect, the present application provides a compound of formula ( I ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 ,- S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group upon attachment to an oxygen atom, a sulfur protecting group upon attachment to a sulfur atom, a nitrogen protecting group upon attachment to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form carbocyclyl, heterocyclyl or -C(=O)-; R ³ is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; each of R ^17a and R ^17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 , or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent.

In some embodiments, R ¹⁹ is hydrogen or alkyl. In some embodiments, R ¹⁹ is unsubstituted alkyl. In some embodiments, R ¹⁹ is substituted alkyl. In some embodiments, R ¹⁹ is -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH(CH ₃ ) ₂ .

In some embodiments, R ² is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ² is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ³ is alkyl (eg, substituted or unsubstituted alkyl), alkenyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ³ is methyl and ethyl (eg, substituted or unsubstituted alkyl).

In some embodiments, R ⁴ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁴ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁴ is hydrogen.

In some embodiments, represents a single bond, and R ⁵ represents hydrogen. In some embodiments, R ⁵ is absent, and represents a single or double bond, and if one represents a double bond, then the other represents a single bond.

In some embodiments, R ⁶ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁶ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁶ is hydrogen.

In some embodiments, R ⁷ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁷ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁷ is hydrogen.

In some embodiments, R ^11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , or R ^11a and R ^11b , together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ^11a and R ^11b, together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a and R ^11b are hydrogen.

In some embodiments, each of ^R2 , ^R4 , ^R6 , ^R7 , ^R11a , and ^R11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, ^-ORA1 , ^-SRA1 , or -N(R ^A1 ) ₂ . In some embodiments, each of ^R2 , ^R4 , R6, R7, ^{R11a ,} and ^R11b is independently hydrogen, halogen, alkyl, or -ORA1. In some embodiments ^{, R2} , ^R4 , ^R6 , ^R7 , ^{R11a ,} and ^R11b are hydrogen.

In some embodiments, each of R ^17a and R ^17b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen. In some embodiments, each of R ^17a and R ^17b is independently hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -SR ^A1 , -N(R ^A1 ) ₂ ,- NHC(=O)R ^A1 -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein at least one of R ^17a and R ^17b is not hydrogen.

In some embodiments, R ^17a is halogen, cyano, nitro, alkyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -S(=O )R ^A2 or -SO ₂ R ^A2 . In some embodiments, R ^17a is halogen, nitro, alkyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -S(=O)R ^A2 or -SO ₂ R ^A2 . In some embodiments, R ^17a is halogen, cyano, nitro, alkyl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ .

In some embodiments, the connection is:

, , ,

, , ,

, ,

or a pharmaceutically acceptable salt of one of them.

In one aspect, the present application provides a compound of formula ( II ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; R ³ is hydrogen, alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; A is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl (e.g., -CH ₃ ) or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or is hydrogen; and

represents a single or double bond, and if one represents a double bond, then the other is a single bond and R ⁵ is absent.

In some embodiments, A is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, or -OR ^A1 .

In some embodiments, R ¹⁹ is hydrogen. In some embodiments, R ¹⁹ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ¹⁹ is -CH ₃ or -CH ₂ CH ₃ . In some embodiments, R ¹⁹ is -C( ^RC ) ₂ OR ^A1 . In some embodiments, R ¹⁹ is -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , or -CH ₂ OCH(CH ₃ ) ₂ .

In some embodiments, R ² is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ² is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ² is hydrogen.

In some embodiments, R ³ is alkyl (eg, substituted or unsubstituted alkyl). In some embodiments, R ³ is methyl and ethyl (eg, substituted or unsubstituted methyl, substituted or unsubstituted ethyl).

In some embodiments, R ⁴ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁴ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁴ is hydrogen.

In some embodiments, represents a single bond, and R ⁵ represents hydrogen. In some embodiments, R ⁵ is absent, and represents a single or double bond, and if one represents a double bond, then the other represents a single bond.

In some embodiments, R ⁶ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁶ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁶ is hydrogen.

In some embodiments, R ⁷ is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , or -N(R ^A1 ) ₂ . In some embodiments, R ⁷ is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ⁷ is hydrogen.

In some embodiments, R ^11a is hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , or R ^11a and R ^11b , together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a is hydrogen, halogen, alkyl, or -OR ^A1 . In some embodiments, R ^11a and R ^11b, together with the carbon atom to which they are attached, form -C(=O)-. In some embodiments, R ^11a and R ^11b are hydrogen.

In some embodiments, each of ^R2 , ^R4 , ^R6 , ^R7 , ^R11a , and ^R11b is independently hydrogen, halogen, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, ^-ORA1 , ^-SRA1 , or -N(R ^A1 ) ₂ . In some embodiments, each of ^R2 , ^R4 , R6, R7, ^R11a , and ^R11b is hydrogen, halogen, alkyl ^, or -ORA1. In some embodiments ^, each of ^R2 , ^R4 , ^R6 , ^R7 , ^{R11a ,} and ^R11b is hydrogen.

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-a ) or ( II-b ):

or

In some embodiments, the compound of formula ( I ) is a compound of formula ( II-c ):

Where:

each of R ^21a and R ^21b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 , or -S(=O) ₂ OR ^A1 ; or R ^21a and R ^21b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl, or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; and n is an integer selected from 1, 2 and 3.

In some embodiments, the compound of formula ( II ) is a compound of formula ( II-d ):

In one aspect, the present application provides a compound of formula ( III-a ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b, together with the carbon atom to which they are attached, form a carbocyclyl, heterocyclyl or -C(=O)- group; Q is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, -OR ^A1 , -SR ^A1 or -N(R ^A1 ) ₂ ; R ¹⁹ is unsubstituted alkyl; R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other is a single bond and R ⁵ is absent.

In one aspect, the present application provides a compound of formula ( III-b ):

or a pharmaceutically acceptable salt thereof, wherein: each of R ² , R ⁴ , R ⁶ , R ⁷ , R ^11a and R ^11b is independently hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, -OR ^A1 , -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 , wherein each R ^A1 is independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R ^A1 groups are joined to form a heterocyclic or heteroaryl ring; and R ^A2 is alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R ^11a and R ^11b together with the carbon atom to which they are attached form a carbocyclyl, heterocyclyl or -C(=O)- group; R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; Q is halogen, cyano, nitro, C-linked heterocyclyl, aryl, C-linked heteroaryl, -O-alkenyl, -O-alkynyl, -SR ^A1 , -N(R ^A1 ) ₂ , -NHC(=O)R ^A1 , -NHC(=O)OR ^A1 , -S(=O)R ^A2 , -SO ₂ R ^A2 or -S(=O) ₂ OR ^A1 ; R ¹⁹ is -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl; R ⁵ is absent or hydrogen; and represents a single or double bond, and if one represents a double bond, then the other is a single bond and R ⁵ is absent.

In one aspect, the present application provides a compound of formula ( 1-A ):

or a pharmaceutically acceptable salt thereof, wherein: R ³ is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; each of R ^X and R ^Y independently is hydrogen, aryl or alkyl, or

R ^X and R ^Y are joined together to form a 3- to 10-membered heterocyclic ring; R ¹⁹ is hydrogen or alkyl (e.g., unsubstituted alkyl or substituted alkyl (e.g., -C(R ^C ) ₂ OR ^A1 , where R ^C is hydrogen or alkyl)); R ⁵ is absent or hydrogen; represents a single or double bond, and if one represents a double bond, then the other is a single bond and R ⁵ is absent; and a is 0 or 1; provided that R ^X and R ^Y are joined together to form a 3- to 8-membered heterocyclic ring only when a is 0.

In some embodiments, R ^X and R ^Y are not both hydrogen. In some embodiments, R ³ is alkyl. In some embodiments, R ¹⁹ is hydrogen.

In some embodiments, the compound is a compound of formula ( 1-A-1 )

where each R ^Y4 is independently alkyl, cyano or halogen; and e is 0, 1, 2, 3, 4 or 5.

In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F. In some embodiments, e is 3. In some embodiments, R ^X is hydrogen. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 3. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 2. In some embodiments, e is 1. In some embodiments, R ^Y4 is -F. In some embodiments, R ^Y4 is -F, and e is 1.

In some embodiments, the compound is a compound of formula ( 1-A-2 )

In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F. In some embodiments, e is 3. In some embodiments, R ^X is hydrogen. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 3. In some embodiments, each R ^Y4 is independently hydrogen, -CH ₃ , -CN, or -F, R ^X is hydrogen, and e is 2. In some embodiments, e is 1. In some embodiments, R ^Y4 is -F.

In some embodiments, the compound is a compound of formula ( 1-A-3 )

where each of R ^Y1 and R ^Y2 is independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and b = 0, 1, 2, 3.

In some embodiments, R ^Y1 and R ^Y2 are both not -CH(CH ₃ ) ₂ .

In some embodiments, the compound is a compound of formula ( 1-A-4 )

In some embodiments, R ^Y1 is hydrogen, -CH ₃ or -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or cycloalkyl. In some embodiments, R ³ is -CH ₃ , -CF ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ . In some embodiments, R ^Y2 is heterocyclyl, aryl or heteroaryl. In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents of: -CH ₃ , -CN, -F, -CF ₃ or a combination thereof, or heteroaryl substituted with 0-5 substituents of: -CH ₃ , -CN, -F, -CF ₃ .

In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ , or R ^X is hydrogen, -CH ₃ , or -CH ₂ CH ₃ . In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ .

In some embodiments, the compound is a compound of formula ( 1-A-5 )

where each R ^Y3 is aryl or heteroaryl, or two R ^Y3 groups are joined together to form a 6-10 membered ring;

c is 0, 1, 2, or 3; and

d is 0, 1, 2, or 3.

In some embodiments, the compound is a compound of formula ( 1-A-6 )

In some embodiments, if d is 2, then two R ^Y3 groups are joined together to form an aryl. In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ . In some embodiments, the compound is a compound of formula ( 1-A-7 ) or formula (1-A-8 )

In some embodiments, R ^Y2 is aryl substituted with 0-5 substituents from: -CH ₃ , -CN, -F, -CF ₃ , or R ³ is -CH ₃ , -CF ₃ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ .

In one aspect, the present application provides a compound of formula ( 2-A )

or a pharmaceutically acceptable salt thereof, _wherein ^R3 is _-CH3 , _-CF3 , _{-CH2OCH3 , -CH2OCH2CH3} ; ^R19 is hydrogen, _-CH3 , or _-CH2ORA1 ^, wherein ^RA1 is optionally substituted alkyl; ^R3 is _-CH3 , _-CF3 , _-CH2OCH3 , _-CH2OCH2CH3 ; ^R17a is ^-NRA2RA3 , -N( _R1 ⁾ C(O) ^RA2 , -N(R1) ^SO2RA2 , _{-ORA3 , cycloalkyl} , heterocyclyl, aryl, or _heteroaryl , wherein each of _RA2 and ^RA3 is independently hydrogen, ^carbocyclyl , heterocyclyl, aryl, heteroaryl, or ^-ORA4 , ^{wherein RA4} is hydrogen or alkyl; or R ^17A is , wherein A is oxazolyl or thiazolyl; R ^17b is hydrogen, hydroxyl, alkyl or alkoxy; and represents a single or double bond, and if one represents a double bond, then the other represents a single bond and R ⁵ is absent; provided that: when R ^17a represents oxazolyl or , then R ^17b is not hydrogen, or when R ^17a is heterocyclyl, then R ¹⁹ is hydrogen, or when R ^17a is -OR ^A4 , then R ¹⁹ is hydrogen.

In some embodiments, R ^17a is -NR ^A2 R ^A3 , -N(R1)C(O)R ^A2 , -N(R1)SO ₂ R ^A2 . In some embodiments, R ^17a is aryl, heteroaryl, cycloalkyl, or heterocyclyl. In some embodiments, R ¹⁹ is hydrogen. In some embodiments, R ^17a is heteroaryl. In some embodiments, R ^17a is heteroaryl and R ¹⁹ is hydrogen. In some embodiments, R ^17a is pyridyl, and R ¹⁹ is hydrogen.

In one aspect, the present application provides a compound of formula ( 3-A )

or a pharmaceutically acceptable salt thereof, wherein R ¹⁹ is hydrogen or alkyl; R ^17a is nitro or alkoxy (e.g., -OCH ₃ ); each of R ² , R ⁴ , R ^11a or R ^11b independently is hydrogen, alkyl or alkoxy, or R ^11a and R ^11b are joined together to form oxo; represents a single or double bond, and if one represents a double bond, then the other represents a single bond, and R ⁵ is absent; and R ⁵ is absent or represents hydrogen according to valence; provided that when R ² , R ^11a and R ^11b are hydrogen, then R ⁴ is alkyl, or when R ⁴ , R ^11a and R ^11b are hydrogen, then R ² is alkyl, or when R ⁴ is hydrogen, then R ² is -OH or alkoxy, R ^11a is hydrogen, and R ^11b is -OH or alkoxy, or R ² is -OH or alkoxy, and R ^11a and R ^11b are joined together to form oxo.

In some embodiments, R ⁴ is hydrogen, R ² is -OH or alkoxy, R ^11a is hydrogen, and R ^11b is -OH or alkoxy. In some embodiments, R ⁴ is hydrogen, R ² is -OH or alkoxy, and R ^11a and R ^11b are joined together to form oxo. In some embodiments, R ^17a is nitro. In some embodiments, R ^17a is alkoxy. In some embodiments, R ^17a is methoxy, and R ² is methyl.

The present application also provides the compounds listed in Table 1 below, or pharmaceutically acceptable salts thereof.

Table 1. Examples of compounds according to the invention

Structure Connection number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 48 49 50 55 56 57 58 60 61 63 64 65 66 69 70 73 74 75 76 77 78 79 80 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 118 119 120 121 122 123 125 125 126

Alternative options implementation

In an alternative embodiment, the compounds described herein may also contain one or more isotopic substitutions that are not a substitution of ¹ H with deuterium. For example, hydrogen may also be ³ H (T or tritium); carbon may be, for example, ¹³ C or ¹⁴ C; oxygen may be, for example, ¹⁸ O; nitrogen may be, for example, ¹⁵ N, etc. In other embodiments, a particular isotope (e.g., ³ H, ¹³ C, ¹⁴ C, ¹⁸ O, or ¹⁵ N) can comprise at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic content of the element present in a particular region of the compound.

Pharmaceuticals compositions

In one aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal.

In general, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by the physician taking into account the relevant circumstances, including the condition being treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

When used to prevent a CNS disorder, the compounds provided herein are administered to a subject at risk of developing such a condition, typically under the advice and supervision of a physician at the dosage levels described above. Subjects at risk of developing a particular condition typically include subjects with a family history of the condition or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition.

The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, such as over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration that may continue indefinitely, such as for the remainder of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, such as within a therapeutic window, over an extended period of time.

The pharmaceutical compositions of the present invention can also be delivered by various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be administered as a bolus, for example, to increase the concentration of the compound in the blood to an effective level. The site of administration of the bolus dose depends on the systemic levels of the active ingredient required throughout the body, for example, an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, while a bolus delivered directly into the veins (for example, by intravenous drip) provides a much faster delivery that quickly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, such as an IV drip, to maintain a constant concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, the pharmaceutical composition can be administered first as a bolus dose and then as a continuous infusion.

Compositions for oral administration may be in the form of bulk liquid solutions or suspensions or bulk powders. However, the compositions are most often presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-dosed ampoules or syringes of liquid compositions or, in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is usually the component present in minor amounts (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), the balance consisting of various carrier media or excipients and processing aids useful in forming the desired dosage form.

When administered orally, a typical administration regimen is one to five, and especially two to four, and typically three oral doses per day. In these dosing regimens, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, preferably each dose provides 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 doses administered by injection, typically in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

Dose levels administered by injection range from about 0.1 mg/kg/hour to about 20 mg/kg/hour, and are administered for about 1 to about 120 hours, and in particular, 24 to 96 hours. To achieve adequate steady state levels, a bolus preload of about 0.1 mg/kg to about 10 mg/kg or more may also be administered. The maximum total dose should not exceed about 5 g/day for a patient weighing 40 to 80 kg.

Liquid forms suitable for oral administration may comprise a suitable aqueous or non-aqueous vehicle, as well as a buffer, suspending and dispensing agents, colorants, flavorings, and the like. Solid forms may comprise, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; a filler such as starch or lactose; a disintegrating agent 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 such as peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are usually based on injectable sterile saline or phosphate buffered saline or other injectable vehicles known in the art. As indicated above, the active compound in such compositions is usually the component present in small amounts, often amounting to about 0.05 to 10% by weight, with the balance being the injectable vehicle and the like.

Transdermal compositions are typically in the form of an ointment or cream for topical application containing the active ingredient(s). When formulated as an ointment, the active ingredients are typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredients may be formulated as a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include additional ingredients to improve stable penetration of the active ingredients or formulations through the skin. All such known transdermal formulations and ingredients are included within the scope of the present application.

The compounds disclosed in this application can also be administered using a transdermal device. Accordingly, transdermal administration can be accomplished using a patch of either a reservoir type, a porous membrane, or a solid matrix type.

The above components for orally administered, injectable or topically administered compositions are provided by way of example only. Other materials, as well as processing methods, etc., are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, incorporated herein by reference.

The compounds of the present invention may also be administered in sustained release forms or by means of sustained release drug delivery systems. A description of typical sustained release materials can be found in Remington's Pharmaceutical Sciences.

The present invention also relates to a pharmaceutically acceptable acid adduct formed by the compound of the present invention. An acid that can be used to prepare a pharmaceutically acceptable salt is an acid that forms a non-toxic acid adduct, i.e. 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, etc.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, for example a composition suitable for injection, for example for intravenous (IV) administration.

Pharmaceutically acceptable excipients include any diluents or other liquid carrier media, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like suitable for the particular dosage form required, e.g., for injection. General rules for the formulation and/or preparation of pharmaceutical compositions and agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy , ^21st Edition (Lippincott Williams & Wilkins, 2005).

For example, injectable preparations such as sterile injectable aqueous suspensions can be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. Typical excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether of β-cyclodextrin, such as sulfobutyl ether of β-cyclodextrin, also known as Captisol®. See, for example, U.S. Pat. No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In a more specific embodiment, the composition comprises hexapropyl-β-cyclodextrin (10-50% in water).

The injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

Typically, the compounds provided herein are administered in an effective amount. The amount of compound actually administered is typically determined by a physician taking into account the relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, etc.

The compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes containing liquid compositions. In such compositions, the compound is usually the component present in minor amounts (from about 0.1% to about 50% by weight, or preferably from about 1% to about 40% by weight), the balance consisting of various carrier media or vehicles and processing aids useful in formulating the desired dosage form.

The compounds provided herein may be administered as a single active agent or may be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. Administration in combination may be by any method obvious to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

Although the description of pharmaceutical compositions provided in the present application is primarily directed to pharmaceutical compositions that are suitable for administration to humans, one skilled in the art will recognize that such compositions are generally suitable for administration to animals of any kind. Modification of pharmaceutical compositions suitable for administration to humans to provide a composition suitable for administration to various animals is obvious, and such modifications can be devised and/or performed by a skilled veterinary pharmacologist by routine experimentation. General considerations for the formulation and/or preparation of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 ^st ed., Lippincott Williams & Wilkins, 2005.

Methods applications And treatment

In one aspect, there is provided a method for alleviating or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In some embodiments, the method alleviates or prevents epileptogenesis.

In some embodiments, such compounds are believed to be useful as therapeutic agents for the treatment of CNS-related disorders (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a seizure disorder, an epileptogenesis disorder, a memory disorder and/or a cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, traumatic brain injury, a vascular disorder, a chemical dependency disorder and/or an abstinence syndrome, or tinnitus) in a subject in need thereof (e.g., a subject with Rett syndrome, fragile X syndrome, or Angelman syndrome). Typical CNS conditions associated with GABA modulation include, but are not limited to, sleep disorder [e.g., insomnia], mood disorder [e.g., depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., type I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive-compulsive disorder (OCD)], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and/or cognitive disorders [e.g., attention deficit hyperactivity disorder (ADHD)], dementia (e.g., Alzheimer's disease dementia, dementia with Lewy bodies, vascular dementia], movement disorders [eg, Huntington's disease, Parkinson's disease], personality disorders [eg, antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders (ASD) [eg, autism, single-gene causes of autism such as synaptopathy such as Rett syndrome, fragile X syndrome, Angelman syndrome], pain [eg, neuropathic pain, pain syndromes associated with trauma, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [eg, stroke, ischemia, vascular malformations], chemical dependency disorders and/or withdrawal syndromes [eg, addiction to opiates, cocaine, and/or alcohol], and tinnitus.

In another aspect, a combination of a compound of the present invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as a single active agent or in combination with other agents. Administration in combination can be by any method obvious to those skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration.

In another aspect, there is provided a method for treating or preventing brain hyperexcitability in a subject susceptible to or affected by a condition associated with brain hyperexcitability, comprising administering to the subject an effective amount of a compound of the present invention.

In another aspect, there is provided a method of treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

In another aspect, there is provided a method for alleviating or preventing insomnia in a subject comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

In another aspect, there is provided a method for inducing sleep and maintaining substantially the level of REM sleep that is observed during normal sleep, in which rebound insomnia is substantially not experienced, comprising administering an effective amount of a compound of the present invention.

In another aspect, there is provided a method for alleviating or preventing PMS or PND in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention.

In another aspect, there is provided a method for treating or preventing mood disorders in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In certain embodiments, the mood disorder is depression.

In another aspect, there is provided a method for improving cognitive function or treating a memory disorder by administering to a subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

In another aspect, there is provided a method of treating an attention disorder by administering to a subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the attention disorder is ADHD.

In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine violations And dysfunction

The present application provides methods that can be used to treat neuroendocrine disorders and dysfunction. As used herein, the term "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to a variety of conditions caused by an imbalance in the body's production of hormones that are directly related to the health of the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Since the hypothalamus and pituitary gland are two areas of the brain that regulate hormone production, damage to the hypothalamus or pituitary gland, such as traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a disorder or health condition in women (e.g., a disorder or health condition in women described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a female health disorder or the condition polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to, behavioral, emotional, sleep-related symptoms, reproductive symptoms, and somatic symptoms; including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, poor concentration, attention problems, loss of libido, infertility, amenorrhea, loss of muscle mass, increased belly fat, low blood pressure, decreased heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

Neurodegenerative diseases And disorders

The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and disorders that are associated with a progressive loss of neuronal structure or function or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including for the treatment, prophylaxis, and prevention of seizures caused by schizoaffective disorder or drugs used to treat schizophrenia); benign forgetfulness; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusional injuries (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impairment of consciousness; Down syndrome; drug-induced or medication-induced parkinsonism (such as acute neuroleptic-induced akathisia, acute dystonia, parkinsonism or tardive dyskinesia, neuroleptic malignant syndrome, or drug-induced postural tremor); epilepsy; fragile X syndrome; Gilles de la Tourette syndrome; head injury; hearing impairment and loss; Huntington's disease; Lennox syndrome; levodopa-induced dyskinesia; mental retardation; movement disorders, including akinesia and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, ALS complex of dementia with parkinsonism, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasticity or weakness, including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal cycloclonus), tremor (such as rest tremor, postural tremor, and intention tremor), and dystonia (including axial dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, and spasmodic dysphonia and torticollis); neuronal injury, including eye injury, retinopathy, or macular degeneration; neurotoxic injury following cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest; Parkinson's disease; seizure; status epilepticus; stroke; tinnitus; tubular sclerosis, and viral infection associated with neurodegeneration (e.g., acquired immunodeficiency syndrome (AIDS) and encephalopathies). Neurodegenerative diseases also include, but are not limited to, neurotoxic injury following cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral spasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest. Methods of treating or preventing a neurodegenerative disease also include treating or preventing the loss of neuronal function characteristic of the neurodegenerative disease.

Disorders moods

The present application also provides methods for treating a mood disorder, such as clinical depression, postpartum depression or postnatal depression, perinatal depression, atypical depression, melancholic depression, psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression due to chronic illness, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior. In some embodiments, the method described herein provides a therapeutic effect for a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., a neuroendocrine disease and disorder, a neurodegenerative disease and disorder (e.g., epilepsy), a movement disorder, a tremor (e.g., Parkinson's disease), a disorder or health condition in women).

Clinical depression , also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistently depressed mood, accompanied by low self-esteem and loss of interest in or ability to enjoy normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and are generally excitable and irritable. Clinical depression affects the way a person feels, thinks, and behaves, and can lead to a variety of emotional and physical problems. People with clinical depression may have difficulty performing everyday activities, and the person may feel as if life is not worth living.

Peripartum depression refers to depression during pregnancy. Symptoms include irritability, crying, feeling restless, difficulty sleeping, extreme exhaustion (emotional and/or physical), changes in appetite, difficulty concentrating, increased anxiety and/or restlessness, feeling disconnected from the baby and/or fetus, and loss of interest in previously enjoyable activities.

Postpartum depression (PND) , also referred to as postnatal depression (PPD) , refers to a type of clinical depression that women suffer from after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying spells, restlessness, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., refractory depression as described herein).

In some embodiments, the subject having PND also experienced depression or had symptoms of depression during pregnancy. Such depression is referred to herein as perinatal depression . In one embodiment, the subject experiencing perinatal depression has an increased risk of developing PND.

Atypical depression (AD) is characterized by mood reactivity (eg, paradoxical anhedonia) and positive emotional responses to positive events, significant weight gain, or increased appetite. Patients with AD may also sleep excessively or be in a drowsy state (hypersomnia), have a feeling of heaviness in the limbs, and significant social impairment due to hypersensitivity to subjectively perceived interpersonal rejection.

Melancholic depression is characterized by a loss of the ability to derive pleasure (anhedonia) from most or all activities, an inability to respond to pleasurable stimuli, depressed mood that is more pronounced than that associated with grief or loss, excessive weight loss, or excessive feelings of guilt.

Major psychotic depression (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, where the person experiences psychotic symptoms such as delusions and hallucinations.

Catatonic depression refers to a deep depression that includes disturbances in motor behavior and other symptoms. The person may become mute and stuporous, or may be motionless or have aimless or strange movements.

Seasonal affective disorder (SAD) refers to a type of seasonal depression in which a person experiences seasonal patterns of depressive episodes that occur during the fall or winter.

Dysthymia is a condition related to unipolar depression, which has the same physical and cognitive problems. It is not as severe and tends to last longer (e.g. at least 2 years).

Double depression refers to a severely depressed mood (dysthymia) that lasts for at least 2 years and is interspersed with periods of major depression.

Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

Recurrent brief depression (RBD) refers to a condition in which people have depressive episodes about once a month, with each episode lasting 2 weeks or less and usually less than 2-3 days.

Mild depressive disorder or mild depression refers to depression in which at least 2 symptoms are present for 2 weeks.

Bipolar disorder , or manic-depressive disorder, causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During periods of mania, a person may feel or act as if they are abnormally happy, energetic, or irritable. They often make poorly thought-out decisions without considering the consequences. The need for sleep is usually reduced. During periods of depression, they may be tearful, have poor eye contact with others, and have a negative outlook on life. The risk of suicide among people with this disorder is high, at more than 6% over 20 years, while self-harm occurs in 30-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

Chronic illness - induced depression refers to depression caused by chronic illnesses such as cancer or chronic pain, chemotherapy, chronic stress.

Treatment - resistant depression refers to a condition in which people have been treated for depression but symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) do not relieve symptoms of depression in people with treatment-resistant depression. In some cases, people with treatment-resistant depression experience relief of symptoms, but then their symptoms return. Refractory depression occurs in patients who have depression that is resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, dual and triple reuptake inhibitors, and/or anxiolytics, as well as nonpharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and/or transcranial magnetic stimulation).

Postoperative depression refers to feelings of depression that follow a surgical procedure (for example, as a result of having to confront death). For example, people may feel persistent sadness or emptiness, loss of the ability to enjoy or interest in previously enjoyable hobbies and activities, or a persistent sense of worthlessness or hopelessness.

Mood disorder associated with health conditions or disorders in women refers to mood disorders (e.g., depression) associated with (e.g., resulting from) a health condition or disorder in women (e.g., as described herein).

Suicidality, suicidal ideation, and suicidal behavior refer to a person's tendency to kill themselves. Suicidal ideation refers to thoughts or unusual preoccupation with suicide. Suicidal ideation can range from fleeting thoughts to deep rumination, detailed planning, role-playing, and unsuccessful attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social contact, preoccupation with death, feeling stuck or hopeless in a situation, increasing alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never be seen again.

Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, loss of energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, problems with motor skills, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from person to person. Symptoms of depression and their relief can be determined by a doctor or psychologist (e.g., through a mental health examination).

In some embodiments, the method provides a therapeutic effect (e.g., as assessed by a decrease in the Hamilton Rating Scale for Depression (HAM-D) score) at 4, 3, 2, 1 day; 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is a decrease in the HAM-D score at the end of the treatment period (e.g., 12, 24, 48 hours after administration; 24, 48, 72, 96 hours or more) relative to the baseline value. In some embodiments, the decrease in the HAM-D score relative to the baseline is significant (e.g., from a HAM-D score of 24 or higher) to asymptomatic (e.g., a HAM-D score of 7 or lower). In some embodiments, the baseline score is between 10 and 52 (e.g., greater than 10, 15, or 20; 10 to 52, 12 to 52, 15 to 52, 17 to 52, 20 to 52, 22 to 52). In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D score at the end of the treatment period is between about 0 and 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, 1.8). In some embodiments, the HAM-D score at the end of the treatment period is less than 10, 7, 5, or 3. In some embodiments, the reduction in HAM-D score from baseline to a HAM-D score in the range of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) is reduced to a HAM-D score in the range of 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, 1.8) at the end of the treatment period. In some embodiments, the reduction in the HAM-D score from baseline to the HAM-D score at the end of the treatment period is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times. In some embodiments, the percentage reduction in the HAM-D score from baseline to the HAM-D score at the end of the treatment period is at least 50% (e.g., 60%, 70%, 80%, 90%). In some embodiments, the therapeutic effect is a reduction in the HAM-D score at the end of the treatment period compared to the baseline value (e.g., 12, 24, 48 hours after administration; 24, 48, 72, 96 hours or more) by at least 10, 15, or 20 points. In some embodiments, the therapeutic effect is a decrease in the HAM-D score at the end of the treatment period compared to the baseline value (e.g., 12, 24, 48 hours after administration; 24, 48, 72, 96 hours or more) by at least 5, 7 or 10 points or more relative to the therapeutic effect provided by placebo treatment.

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score) in 4, 3, 2, 1 day; 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (related to marked sadness, marked sadness, inner tension, worsening sleep, worsening appetite, problems concentrating, fatigue, inability to feel, pessimistic and suicidal ideation) that psychiatrists use to assess the severity of depressive episodes in patients with mood disorders: scores of 0-6 indicate normal/no symptoms; scores of 7-19 indicate mild depression; scores of 20-34 indicate moderate depression; and a score >34 indicates severe depression. In some embodiments, the therapeutic effect is a decrease in MADRS score at the end of the treatment period compared to a baseline value (e.g., 12, 24, 48 hours after administration; 24, 48, 60, 72, 96 hours or more). In some embodiments, the decrease in MADRS score from baseline is from severe (e.g., a MADRS score of 30 or higher) to asymptomatic (e.g., a MADRS score of 20 or lower). For example, with treatment with a compound disclosed herein, the mean change in MADRS total score from baseline is about -15, -20, -25, -30, whereas the mean change in MADRS total score from baseline with placebo treatment is about -15, -10, -5.

In some embodiments, the method provides a therapeutic effect (e.g., as assessed by a decrease in the Edinburgh Postnatal Depression Scale (EPDS) score) in 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is an improvement as assessed by the EPDS scale.

In some embodiments, the method provides a therapeutic effect (e.g., as assessed by a decrease in the Clinical Global Impression (CGI) score) in 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours or less. In some embodiments, the therapeutic effect is a CGI score of 2 or less.

In some embodiments, the method provides a therapeutic effect (e.g., as assessed by a decrease in the score on the 7-point scale of generalized anxiety disorder (GAD-7)) in 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours or less.

Disturbing disorders

This application presents methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobia, post-traumatic stress disorder). Anxiety disorder is a general term that encompasses several different forms of pathological fear and worry. Current psychiatric diagnostic criteria recognize a wide range of anxiety disorders.

Generalized anxiety disorder is a common, chronic disorder characterized by long-term anxiety that is not focused on any one thing or situation. Those who suffer from generalized anxiety experience nonspecific, persistent fear and worry and become overly preoccupied with everyday activities. Generalized anxiety disorder is the most common anxiety disorder in older adults.

Panic disorder involves a person suffering from brief episodes of intense terror and fear, often with marked shaking, trembling, confusion, dizziness, nausea, and difficulty breathing. These panic attacks, defined by the APA as sudden fear or discomfort that begins and peaks in less than ten minutes, can last for several hours and may be triggered by stress, fear, or even exercise; although the specific cause is not always obvious. In addition to recurring, unexpected panic attacks, a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry about the potential consequences of the attacks, persistent fear of future attacks, or significant changes in behavior associated with the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes. Often, people with panic disorder place great emphasis on normal changes in their heartbeat, fearing that something is wrong with their heart or that they are about to have another panic attack. In some cases, heightened attention (hypervigilance) to the functioning of the body occurs during panic attacks, where any perceived physiological change is interpreted as a possible life-threatening illness (i.e., extreme hypochondriasis).

Obsessive-compulsive disorder is a type of anxiety disorder primarily characterized by recurring obsessions (worrying, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific actions or rituals). The OCD thought pattern has been likened to superstition, as it involves a belief in a cause-and-effect relationship that does not actually exist. Often, the process is completely illogical; for example, an obsessive urge to walk in a particular pattern may be used to relieve an obsessive thought about impending danger. And in many cases, the compulsions are completely inexplicable, simply a desire to complete a ritual triggered by nervousness. More rarely, OCD sufferers may experience only the obsession, without overt compulsions; a much smaller number of patients experience only compulsions.

The largest category of anxiety disorders is phobia , which includes all instances in which fear and anxiety are caused by a specific stimulus or situation. Those with a phobia typically expect terrible consequences from encountering the object of their fear, which can be anything from an animal to a place where bodily fluid is found.

Post-traumatic stress disorder , or PTSD , is an anxiety disorder that results from a traumatic experience. PTSD can result from an extreme situation, such as a fight, rape, hostage situation, or even a serious accident. It can also result from long-term (chronic) exposure to a severe stressor, such as soldiers who have been in isolated battles but who cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behavior, and depression.

Disorders female health

The present application provides methods for treating conditions or disorders related to women's health. Conditions or disorders related to women's health include, but are not limited to, gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to the general health and well-being of women (e.g., menopause).

Gynecologic health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor dysfunction; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks before the start of your menstrual cycle. Symptoms can vary but may include bleeding, mood swings, tender breasts, food cravings, fatigue, irritability, acne, and depression.

Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, worsening mood or feelings of hopelessness, increased anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of being out of control or unable to cope, sleep problems, physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

Pregnancy problems include preconception and antenatal care, pregnancy loss (miscarriage and stillbirth), spontaneous abortion and preterm birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

Spontaneous abortion refers to a pregnancy that ends on its own within the first 20 weeks of pregnancy.

Abortion refers to the intentional termination of a pregnancy, which can occur during the first 28 weeks of pregnancy.

Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis , and primary ovarian insufficiency.

Polycystic ovary syndrome (PCOS) refers to an endocrine disorder in women of reproductive age. PCOS is a collection of symptoms caused by elevated levels of male hormones in women. Most women with PCOS have many small cysts on their ovaries. Symptoms of PCOS include irregular or absent periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, dark, velvety skin. PCOS may be associated with conditions such as type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

Issues related to women's overall health and well-being include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

Menopause refers to the 12 months after a woman's last menstrual period and marks the end of the menstrual cycle. Menopause usually occurs in her 40s or 50s. Physical symptoms, such as hot flashes, and emotional symptoms of menopause may disrupt sleep, decrease energy, or cause anxiety or feelings of sadness or loss. Menopause includes sleep menopause and surgical menopause, which is a type of induced menopause as a result of an event such as surgery (eg, hysterectomy, oophorectomy; cancer). Menopause may be caused by serious damage to the ovaries, such as from radiation, chemotherapy, or other drugs.

Epilepsy

The compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can be used in a method described herein, for example, to treat a disorder described herein, such as epilepsy, status epilepticus, or seizure, for example, as described in WO2013/112605 and WO2014/031792, the contents of which are incorporated herein in their entirety.

Epilepsy is a disorder of the brain characterized by recurring seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy such as childhood absence epilepsy, juvenile myoclonic epilepsy, grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy such as temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

The compounds and methods described in this application can be used to treat or prevent epileptogenesis. Epileptogenesis is a gradual process by which epilepsy (a chronic condition that causes seizures) develops in the normal brain. Epileptogenesis occurs as a result of neuronal damage caused by an initial injury (e.g., status epilepticus).

Epileptic status (SE)

Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges. Convulsive status epilepticus is characterized by the presence of status epilepticus seizures and may include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line and second-line therapy. Treatment-refractory status epilepticus is characterized by seizures of status epilepticus that persist despite treatment with first-line and second-line therapies and general anesthetics. Super-refractory status epilepticus is characterized by seizures of status epilepticus that persist for 24 hours or more despite treatment with first-line therapies, second-line therapies and general anesthetics.

Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, mild partial non-convulsive status epilepticus, mild non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as non-late-onset status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

The compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can also be administered as a prophylactic agent to a subject with a CNS disorder, such as a traumatic brain injury, an epileptic status, such as a convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; a non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.

Seizures

Seizures are physical or behavioral changes that occur after an episode of abnormal electrical activity in the brain. The terms seizure and convulsion are often used interchangeably. Convulsions are rapid, uncontrollable shaking of the body. During a convulsion, a person's muscles contract and relax repeatedly.

Depending on the type of behavior and brain activity, seizures are divided into two broad categories: generalized and partial (also called focal or local). Classifying the type of seizure helps doctors determine whether a patient has epilepsy.

Generalized seizures are generated by electrical impulses from throughout the brain, whereas partial seizures are generated (at least initially) by electrical impulses from a relatively small area of the brain. The area of the brain that is causing the seizures is sometimes called the focus.

There are six types of generalized seizures. The most common and dramatic, and therefore the best known, are generalized seizures, also called grand mal seizures. In this type of seizure, the patient loses consciousness and usually falls. The loss of consciousness is followed by generalized numbness of the body (called the "tonic" phase of the seizure) for 30 to 60 seconds, then violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient goes into a deep sleep (the "post-tictal" or post-seizure period). Injuries and accidents such as tongue biting and urinary incontinence can occur during grand mal seizures.

Absence seizures involve a brief loss of consciousness (only a few seconds) with few or no symptoms. The patient, most often a child, typically stops activity and stares blankly. These seizures begin and end suddenly and may occur several times a day. Patients are usually unaware that they are having a seizure, except that they may be aware of "losing time."

Myoclonic seizures consist of sporadic jerking movements, usually on both sides of the body. Patients sometimes describe the jerking movements as short electric shocks. In severe cases, these seizures may result in falling or involuntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerking movements that affect both sides of the body at the same time.

Tonic seizures are characterized by muscle stiffening.

Atonic seizures consist of a sudden and general loss of muscle tone, especially in the arms and legs, often resulting in a fall.

The seizures described herein may include epileptic seizures; acute recurrent seizures; cluster seizures; persistent seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, such as refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized seizures; infantile spasms; Jackson seizures; massive bilateral myoclonus; multifocal seizures; seizures in neonates; nocturnal seizures; seizures originating in the occipital lobe; posttraumatic seizures; subtle seizures; seizures in children; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or epilepsy in girls caused by a mutation in the PCDH19 gene.

Motor disorder

The present application also describes methods for treating a movement disorder. As used herein, the term "movement disorders" refers to a variety of diseases and disorders that involve hyperkinetic movement disorders and related muscle control disorders. Examples of movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (defined in particular by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette's syndrome, restless legs syndrome, rigid person syndrome, and gait disorder.

Tremor

The methods described in this application can be used to treat tremor, can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor or rubral tremor. Tremor includes hereditary, degenerative and idiopathic disorders such as Wilson's disease, Parkinson's disease and essential tremor, respectively; metabolic diseases (e.g., thyroid and parathyroid diseases, liver diseases and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Roussy-Levy syndrome, diabetes mellitus, complex regional pain syndrome); tremor caused by toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced tremor (induced by narcotics, tricyclic compounds, lithium compounds, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndromes (including classic tremor, primary orthostatic tremor, and task-related/postural tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

Tremor is an involuntary, sometimes rhythmic, muscle contraction and relaxation that may involve shaking or twitching of one or more body parts (eg, arms, upper limbs, eyes, face, head, vocal cords, trunk, legs).

Cerebellar tremor or intention tremor is a slow, coarse tremor of the limbs that occurs after a purposeful movement. Cerebellar tremor is caused by damage or injury to the cerebellum, such as a tumor, stroke, or disease (such as multiple sclerosis, an inherited degenerative disorder).

Dystonic tremor occurs in people who have dystonia, a movement disorder in which sustained involuntary muscle contractions cause repetitive, twisting movements and/or painful and abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremors occur irregularly and often fade away before relaxing completely.

Essential tremor or benign tremor is the most common type of tremor. In some cases, essential tremor may be mild and non-progressive, or it may be slowly progressive, starting on one side of the body and affecting both sides over 3 years. The arms are most commonly affected, but the head, voice, tongue, legs, and trunk may also be affected. The frequency of tremors may decrease with age, but the severity may increase. Intense emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Symptoms tend to develop over time and may be visible or persistent once the disorder has begun.

Orthostatic tremor is characterized by rapid (eg, greater than 12 Hz), rhythmic muscle contractions that occur in the legs and trunk immediately after standing. The spasms are felt in the hips and legs, and the patient may shake uncontrollably when asked to stand still. Orthostatic tremor may occur in patients with essential tremor.

Parkinsonian tremor is caused by damage to the brain structures that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and typically appears as a "pill rolling" motion in the hands, which can also affect the chin, lips, legs, and trunk. Parkinsonian tremor usually begins to develop after age 60. The movement begins in one limb or on one side of the body and may progress to affect the other side.

Physiological tremor may occur in normal individuals and may not be clinically significant. It can be seen in all muscle groups in volunteers. Physiological tremor may be caused by certain medications, alcohol withdrawal, or medical conditions including overactive thyroid and hypoglycemia. Classically, the frequency of tremor is approximately 10 Hz.

Psychogenic tremor or hysterical tremor may occur at rest or during postural or kinetic movement. A patient with psychogenic tremor may have conversion disorder or another mental illness.

Rubral tremor is characterized by a coarse, slow tremor that may be present at rest, in certain postures, and with certain intentions. The tremor is associated with conditions that affect the red nucleus in the midbrain, the classic unusual seizures.

Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinsonism also shares the symptoms seen in Parkinson's disease, but it is a symptom complex rather than a progressive neurodegenerative disease.

Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that cause abnormal, often repetitive, movements or postures. Dystonic movements may be stereotyped, twisting, and may be shaky. Dystonia is often initiated or aggravated by voluntary action and is associated with an overflow effect - muscle activation.

Chorea is a neurological disorder characterized by sudden, involuntary movements, usually affecting the shoulders, hips, and face.

Huntington's disease is an inherited disorder that causes the loss of nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

Ataxia refers to the loss of complete control over body movements and can affect the fingers, arms, shoulders, legs, body, speech, and eye movements.

Myoclonus and flinching are reactions to a sudden and unexpected stimulus, which may be acoustic, tactile, visual, or vestibular.

Tics are involuntary movements that usually begin suddenly, are brief, repetitive but not rhythmic, usually mimic normal behavior, and often occur in the context of normal activity. Tics can be classified as motor or vocal, with motor tics involving movements and vocal tics involving sound. Tics can be described as simple or complex. For example, simple motor tics involve only a few muscles limited to a specific part of the body. Tourette syndrome is an inherited neuropsychiatric disorder that begins in childhood and is characterized by multiple motor tics and at least one vocal tic.

Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

Stiff- person syndrome is a progressive movement disorder characterized by involuntary, painful spasms and rigidity of muscles, usually affecting the lower back and legs. A stiff gait with exaggerated lumbar hyperlordosis typically occurs. EMG recordings typically show a characteristic abnormality with continuous motor activity of the paraspinal axial muscles. Variants include "stiff limb syndrome," which causes focal rigidity, usually affecting the lower extremities and feet.

Gait disorders refer to abnormalities in the manner or style of walking resulting from neuromuscular, arthritic, or other changes in the body. Gait is classified according to the system responsible for the abnormal locomotion and includes hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreic gait, ataxic gait, and sensory gait.

Anesthesia/sedation effect

Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, blunting, loss of skeletal muscle reflexes, decreased stress response, or all of these simultaneously. These effects may be produced by a single drug that alone produces the right combination of effects, or sometimes by a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to produce very specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the stress and pain they might otherwise experience.

Sedation is the reduction of irritability or agitation by the administration of a pharmacologic agent, usually to facilitate a medical procedure or diagnostic procedure.

Sedation and analgesia include a range of states of consciousness, ranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular functions are usually unaffected.

Mild sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness in which the patient responds purposefully to verbal commands alone or to verbal commands accompanied by mild tactile stimulation. No intervention is usually required to maintain the patient's breathing. Spontaneous ventilation is usually adequate. Cardiovascular function is usually preserved.

Deep sedation/analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused but responds purposefully (nonreflexive withdrawal from painful stimuli) to repeated or painful stimulation. Independent ventilatory function may be impaired, and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

General anesthesia is a drug-induced loss of consciousness in which the patient is unresponsive even to painful stimuli. The ability to maintain independent ventilation is often impaired, and assistance to maintain a patent airway is often required. Positive pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced reduction in neuromuscular function. Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) reduces the patient's awareness of the environment and their response to external stimulation. It may play a role in the care of the critically ill patient and covers a wide spectrum of symptom control that will vary from patient to patient and may change over the course of the disease in individuals. Deep sedation in the ICU is used to facilitate tolerance of the endotracheal tube and synchrony with the ventilator, often in conjunction with neuromuscular blocking agents.

In some embodiments, sedation (e.g., prolonged sedation, continuous sedation) is induced and maintained in an intensive care unit for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives may have a long duration of action. Sedatives in the intensive care unit may have a short half-life.

Procedural sedation and analgesia, also called conscious sedation, is a method of administering sedative or dissociative agents with or without analgesics to induce a state that allows the subject to tolerate unpleasant procedures while maintaining cardiorespiratory function.

Examples

For a more complete understanding of the invention described in this application, the following examples are provided. The synthesis examples described in this application are offered to illustrate the invention presented in this description and should not be considered as limiting its scope.

Materials And methods

The compounds disclosed herein can be prepared from readily available starting materials by the following general methods and procedures. It is understood that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressure, etc.) are given, other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art through routine optimization.

In addition, as will be apparent to one skilled in the art, conventional protecting groups may be required to prevent certain functional groups from participating in undesirable reactions. The selection of an appropriate protecting group for a particular functional group, as well as appropriate conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups, as well as their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein.

The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are detailed with respect to the preparation of representative oxysterols listed in this application. The compounds provided herein can be prepared by one skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Representative chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided 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.

An example general method for preparative HPLC: Column: Durashell. Mobile phase: A: water, B: acetonitrile. %B at 0 min: 41%, %B after 8 min: 71%, flow rate: 35 ml/min, detection wavelength: 220 nm.

An example of a general analytical HPLC method: mobile phase: A: water (10 mM NH ₄ HCO ₃ ), B: acetonitrile gradient: 5%-95% B over 1.6 or 2 min, flow rate: 1.8 or 2 ml/min; column: XBridge C18, 4.6*50 mm, 3.5 μm at 45°C.

Example general SFC method: Column: CHIRALPAK® AD (250 mm*30 mm, 5 µm), A=supercritical _CO2 , B=MeOH (0.1% _NH3 - _H2O ), A:B=70:30, flow rate: 60 ml/min, column temperature: 38°C, nozzle pressure: 100 bar, detection wavelength=220 nm.

Example LC/MS conditions include:

30-90AB_2MIN_E Column Xtimate C18 2.1*30mm, 3 microns Mobile phase A: water (4L)+TFA (1.5ml) B: acetonitrile (4l) + TFA (0.75 ml) Time (min) B, % 0 30 0.9 90 1.5 90 1.51 30 2 30 Flow rate 1.2 ml/min Wavelength UV 220 nm Temperature in the drying cabinet 50°C Ionization in MS ESI Detector PDA, ELSD

10-80AB_2MIN_E Column Xtimate C18 2.1*30mm, 3 microns Mobile phase A: water (4L)+TFA (1.5ml) B: acetonitrile (4l) + TFA (0.75 ml) Time (min) B, % 0 10 0.9 80 1.5 80 1.51 10 2 10 Flow rate 1.2 ml/min Wavelength UV 220 nm Temperature in the drying cabinet 50°C Ionization in MS ESI Detector PDA, ELSD

30-90CD_3MIN_E Column Xbrige Shield RP-18, 5 microns, 2.1*50 mm Mobile phase A: water (1l)+NH ₃ H ₂ O (0.5 ml) B: acetonitrile Time (min) B, % 0 30 2 90 2.48 90 2.49 30 3 30 Flow rate 1.0 ml/min Wavelength UV 220 nm Temperature in the drying cabinet 30°C Ionization in MS ESI Detector PDA, ELSD

Inhibition steroids bindings TBP

Binding assays of [ ^35S ]-tert-butylbicyclophosphorothionate (TBPS) in the presence of 5 mM GABA in rat cerebral cortex membrane have been described (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, AH et al., Mol. Pharmacol. 1989, 35, 189-194).

Briefly, cortex was rapidly removed after decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200–250 g). Cortex was homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass/Teflon homogenizer and centrifuged at 1,500 g for 10 min at 4 °C. The resulting supernatants were centrifuged at 10,000 × g for 20 min at 4 °C to generate P2 pellets. P2 pellets were resuspended in 200 mM NaCl/50 mM Na-K-phosphate buffer, pH 7.4, and centrifuged at 10,000 × g for 10 min at 4 °C. This washing procedure was repeated twice, and the pellets were resuspended in 10 volumes of buffer. Aliquots (100 ml) of membrane suspensions were incubated with 3 nM [ ^35S ]-TBPS and 5 ml aliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final concentration 0.5%) in the presence of 5 mM GABA. The incubation volume was adjusted to a final volume of 1.0 ml using buffer. Non-specific binding was determined in the presence of 2 mM unlabeled TBPS and ranged from 15 to 25%. After 90 min incubation at room temperature, assays were stopped by filtration through glass fiber filters (Schleicher and Schuell no. 32) using a cell harvester (Brandel) and washed three times with ice-cold buffer. Filter-bound radioactivity was measured by liquid scintillation spectrometry. Nonlinear fits of the data for each drug, averaged over each concentration, were performed using Prism software (GraphPad). Data were fitted to a partial rather than complete inhibition model if the sum of squares was significantly lower than that predicted by the F-test. Similarly, data were fitted to a two-compartment model rather than a one-compartment inhibition model if the sum of squares was significantly lower than that predicted by the F-test. The concentration of test compound causing 50% inhibition (IC ₅₀ ) of specific binding and the maximal degree of inhibition (I _max ) were determined in separate experiments using the same model used for all data, and the mean values + SEM for individual experiments were calculated. Pyrotoxin served as a positive control in these studies, as it has been shown to effectively inhibit TBPS binding.

Various compounds were or could be screened to determine their efficacy as modulators of [ ^35S ]-TBPS binding in vitro . These assays were or could be performed according to the procedures described above. The results of the TBPS binding assays are shown in Table 2.

Abbreviations

PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu ₃ P) ₂ : bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO) ₄ Ti: titanium tetraisopropoxide; BHT: 2,6-di-tert-butyl-4-methylphenoxide; Me: methyl; i-Pr: isopropyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: ethyl magnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl, Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF ₃ : (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr) ₄ : tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H ₂ O: lithium hydroxide hydrates; MAD: methylaluminum bis(2,6-di-tert-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS: N-bromosuccinimide; Na ₂ SO ₄ : sodium sulfate; Na ₂ S ₂ O ₃ : sodium thiosulfate; PE: petroleum ether; MeCN: acetonitrile; MeOH: methanol; Boc: tert-butoxycarbonyl; MTBE: methyl tert-butyl ether; EDCI: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

Example 1. Synthesis connections 1

The synthesis of A1 is disclosed in WO2013/56181 A1.

Step 1 (A2). Liquid bromine (7.46 g, 46.7 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (62.3 mL, 3 M, 187 mmol) at 0 °C. When all the bromine had dissolved, the mixture was diluted with cold dioxane (15 mL) and slowly added to a stirred solution of A1 (5 g, 15.6 mmol) in dioxane (20 mL) and water (15 mL). The homogeneous yellow solution slowly decolorized and a white precipitate formed. The reaction mixture was stirred at 25 °C for 16 h. The remaining oxidizing reagent was blocked with an aqueous solution of Na ₂ S ₂ O ₃ (30 mL), and the mixture was then heated at 80 °C until the solid dissolved. Acidification of the solution with hydrochloric acid (3 N) resulted in the formation of a white precipitate. The solid was collected by filtration and washed with water (3 x 100 mL) to give a solid, which was dried under vacuum to give the crude product. The crude product was triturated with toluene (40 mL) to give A2 (3.6 g, 72%) as a solid.

¹ H NMR(CDCl₃,400M Hz) δ 2.43-2.38 (m, 1H), 2.07-2.04 (m, 2H), 1.82-1.79 (m, 4H), 1.57-1, 60 (m, 3H), 1.57-1.40 (m, 7H), 1.39-1.30 (m, 8H), 1.29-1.06 (m, 3H), 0.72 ( s, 3H).

Step 2 (Compound 1). To a solution of A2 (100 mg, 0.312 mmol) in DCM (8 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, phenylmethylamine (53.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 12 h. Water (8 mL) was added. The mixture was extracted with DCM (2×8 mL). _The combined organic layers were washed with brine, dried over _Na2SO4 , concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Column: Xtimate C18 150*25mm*5μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Gradient 50%-80% B; Gradient time (min): 10) and lyophilized to give compound 1 (77 mg, 61%) as a solid.

¹ H NMR(CDCl₃, 400M Hz) δ 7.40-7.26 (m, 5H), 5.54 (s, 1H), 4.55-4.35 (m, 2H), 2.25-2.10 (m, 2H), 1.96-1.60 (m, 8H), 1.57-1.30 (m, 6H), 1.25-1.15 (m, 8H), 1.15-1.00 ( m, 4H), 0.71 (s, 3H).

LC/MS Rt=1.797 min in 3 _min chromatography, 30-90 CD, purity 100%, ESI MS calcd for _C27H40NO2 ⁺ [M ₊ H] ⁺ 410, found 410.

Example 2. Synthesis connections 2

Step 1 (Compound 2). To a solution of A2 (100 mg, 0.312 mmol) in DCM (8 mL) were added TEA (236 mg, 2.34 mmol) and HATU (266 mg, 0.702 mmol). After stirring for 10 min, diethylamine (54.7 mg, 0.749 mmol) was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was treated with water (8 mL) and extracted with DCM (2×8 mL). _The combined organic layers were washed with brine, dried over _Na2SO4 , concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Column: Xtimate C18 150*25mm*5μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Gradient 52%-82% B; Gradient time (min): 10) and lyophilized to give compound 2 (100 mg, 57%) as a solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.77-3.65 (m, 2H), 3.15-2.99 (m, 2H), 2.65-2.55 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.55 (m, 8H), 1.50-1.30 (m, 7H), 1.30-1.15 (m, 8H), 1.15-1.00 (m, 9H), 0.74 (s, 3H).

LC/MS Rt=1.739 min in 3 min chromatography, 30-90 CD, purity 100%, _ESI MS calcd for _C24H42NO2 ⁺ [M ₊ H] ⁺ 376, found 376.

Example 3. Synthesis connections 3

Step 1 (Compound 3). To a solution of A2 (200 mg, 0.62 mmol) in DCM (8 mL) were added TEA (314 mg, 3.11 mmol) and HATU (355 mg, 0.936 mmol) at 25 °C. After stirring at 25 °C for 30 min, aniline (92.9 mg, 0.998 mmol) was added. The mixture was stirred at 25 °C for 16 h and treated with water (8 mL), extracted with DCM (2 x 8 mL). The organic layers were washed with brine (2 x 10 mL), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to give the crude product, which was triturated with MeOH (12 mL) at 25 °C to give 90 mg of impure product. The impure product was recrystallized from MeCN (20 mL) at 65°C and filtered at 25°C to give the product, which was dissolved in MeCN (30 mL) at 65°C and concentrated in vacuo to give compound 3 (44 mg, 49%) as a solid.

¹ H NMR (400 M Hz, CDCl ₃ ) δ 7.51 (d, J = 7.8 Hz, 2H), 7.35-7.28 (m, 2H), 7.12-7.05 (m , 1H), 6.95 (br.s, 1H), 2.35-2.22 (m, 2H), 2.06-1.98 (m, 1H), 1.89-1.60 (m , 7H), 1.52-1.23 (m, 15H), 1.20-1.04 (m, 3H), 0.75 (s, 3H).

LC/MS Rt=0.932 min in 2 min chromatography, 5-95AB_220&254, purity 100%, ESI MS _calcd for _C26H38NO2 [M ₊ H] ⁺ 396, found 396.

Example 4. Synthesis connections 4

Step 1 (Compound 4). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. N-methyl-1-phenylmethanamine (60.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (5 mL) was added. The mixture was extracted with DCM (2×5 mL), washed with brine, dried over _Na2SO4 , concentrated in vacuo to give the crude product, which was purified by preparative HPLC ( _Column : Xtimate C18 150*25mm*5μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Initial B: 57; Final B: 87; 100% B, Retention Time (min): 2.5; Flow Rate (mL/min): 25; Injections: 8) to give a solution of the product in water/ _CH3CN and concentrated in vacuo to give compound 4 (109 mg, 83%) as a solid.

^1H NMR (400M Hz, CDCl ₃ ) δ 7.38-7.28 (m, 2H), 7.26-7.22 (m, 2H), 7.16-7.09 (m, 1H), 5.11-4.83 (m, 1H), 4.40-4.17 (m, 1H), 2.99-2.90 (m, 3H), 2.82-2.67 (m, 1H ), 2.38-2.26 (m, 1H), 1.91-1.74 (m, 4H), 1.74-1.59 (m, 4H), 1.54-1.36 (m , 5H), 1.36-1.30 (m, 3H), 1.29-1.20 (m, 6H), 1.20-1.01 (m, 4H), 0.81 (s, 3H).

LC/MS Rt=1.325 min in 2 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C28H42NO2 [M ₊ H] ⁺ 424, found 424.

Example 5. Synthesis connections 5

Step 1 (Compound 5). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. Piperidine (42.4 mg, 0.449 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (8 mL) was added. The mixture was extracted with DCM (2×10 mL), washed with brine, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was triturated with acetonitrile (5 mL) at 25 °C to give compound 5 (34 mg, 28%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.65-3.40 (m, 4H), 2.75-2.64 (m, 1H), 2.35-2.25 (m, 1H), 1.90-1.75 (m , 4H), 1.75-1.55 (m, 10H), 1.55-1.49 (m, 5H), 1.49-1.18 (m, 10H), 1.18-1.05 (m, 3H), 0.72 (s, 3H).

LC/MS Rt=1.896 min in 2.0 min chromatography, 30-90 CD_POS_E.M, purity 100%, ESI MS calcd for C ₂₅ H ₄₂ NO ₂ [M+H] ⁺ 388, found 388.

Example 6. Synthesis connections 6

Step 1 (Compound 6). To a solution of A2 (150 mg, 0.468 mmol) in DCM (6 mL) were added TEA (236 mg, 2.34 mmol) and HATU (266 mg, 0.7 mmol) at 25 °C. After stirring at 25 °C for 30 min, 1,4-oxazepane (75.6 mg, 0.748 mmol) was added. The mixture was stirred at 25 °C for 1 h and the reaction was quenched with water (8 mL). The mixture was extracted with DCM (2×8 mL). The organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give a crude product, which was purified by preparative HPLC ( _Column : Waters Xbridge (150mm*25mm, 5μm)), gradient: 60-90% B (A=10 mM _{NH4HCO3 / H2O} , B=MeCN), flow rate: 25 mL/min) to give a solid. The solid was treated with water (5 mL), heated to 80°C and stirred for 2 h, filtered and concentrated to give compound 6 (32 mg).

¹ H NMR(400 MHz, CDCl₃) δ 4.02-3.92 (m, 1H), 3.90-3.65 (m, 4H), 3.65-3.62 (m, 1H), 3.52-3.35 (m , 2H), 2.73-2.59 (m, 1H), 2.35-2.18 (m, 1H), 2.05-1.78 (m, 6H), 1.78-1.60 (m, 5H), 1.51-1.38 (m, 5H), 1.36-1.18(m, 9H), 1.18-1.02(m, 3H), 0.80-0 .70 (s, 3H).

LC/MS Rt=0.863 min in 2.0 min chromatography, 30-90AB, purity 100%, ESI MS _calcd for _C25H42NO3 [M ₊ H] ⁺ 404, found 404.

Example 7. Synthesis connections 7

Step 1 (Compound 7). To a solution of A2 (80 mg, 0.25 mmol) in DCM (3 mL) were added TEA (125 mg, 1.24 mmol) and HATU (142 mg, 0.37 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methylaniline (42.7 mg, 0.40 mmol) was added. The mixture was stirred at 25 °C for 16 h and the reaction was quenched with water (5 mL). The mixture was extracted with DCM (2×4 mL). The organic phase was washed with brine (2×8 mL), dried over _Na2SO4 , filtered, concentrated in vacuo to give a crude product, which was purified by preparative HPLC ( _Column : Xtimate C18 150*25mm*5μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN, 61%-91% B; Gradient time (min): 10; 100% B Retention time (min): 2.5; Flow rate (mL/min): 25) to give a solid, which was triturated with MeCN (5 mL) at 25°C for 4 h to give compound 7 (14 mg, 14%) as a solid.

1H NMR (400 M Hz, CDCl ₃ ) δ 7.50-7.40 (m, 2H), 7.40-7.30 (m, 1H), 7.15-7.05 (m, 2H), 3.26 (s, 3H), 2.50-2.40 (m, 1H), 2.15-2.00 (m, 1H), 1.90-1.60 (m, 6H), 1. 50-1.20 (m, 14H), 1.10-0.75 (m, 8H), 0.65-0.50 (m, 1H).

LC/MS Rt=1.036 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₇ H ₄₀ NO ₂ [M+H] ⁺ 410.

Example 8. Synthesis connections 8

Step 1 (Compound 8). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, cyclohexamine (49.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (4 mL), and the reaction mixture was extracted with DCM (2×4 mL). The organic layers were washed with brine (2×5 mL), dried over _{Na2SO4 ,} filtered, concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel eluting with PE/EtOAc=3/1 to give the impure product. The impure product was recrystallized (85 °C) from MeCN (2 mL) and water (20 mL) to give compound 8 (86 mg, 69%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.20-5.05 (m, 1H), 3.85-3.70 (m, 1H), 2.25-2.10 (m, 1H), 2.09-2.00 (m , 1H), 1.95-1.55 (m, 12H), 1.54-1.30 (m, 8H), 1.29-1.00 (m, 16H), 0.66 (s, 3H ).

LC/MS Rt=1.176 min in 2.0 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C26H44NO2 [M ₊ H] ⁺ 402, found 402.

Example 9. Synthesis connections 9

Step 1. (Compound 9) To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methylcyclohexamine (56.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (4 mL), and the reaction mixture was extracted with DCM (2×4 mL). The organic layers were washed with brine (2×5 mL), dried over _{Na2SO4 ,} filtered, concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel eluted with PE/EtOAc=3/1 to give a solid, which was lyophilized to give compound 9 (44 mg, 34%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.55-4.45 (m, 0.5H), 3.80-3.70 (m, 0.5H), 2.90-2.70 (m, 3H), 2.69-2 .60 (m, 1H), 2.35-2.20 (m, 1H), 1.90-1.50 (m, 15H), 1.49-1.15 (m, 18H), 1.14 -1.00 (m, 3H), 0.73 (s, 3H).

LC/MS Rt=1.239 min in 2.0 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C27H46NO2 [M ₊ H] ⁺ 416, found 416.

Example 10. Synthesis connections 10

To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (112 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyltetrahydro-2H-pyran-4-amine (57.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (4 mL), and the reaction mixture was extracted with DCM (2×4 mL). The organic layers were washed with brine (2×5 mL), dried over _Na2SO4 , _filtered , concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel eluting with PE/EtOAc=3/1 to give the desired compound. The compound was lyophilized to give a solid (80 mg), which was further recrystallized (85 °C) from MeCN (2 mL) and water (20 mL) to give compound 10 (66 mg, 51%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.85-4.70 (m, 0.5H), 4.15-3.95 (m, 2H), 3.55-3.40 (m, 1.5H), 2.90-2 .70 (m, 3H), 2.69-2.60 (m, 1H), 2.35-2.20 (m, 1H), 1.90-1.60 (m, 10H), 1.59 -1.16 (m, 18H), 1.15-1.00 (m, 3H), 0.72 (s, 3H).

LC/MS Rt=1.005 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS _calcd for _C26H44NO3 [M ₊ H] ⁺ 418, found 418.

Example 11. Synthesis connections 11

Step 1 (Compound 1). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, pyridin-4-ylmethylamine (50.6 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (20 mL) was added. The mixture was extracted with DCM (2×20 mL), washed with brine (20 mL), dried over _Na2SO4 , concentrated in _vacuo to give the crude product, which was purified on a flash column (0~30% EtOAc in PE) to give compound 11 (68 mg, 53%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 8.56 (d,J=4.0 Hz, 2H), 7.20 (d,J=4.0 Hz, 2H), 5.68 (br.s, 1H), 4.51 (d, J=8 Hz, 1H), 4.44 (d,J=8 Hz, 1H), 2.22-2.15 (m, 2H), 1.91-1.79 (m, 5H), 1.75-1.62 (m, 3H), 1.50- 1.37 (m, 6H), 1.35-1.23 (m, 8H), 1.18-1.08 (m, 4H), 0.71 (s, 3H).

LC/MS Rt=1.453 min in 3.0 min chromatography, 10-80AB, ^{purity 100%, ESI MS calcd for C26H39N2O2 [M+H] +} _{411 , found 411} .

Example 12. Synthesis connections 12

Step 1 (Compound 12). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, pyridin-3-ylmethylamine (50.6 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h. Water (20 mL) was added. The mixture was extracted with DCM (2×20 mL), washed with brine (20 mL), dried over _Na2SO4 , concentrated in _vacuo to give the crude product, which was purified on a flash column (0~30% EtOAc in PE) to give compound 12 (63 mg, 49%) as a solid.

¹ H NMR (400M Hz, CDCl ₃ ) δ 8.55-8.53 (m, 2H), 7.65 (d, J =8.0 Hz, 1H), 7.27 (d, J =8, 0 Hz, 1H), 5.63-5.61 (m, 1H), 4.57-4.39 (m, 2H), 2.22-2.11 (m, 2H), 1.89-1 .74 (m, 5H), 1.72-1.61 (m, 3H), 1.49-1.36 (m, 6H), 1.31-1.19 (m, 8H), 1.17 -1.02 (m, 4H), 0.68 (s, 3H)

LC/MS _Rt =2.016 min in 4.0 min chromatography, 10-80AB, purity 100%, ESI MS _calcd for _C26H39N2O2 [M ₊ H] ⁺ 411, found 411.

Example 13. Synthesis connections 13

To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-1-(pyridin-4-yl)methylamine (57.1 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h, quenched with water (20 mL), and the reaction mixture was extracted with DCM (2×20 mL). The organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give compound 13 (81 mg, 61%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 8.59-8.54 (m, 2H), 7.15 (d, J=4.0 Hz, 1.4H), 7.07 (d,J=4.0 Hz, 0.6H), 5.00 (d,J=20 Hz, 0.3H), 4.89 (d,J=16 Hz, 0.7H), 4.37-4.26 (m, 1H), 3.03 (s, 2.2H), 2.96 (m, 0.8H), 2.81 (t, J=12 Hz 0.8H), 2.56 (t,J=12 Hz 0.2H) 2.34-2.26 (m, 1H), 1.81-1.74 (m, 4H), 1.72-1.61 (m, 3H), 1.52- 1.21 (m, 16H), 1.13-1.11 (m, 3H), 0.79 (s, 3H)

LC/MS Rt=1.491 min in 3.0 min chromatography, 10-80AB, ^{purity 100%, ESI MS calcd for C27H41N2O2 [M+H]+} _{425 , found 425} .

Example 14. Synthesis connections 14

To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-1-(tetrahydro-2H-pyran-4-yl)methylamine (64.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (15 mL), and the reaction mixture was extracted with DCM (2×10 mL). The organic layers were washed with brine, dried over _{Na2SO4 ,} filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0~40% EtOAc in PE) to give compound 14 (31 mg, 23%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.05-3.91 (m, 2H), 3.69-3.53 (m, 1H), 3.45-3.27 (m, 2H), 3.10-3.03 (m, 2H), 3.02-2.89 (m, 2H), 2.77-2.65 (m, 1H), 2.32-2.16 (m, 1H), 1.99-1.73 (m, 5H), 1.73-1.60 (m, 4H), 1.60-1.56 (m, 1H), 1.55-1.47 (m, 2H), 1.46-1.35 (m, 6H), 1.35-1.18 (m, 10H), 1.17-1.025 (m, 3H), 0.74 (s, 3H).

LC/MS _Rt =1.013 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C27H46NO3 [M ₊ H] ⁺ 432, found 432.

Example 15. Synthesis connections 15

To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 1 min, pyridin-2-ylmethylamine (53.9 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (15 mL), and the reaction mixture was extracted with DCM (2×10 mL). _The organic layers were washed with brine, dried over _Na2SO4 , concentrated in vacuo to give 110 mg of crude product, which was purified by preparative HPLC (Column: Kromasil 150*25mm*10μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Initial B: 40; Final B: 70; Gradient Time (min): 8; 100% B Retention Time (min): 2; Flow Rate (mL/min): 30; Injections: 6) and concentrated in vacuo to give compound 15 (26 mg, 24%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.58-8.50 (m, 1H), 7.70-7.62 (m, 1H), 7.30-7.27 (m, 1H), 7.21-7.16 (m , 1H), 6.64-6.48 (m, 1H), 4.62-4.53 (m, 2H), 2.30-2.16 (m, 1H), 2.03-1.95 (m, 1H), 1.89-1.76 (m, 4H), 1.74-1.59 (m, 4H), 1.50-1.36 (m, 6H), 1.34-1 .26 (m, 7H), 1.25-0.99 (m, 5H), 0.67 (s, 3H).

LC/MS _Rt =0.601 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS _{calcd for C26H39N2O2 [} M ₊ H] ⁺ 411, found 411.

Example 16. Synthesis connections 16

To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-1-(pyridin-3-yl)methylamine (60.9 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h, quenched with water (15 mL), and the reaction mixture was extracted with DCM (2×10 mL). _The combined organic layers were washed with brine, dried over _Na2SO4 , concentrated in vacuo to obtain 120 mg of crude product, which was purified by preparative HPLC (Column: Kromasil 150*25mm*10μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Initial B: 40; Final B: 70; Gradient Time (min): 8; 100% B Retention Time (min): 2; Flow Rate (mL/min): 30; Injections: 5) and concentrated to afford compound 16 (6 mg, 5%) as a solid. NMR of the compound revealed the presence of rotamers.

¹ H NMR(400 MHz, CDCl₃) δ 8.60-8.44 (m, 2H), 7.66-7.41 (m, 1H), 7.31-7.26 (m, 1H), 5.00-4.90 (m , 0.2H), 4.90-4.76 (m, 0.8H), 4.36-4.28 (m, 0.8H), 4.28-4.20 (m, 0.2H) , 2.94 (s, 2.4H), 2.85 (s, 0.6H), 2.75-2.67 (m, 0.8H), 2.67-2.60 (m, 0 ,2H), 2.35-2.23 (m, 1H), 1.87-1.62 (m, 9H), 1.51-1.38 (m, 6H), 1.36-1.27 (m, 5H), 1.25-1.19 (m, 2H), 1.15-1.05 (m, 3H), 0.83-0 .71 (m, 4H).

LC/MS _Rt =0.647 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS _calcd for _C27H41N2O2 [M ₊ H] ⁺ 425, found 425.

Example 17. Synthesis connections 17

Step 1 (Compound 17). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, cyclohexylmethanamine (56.4 mg, 0.499 mmol) was added. The mixture was stirred at 25 °C for 16 h and treated with water (15 mL). The mixture was extracted with DCM (2×10 mL). The organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated to give the crude product, which was purified _by flash chromatography on silica gel (0~30% EtOAc in DCM) to give compound 17 (23 mg, 18%) as a solid. The crude product was recrystallized from MeOH (15 mL) to give compound 17 (9 mg, 39%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.34-5.24 (m, 1H), 3.24-3.13 (m, 1H), 3.09-2.97 (m, 1H), 2.23-2.12 (m , 1H), 2.12-2.06 (m, 1H), 1.94-1.79 (m, 4H), 1.77-1.61 (m, 9H), 1.50-1.34 (m, 8H), 1.32-1.20 (m, 9H), 1.19-1.03 (m, 5H), 0.98-0.87 (m, 2H), 0.68 (s , 3H).

LC/MS Rt=1.197 min in 2 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C27H46NO2 [M ₊ H] ⁺ 416, found 416.

Example 18. Synthesis connections 18

Step 1 (Compound 18). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (213 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, N-methyl-2-phenylethanamine (63.2 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 1 h, treated with water (20 mL) and extracted with DCM (2×20 mL). The organic layers were washed with brine (20 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give _the crude product, which was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give compound 18 (39 mg, 29%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.37-7.26 (m, 2H), 7.26-7.12 (m, 3H), 4.00-3.83 (m, 1H), 3.42-3.23 (m , 1H), 2.94-2.97 (m, 3H), 2.87-2.76 (m, 2H), 2.67 (t, J=8.0 Hz, 0.6H), 2.43 (t,J=8.0 Hz, 0.4H), 2.31-2.08 (m, 1H), 1.88-1.75 (m, 3H), 1.71-1.58 (m, 4H), 1.50-1.30 (m, 7H), 1.30-0.97 (m, 12H), 0.68-0.70 (m, 3H).

LC/MS Rt=3.174 min in 4.0 min chromatography, 10-80AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₄ NO ₂ [M+H] ⁺ 438, found 438.

Example 19. Synthesis connections 19

Step 1 (Compound 19). To a solution of A2 (100 mg, 0.312 mmol) in DCM (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. 2-Phenylethanamine (37.8 mg, 0.312 mmol) was added. The mixture was stirred at 25 °C for 12 h, treated with water (20 mL) and extracted with DCM (2×20 mL). The organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give compound 19 (21 mg, 16%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.33-7.28 (m, 2H), 7.25-7.18 (m, 3H), 5.25-5.20 (m, 1H), 3.66-3.60 (m , 1H), 3.51-3.42 (m, 1H), 2.82 (t, J=8.0 Hz, 2H), 2.19-2.08 (m, 1H), 2.05-2.00 (m, 1H), 1.86-1.76 (m, 3H), 1, 74-1.59 (m, 5H), 1.48-1.32 (m, 7H), 1.30-1.22 (m, 6H), 1.15-1.00 (m, 5H), 0.62 (s, 3H).

LC/MS Rt=2.344 min in 4.0 min chromatography, 30-90AB, purity 98.4%, _ESI MS calcd for _C28H42NO2 [M ₊ H] ⁺ 424, found 424.

Example 20. Synthesis connections 20

Step 1 (Compound 20). To a solution of A2 (100 mg, 0.312 mmol) in DMF (5 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. ( R )-1-phenylethanamine (56.7 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 12 h, treated with water (20 mL) and extracted with DCM (2×20 mL). The organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give compound 20 (51 mg, 39%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.39-7.30 (m, 4H), 7.29-7.27 (m, 1H), 5.45-5.42 (m, 1H), 5.22-5.14 (m , 1H), 2.25-2.14 (m, 1H), 2.08 (t, J=8.0 Hz, 1H), 1.97-1.91 (m, 1H), 1.89-1.79 (m, 3H), 1.77-1.62 (m, 4H), 1. 50 (d, J=4.0 Hz, 3H), 1.47-1.34 (m, 6H), 1.32-1.20 (m, 8H), 1.18-1.04 (m, 4H), 0. 71 (s, 3H).

LC/MS Rt=3.095 min in 4.0 min chromatography, 10-80AB, purity 100%, _ESI MS calcd for _C28H42NO2 [M ₊ H] ⁺ 424, found 424.

Example 21. Synthesis connections 21

Step 1 (Compound 21): To a solution of A2 (100 mg, 0.312 mmol) in DMF (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 30 °C for 30 min, ( S ))-N-methyl-1-phenylethanamine (63.2 mg, 0.468 mmol) was added. The mixture was stirred at 30 °C for 16 h and then treated with water (8 mL). The precipitate was collected by filtration and purified by HPLC (Waters Xbridge (150mm*25mm, 5μm), water (10 _{mM NH4HCO3} )-ACN, gradient: 55-85% B, flow rate: 25 ml/min) to afford compound 21 (40 mg, 30%) as a solid.

¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.40-7.32 (m, 2H), 7.21-7.29 (m, 3H), 6.02-5.72 (m, 1H), 3.94-3.81 (m , 1H), 3.15-2.98 (m, 3H), 2.90-2.81 (m, 1H), 2.71-2.62 (m, 3H), 2.38-2.11 (m, 1H), 1.82-1.57 (m, 8H), 1.57-1.20 (m, 10H), 1.19-1.01 (s, 7H), 0.74 (s , 3H).

LC/MS Rt=1.174 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₄ NO ₂ [M+H] ⁺ 438, found 438.

Example 22. Synthesis connections 22

Step 1 (Compound 22) : To a solution of A2 (100 mg, 0.312 mmol) in DMF (4 mL) were added TEA (0.213 mL, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 30 °C. After stirring at 30 °C for 30 min, N-methyl-1-(pyridin-2-yl)methanamine (60.9 mg, 0.499 mmol) was added. The mixture was stirred at 30 °C for 16 h, treated with water (8 mL), filtered and concentrated. The crude product was purified by HPLC (Waters Xbridge (150mm*25mm, _5μm ), water (10 mM _NH4HCO3 )-ACN, gradient: 40-70% B, flow rate: 25 ml/min) to afford compound 22 (13 mg, 10%) as a solid.

¹ H NMR(400 MHz, DMSO-d ₆ ) δ 8.58-8.48 (m, 1H), 7.81-7.70 (m, 1H), 7.30-7.18 (m, 2H), 5.10-4.70 (m , 1H), 4.49-4.45 (m, 1H), 3.95-3.78 (m, 1H), 2.98-2.80 (m, 3H), 2.20-2.05 (m, 3H), 1.85-1.71 (m, 5H), 1.71-1.57 (m, 5H), 1.49-1.19 (m, 5H), 1.19-1 .10 (m, 5H), 1.10-0.98 (m, 4H), 0.70 (s, 3H).

LC/MS _Rt =0.668 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS _{calcd for C27H41N2O2 [} M ₊ H] ⁺ 425, found 425.

Example 23. Synthesis connections 23

Step 1 (Compound 23). To a solution of A2 (100 mg, 0.312 mmol) in DCM (2 mL) were added HATU (177 mg, 0.468 mmol), TEA (0.213 mL, 1.55 mmol) and azepane (108 mg, 1.09 mmol) at 25 °C. After stirring at 25 °C for 24 h, the mixture was poured into water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 0:1) and lyophilized to give compound 23 (78 mg, 62%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.90-3.70 (m, 2H), 3.30-3.15 (m, 2H), 2.70-2.60 (m, 1H), 2.25-2.15 (m, 1H), 1.85-1.55 (m, 13H), 1.54-1.45 (m, 8H), 1.44-1.05 (m, 13H), 0.76 (s, 3H).

LC/MS Rt=1.121 min in 2 _min chromatography, 30-90 AB, purity 98%, ESI calcd for _C26H44NO2 [M ₊ H] ⁺ 402, found 402.

Example 24. Synthesis connections 24

Step 1 (Compound 24). To a solution of A2 (100 mg, 0.312 mmol) in DCM (2 mL) were added HATU (177 mg, 0.468 mmol), TEA (0.213 mL, 1.55 mmol), and (tetrahydro-2H-pyran-4-yl)methanamine (125 mg, 1.09 mmol) at 25 °C. After stirring at 25 °C for 12 h, the mixture was poured into water (200 mL) and extracted with DCM (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=0:1) and lyophilized to give compound 24 (48 mg, 37%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.40-5.30 (m, 1H), 4.05-3.90 (m, 2H), 3.40-3.30 (m, 2H), 3.25-3.15 (m , 1H) 3.10-3.00 (m, 1H), 2.15-2.05 (m, 2H), 1.90-1.55 (m, 12H), 1.50-1.00 ( m, 19H), 0.67 (s, 3H).

LC/MS Rt=0.934 min in 2 _min chromatography, 30-90 AB, purity 97%, ESI calcd for _C26H44NO3 [M ₊ H] ⁺ 418, found 418.

Example 25. Synthesis connections 25

Step 1 (Compound 25). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring for 30 min, (R)-2-methylpiperidine (60.4 mg, 0.499 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was triturated with EtOAc (10 mL) and n -hexane (10 mL) to give compound 25 (23 mg, 18%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 5.11-3.76 (m, 2H), 3.31-2.99 (m, 1H), 2.77-2.54 (m, 1H), 2.42-2.26 (m, 1H), 1.88-1.74 (m, 3H), 1.73-1.53 (m, 10H), 1.51-1.20 (m, 17H), 1.19-1.10 (m, 5H), 0.70-0.65 (m, 3H)

LCMS , Rt=1.113 min in 2.0 min chromatography, 30-90AB, purity 97.674%, _{ESI MS calcd for C26H44NO2 [} M ₊ H] ⁺ 402, found 402.

Example 26. Synthesis connections 26

Step 1 (Compound 26). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. To the reaction mixture was added 1-cyclohexyl-N-methylmethanamine (60.4 mg, 499 mmol). The reaction mixture was stirred at 25 °C for 2 h. The residue was diluted with water (10 mL), extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc=3/1 to 1/1) to give compound 26 (76 mg, 57%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 3.62-3.49 (m, 1H), 3.02 (s, 1H), 2.93-2.85 (m, 2H), 2.77-2.65 (m, 1H), 2.32-2.19 (m, 1H), 1.88-1.58 (m, 14H), 1.50-1.23 (m, 15H), 1.23-0.81 (m, 9H ), 0.73 (m, 3H).

LC/MS Rt=1.228 min in 2.0 min chromatography, 30-90AB, purity 100%, _ESI MS calcd for _C28H48NO2 [M ₊ H] ⁺ 430, found 430.

Example 27. Synthesis connections 27

Step 1 (Compound 27). To a solution of A2 (100 mg, 0.312 mmol) in DCM (4 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. To the reaction mixture was added (S)-1-phenylethanamine (60.4 mg, 0.499 mmol). The reaction mixture was stirred at 25 °C for 2 h. The residue was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with EtOAc (10 mL) and n-hexane (10 mL) to give compound 27 (28 mg, crude) as a solid, which was purified by HPLC (Method: Column YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05% HCl)-ACN; Initial B: 60; Final B: 90; Gradient Time (min): 9.5; 100% B Retention Time (min): 2.5; Flow Rate (mL/min); 25) to give compound 27 (14 mg, 11%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.36-7.29 (m, 4H), 7.26-7.23 (m, 1H), 5.52-5.46 (m, 1H), 5.19-5.10 (m , 1H), 2.23-2.05 (m, 1H), 1.87-1.59 (t, 8H), 1.51-1.28 (m, 10H), 1.28-1.00 (m, 11H), 0.58 (s, 3H)

LC/MS Rt=2.327 min in 4.0 min chromatography, 30-90AB, purity 99%, _ESI MS calcd for _C28H42NO2 [M ₊ H] ⁺ 424, found 424.

Example 28. Synthesis connections 28

Step 1 (Compound 28). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. The mixture was stirred at 25 °C for 30 min. (S)-2-methylpiperidine (46.4 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with water (10 mL) and the reaction mixture was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give compound 28 (18 mg, 14%) as a solid.

¹ H NMR(400 MHz, DMSO-d ₆ , t=80°C) δ 4.80-4.47 (m, 1H), 4.18-3.83 (m, 2H), 2.99-2.82 (m, 1H), 2.79-2.69 (m, 1H), 2.21-2.02 (m, 2H), 1.82-1.57 (m, 9H), 1.56-1.46 (m, 3H), 1.45-1.18 (m, 11H), 1.17-0.96 (m, 10H), 0.67 (s, 3H).

LC/MS Rt=1.123 min in 2 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C26H44NO2 [M ₊ H] ⁺ 402, found 402.

Example 29. Synthesis connections 29

Step 1 (Compound 29). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added TEA (156 mg, 1.55 mmol) and HATU (177 mg, 0.468 mmol) at 25 °C. After stirring at 25 °C for 30 min, tetrahydro-2H-pyran-4-amine (47.3 mg, 0.468 mmol) was added. The mixture was stirred at 25 °C for 16 h and treated with water (10 mL). The mixture was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over _Na2SO4 , concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0~5% _MeOH in DCM) to give a solid. The crude residue (113 mg) was then triturated with MTBE (8 mL) at 15 °C to give compound 29 (80 mg, 71%) as a solid. The compound was dissolved in DCM (30 mL), and the solution was washed with citric acid (2 x 20 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo to give the crude product. The crude product was dissolved in MeCN/ _H2O =1/2 (30 mL), concentrated under vacuum to remove most of the MeCN, and lyophilized to give compound 29 (42 mg, 33%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.19-5.08 (m, 1H), 4.09-3.99 (m, 1H), 3.98-3.90 (m, 2H), 3.55-3.44 (m , 2H), 2.23-2.11 (m, 1H), 2.10-2.03 (m, 1H), 1.96-1.80 (m, 6H), 1.79-1.62 (m, 4H), 1.52-1.39 (m, 8H), 1.34-1.23 (m, 8H), 1.19-1.04 (m, 4H), 0.67 (s , 3H).

LC/MS Rt=0.902 min in 2 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for C ₂₅ H ₄₂ NO ₃ [M+H] ⁺ 404, found 404.

Example 30. Synthesis connections 30

Step 1 (Compound 30). To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added HATU (177 mg, 0.468 mmol) and Et ₃ N (156 mg, 1.55 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, (S)-3-phenylpyrrolidine (73.4 mg, 0.499 mmol) was added. The reaction mixture was stirred at 40 °C for 10 h, treated with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified on a flash column (0~30% EtOAc in PE) to give compound 30 (31 mg, 22%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.37-7.29 (m, 2H), 7.28-7.21 (m, 3H), 4.14-3.68 (m, 2H), 3.59-3.27 (m , 3H), 2.61-2.49 (m, 1H), 2.39-2.16 (m, 2H), 2.11-1.91 (m, 1H), 1.89-1.64 (m, 9H), 1.49-1.31 (m, 9H), 1.29-1.24 (m, 5H), 1.15-1.02 (m, 3H), 0.85-0 .78 (m, 3H).

LC/MS Rt=1.095 min in 2 _min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C30H44NO2 [M ₊ H] ⁺ 450, found 450.

SFC Rt=9.574 min in 15 min chromatography, IC_ETOH(DEA)_40_2.5ML_15MIN, 99% de. (Column: Chiralpak IC-3 150×4.6mm ID, 3μm; Mobile phase: 40% ethanol (0.05% DEA) in CO ₂ . Flow rate: 2.5 ml/min Column temperature: 40°C).

Example 31. Synthesis connections 31

Step 1 (Compound 31) To a solution of A2 (100 mg, 0.312 mmol) in DCM (3 mL) were added HATU (177 mg, 0.468 mmol) and Et ₃ N (156 mg, 1.55 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, (R)-3-phenylpyrrolidine (73.4 mg, 0.499 mmol) was added at 25 °C. The reaction mixture was stirred at 40 °C for 10 h and quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC (Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient 80%-100% B; Gradient time (min): 9.5) to give compound 31 (8 mg, 6%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.37-7.29 (m, 2H), 7.26-7.21 (m, 2H), 4.04-3.93 (m, 1H), 3.82-3.70 (m , 1H), 3.66-3.28 (m, 3H), 2.64-2.50 (m, 1H), 2.39-2.18 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.62 (m, 8H), 1.54-1.22 (m, 17H), 1.13-1.05 (m, 2H), 0.79 (s , 3H).

LC/MS Rt=1.090 min in 2.0 min chromatography, 30-90AB, purity ₁₀₀ %; ESI calcd for _C30H44NO2 [M ₊ H] ⁺ 450, found 450.

SFC Rt=11.297 min in 15 min chromatography, IC_ETOH(DEA)_40_2.5ML_15MIN, 100% de.(Column: Chiralpak IC-3 150×4.6mm ID, 3 μm; Mobile phase: 40% ethanol (0.05% DEA) in CO ₂ . Flow rate: 2.5 ml/min; Column temperature: 40°C).

Example 32. Synthesis connections 32

Step 1 (Compound 32). To a solution of A2 (200 mg, 0.624 mmol) in DCM (2 mL) were added HATU (355 mg, 0.936 mmol) and TEA (125 mg, 1.24 mmol). The mixture was stirred at 25 °C for 20 min. To the mixture was added (R)-N-methyl-1-phenylethanamine (126 mg, 0.936 mmol). The mixture was stirred at 25 °C for another 12 h. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by HPLC (Column: Xtimate C18 150*25mm*5μm, Gradient: 64-89% B, Conditions: water (0.05% HCl)-ACN, Flow Rate: 30 mL/min) to give compound 32 (50 mg) as a solid. Compound 32 was further purified by SFC (Column: OD (250mm*30mm,5μm), Conditions: 0.1% NH ₃ H ₂ O ETOH, Gradient: 35% to 30%, Flow Rate (mL/min): 50 mL/min, 25°C) to give compound 32 (35 mg, 13%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.37-7.23 (m,5H), 6.18 (sq.,J=12.0 Hz, 1H), 2.82-2.54 (m, 4H), 2.39-2.26 (m, 1H), 1.90-1.61 (m, 7H), 1, 56 (s, 3H), 1.50-1.20 (m, 16H), 1.16-1.05 (m, 3H), 0.81 (s, 3H).

LC/MS Rt=0.952 min in 1.5 min chromatography, 5-95AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₄ NO ₂ [M+H] ⁺ 438, found 438.

Example 33. Synthesis connections 33 And connections 34

Step 1 (Compound 33 and Compound 34) : To a solution of A2 (1 g, 3.12 mmol) in DCM (10 mL) were added HATU (1.77 g, 4.68 mmol) and TEA (1.57 g, 15.6 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added 1-(4-fluorophenyl)propan-1-amine (764 mg, 4.99 mmol) at 25 °C. The reaction mixture was stirred at 40 °C for 10 h. The reaction mixture was treated with water (20 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic phase was washed with water (2×20 mL) and brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~25% EtOAc in PE) to afford compound 33 (peak 1, 207 mg, 14%) and compound 34 (peak 2, 250 mg, 17%) as a solid.

(250 mg, 0.54 mmol) was further purified by flash column (0~25% EtOAc in PE) to afford compound 34 (150 mg,) as a fluffy solid. Compound 34 with impurities was re-purified by SFC (Chiralcel OJ 250*30mm, 5μm), gradient: 25-25% B (A=0.1% _NH3 / _H2O , B=EtOH), flow rate: 60 mL/min) to afford compound 34 (51 mg, 3%) as a solid.

Compound 33:

¹ H NMR (400 M Hz, CDCl3) δ 7.25-7.21 (m, 2H), 7.06-6.96 (m, 2H), 5.46-5.38 (d, J=7.6 Hz, 1H), 4.93-4.82 (sq., J=7.2 Hz,J=15.2 Hz, 1H), 2.22-2.04 (m, 2H), 2.02-1.91 (m, 1H), 1.89-1.62 (m, 10H), 1, 49-1.38 (m, 6H), 1.37-1.30 (m, 2H), 1.28-1.26 (m, 4H), 1.22-1.03 (m, 5H), 0.92-0.87 (t, J=7.2 Hz, 3H), 0.70 (s, 3H).

LC/MS Rt=1.100 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₃ FNO ₂ [M+H] ⁺ 456, found 456.

SFC Rt=3.350 min in 10 min chromatography, OJ-H_EtOH(DEA)_5_40_2.5M, 100%de. (Column: ChiralCel OJ-H 150×4.6mm ID, 5μm; Mobile phase: A: _CO2 B: Ethanol (0.05% DEA); Gradient: from 5% to 40% B in 5.5 min and maintaining 40% for 3 min, then 5% B for 1.5 min; Flow rate: 2.5ml/min Column temperature: 40°C).

SFC mixture of compound 33 and compound 34; Peak 1 : Rt=3.121 min and Peak 2 : Rt=3.372 min in 10 min chromatography, Conditions: OJ-H_EtOH(DEA)_5_40_2.5M (Column: ChiralCel OJ-H 150×4.6mm ID, 5μm Mobile phase: A: _CO2 B: Ethanol (0.05% DEA). Gradient: from 5% to 40% B in 5.5 min and maintaining 40% for 3 min, then 5% B for 1.5 min Flow rate: 2.5ml/min; Column temperature: 40°C).

Compound 34

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.21 (m, 2H), 7.04-6.96 (m, 2H), 5.49-5.41 (d,J=8 Hz, 1H), 4.89-4.81 (sq., J=7.6 Hz,J=15.2 Hz, 1H), 2.22-2.07 (m, 2H), 1.88-1.61 (m, 10H), 1.49-1.29 (m, 7H), 1, 28-1.23 (m, 5H), 1.22-0.94 (m, 6H), 0.92-0.84 (t, J=7.2 Hz, 3H), 0.50 (s, 3H).

LC/MS Rt=1.085 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₃ FNO ₂ [M+H] ⁺ 456, found 456.

SFC Rt=3.116 min in 10 min chromatography, OJ-H_EtOH(DEA)_5_40_2.5M, 100% de. (Column: ChiralCel OJ-H 150×4.6mm ID, 5μm; Mobile phase: A: _CO2 B: Ethanol (0.05% DEA); Gradient: from 5% to 40% B in 5.5 min and maintaining 40% for 3 min, then 5% B for 1.5 min; Flow rate: 2.5ml/min; Column temperature: 40°C).

Example 34. Synthesis connections 35

Step 1 (A3): To a solution of A2 (1 g, 3.12 mmol) in toluene (20 mL) were added 1,2-di(pyridin-2-yl)disulfane (1.37 g, 6.24 mmol) and triphenylphosphine (1.63 g, 6.24 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was immediately purified by silica gel chromatography (PE/EtOAc=5/1) to give A3 (750 mg, 58%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.62-8.61 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (d, J=8 Hz, 1H), 7.28-7.27 ( m, 1H), 2.73 (t, J=8 Hz, 1H), 2.26-2.20 (m, 2H), 1.89-1.71 (m, 7H), 1.49-1 .27 (m, 10H), 1.26-1.24 (m, 4H), 1.19-1.03 (m, 4H), 0.75 (s, 3H).

Step 2 (Compound 35). To a solution of A3 (100 mg, 0.242 mmol) in DCM (3 mL) was added AgOTf (62.1 mg, 0.242 mmol) followed by 1,2,3,4-tetrahydroquinoline (48.2 mg, 0.363 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the residue was washed with DCM (15 mL). The combined organic layers were washed with 1 M HCl (10 mL), brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 35 (125 mg, crude) as an oil. The crude product was purified by HPLC (Column: YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-CAN; Initial B: 80; Final B: 100; Gradient Time (min): 10; 100% B Retention Time (min): 1; Flow Rate (mL/min): 25) to give compound 35 (4 mg, 4%) as a solid.

LC/MS Rt=1.126 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₂ NO ₂ [M+H] ⁺ 436, found 436.

¹ H NMR(400 MHz, CDCl₃) δ 7.24-7.04 (m, 4H), 4.44-4.19 (m, 1H), 3.40-3.10 (m, 2H), 2.82-2.58 (m , 2H), 2.37-2.01 (m, 3H), 1.86-1.70 (m, 7H), 1.41-1.23 (m, 13H), 1.08-0.92 (m, 5H), 0.74 (s, 4H).

Example 35. Synthesis connections 36

Step 1 (Compound 36). To a solution of A3 (150 mg, 0.362 mmol) in DCM (3 mL) was added AgOTf (93 mg, 0.362 mmol) followed by the addition of 4-amino-3-methylbenzonitrile (71.7 mg, 0.543 mmol) at 25 °C. After stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was filtered and the residue was washed with DCM (15 mL). The combined organic layers were washed with 1 M HCl (10 mL), brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 36 (130 mg, crude) as an oil. Crude compound 36 (125 mg, 0.2869 mmol) was purified by HPLC (Method: Column: YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN Initial B: 70; Final B: 100; Gradient Time (min): 10; 100% B Retention Time (min): 1; Flow Rate (mL/min): 25) to give compound 36 (8 mg, 6%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.38-8.31 (m, 1H), 7.55-7.48 (m, 1H), 7.46 (s, 1H), 6.96 (s, 1H), 2.40- 2.22 (m, 5H), 2.09-1.99 (m, 1H), 1.88-1.75 (m, 6H), 1.50-1.39 (m, 7H), 1. 35-1.24 (m, 9H), 1.17-1.06 (m, 3H), 0.75 (s, 3H).

LC/MS _Rt =1.081 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS _{calcd for C28H39N2O2 [} M ₊ H] ⁺ 435, found 435.

Example 36. Synthesis connections 37

Step 1 (Compound 37). To a solution of A3 (150 mg, 0.362 mmol) in DCM (3 mL) was added AgOTf (93 mg, 0.362 mmol) followed by the addition of 2-amino-5-fluorobenzonitrile (73.9 mg, 0.543 mmol) at 25 °C. After stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was filtered and the residue was washed with DCM (15 mL). The combined organic layers were washed with 1 M HCl (10 mL), brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford compound 37 (136 mg, crude) as an oil. Crude compound 37 (125 mg, 0.2869 mmol) was purified by HPLC (Method: Column: YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN Initial B: 70; Final B: 100; Gradient Time (min): 10; 100% B Retention Time (min): 1; Flow Rate (mL/min): 25) to give compound 37 (2 mg, 2%) as a solid.

LC/MS Rt=1.044 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS _calcd for _C27H34FN2O [M _{+ HH2O} ] ⁺ 421, found 421.

¹ H NMR(400 MHz, CDCl₃) δ 8.48-8.40 (m, 1H), 7.49-7.42 (s, 1H), 7.33-7.27 (m, 2H), 2.44-2.35 (m , 1H), 2.34-2.21 (m, 1H), 2.19-2.07 (m, 1H), 1.93-1.71 (m, 6H), 1.52-1.37 (m, 7H), 1.36-1.21 (m, 9H), 1.19-1.01 (m, 3H), 0.75 (s, 3H).

Example 37. Synthesis connections 38

The synthesis of B1 is disclosed in WO2014/169833.

Step 1 (Compound 38). To a solution of B1 (200 mg, 0.503 mmol) in DMF (5 mL) were added aniline (56.2 mg, 0.604 mmol) and TEA (151 mg, 1.50 mmol) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was poured into saturated aqueous LiCl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (2×50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to give a fluffy solid, which was purified by preparative HPLC (Column: YMC-Actus Triart C18 150*30mm, 5μm; Conditions: water (0.05% HCl)-ACN; Gradient 46%-76% B; Gradient time (min): 8) and lyophilized to give compound 38 (42.0 mg, 21%) as a fluffy solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.15 (m, 2H), 6.72-6.68 (m, 1H), 6.62-6.55 (m, 2H), 4.72-4.65 (m , 1H), 4.00-3.85(m, 2H), 3.52-3.45 (m, 1H), 2.60-2.53 (m, 1H), 2.30-2.15 (m, 1H), 2.00-1.55 (m, 8H), 1.50-1.20(m, 14H), 1.15-0.90 (m, 3H), 0.65(s , 3H).

LC/MS Rt=1.160 min in 2.0 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C27H40NO2 [M ₊ H] ⁺ 410, found 410.

Example 38. Synthesis connections 39

Step 1 (Compound 39). To a solution of B1 (200 mg, 0.503 mmol) in DMF were added N-methylaniline (64.6 mg, 0.604 mmol) and TEA (151 mg, 1.50 mmol) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was poured into aqueous LiCl (50 mL, 1N) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give a loose solid. The crude product was purified by preparative HPLC (Column: YMC-Actus Triart C18 150*30mm, 5μm; Conditions: water (0.05% HCl)-ACN; Gradient 46%-76% B; Gradient time (min): 8) to afford compound 39 (50 mg, containing residual ammonium salt) as a fluffy solid. The product was dissolved in DCM (5 mL) and washed with aqueous _NaHCO3 (10 mL). The aqueous layer was extracted with DCM (2×10 mL). The combined organic phase was dried over anhydrous _{Na2SO4 ,} filtered and concentrated to afford compound 39 (21 mg, 10%) as a fluffy solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.15 (m, 2H), 6.72-6.68 (m, 1H), 6.62-6.55 (m, 2H), 4.10-3.98 (m , 2H), 3.00 (s, 3H), 2.62-2.53 (m, 1H), 2.18-2.07 (m, 1H), 1.98-1.92 (m, 1H ), 1.85-1.55 (m, 7H), 1.50-1.35 (m, 7H), 1.35-1.18 (m, 8H), 1.18-1.00 (m , 3H), 0.67(s, 3H).

LC/MS Rt=1.182 min in 2.0 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C28H42NO2 [M ₊ H] ⁺ 424, found 424.

Example 39. Synthesis connections 40

Step 1 (Compound 40). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) were added 4-fluoroaniline (33.4 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C under N ₂ atmosphere. The mixture was stirred at 25 °C for 16 h to give a yellow solution. The mixture was concentrated to give a fluffy solid. The solid was purified by preparative HPLC (Column: Phenomenex Gemini 150*25mm*10μm; Conditions: water (0.05% HCl)-ACN; Gradient 60%-100% B; Gradient time (min): 10) to give compound 40 (25 mg, 23%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 6.95-6.86 (m, 2H), 6.68-6.60 (m, 2H), 4.00-3.85 (m, 2H), 2.58-2.52 (m , 1H), 2.26-2.12 (m, 1H), 1.95-1.55 (m, 9H), 1.50-1.14 (m, 15H), 1.14-0.96 (m, 3H), 0.63(s, 3H).

LC/MS Rt=0.962 min in 1.5 min chromatography, 5-95 AB, purity 100%, _{ESI MS calcd for C27H39FNO2 [} M ₊ H] ⁺ 428, found 428.

Example 40. Synthesis connections 41

Step 1 (Compound 41). To a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) were added 3-fluoroaniline (33.4 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C under N ₂ atmosphere. The mixture was stirred at 25 °C for 16 h to give a yellow solution. The mixture was concentrated to give a fluffy solid. The solid was purified by preparative HPLC (Column: Phenomenex Gemini 150*25mm*10μm; Conditions: water (0.05% HCl)-ACN; Gradient 60%-100% B; Gradient time (min): 10) to give compound 41 (7 mg, 7%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.13-7.05 (m, 1H), 6.45-6.33 (m, 2H), 6.30-6.22 (m, 1H), 3.96-3.83 (m , 2H), 2.58-2.52 (m, 1H), 2.26-2.12 (m, 1H), 2.02-1.55 (m, 10H), 1.50-1.14 (m, 14H), 1.14-0.93 (m, 3H), 0.65 (s, 3H).

LC/MS Rt=0.988 min in 1.5 min chromatography, 5-95 AB, purity 100%, _{ESI MS calcd for C27H39FNO2 [} M ₊ H] ⁺ 428, found 428.

Example 41. Synthesis connections 42

Step 1 (Compound 42): To a suspension of diisopropylethylamine (42.1 mg, 0.326 mmol) in DMF (5 mL) was added 3-fluoro-N-methylaniline (62.7 mg, 0.502 mmol) at 25 °C under N ₂ atmosphere. After stirring at 25 °C for 30 min, a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) was added. The mixture was stirred at 40 °C for 16 h to give a yellow solution. The mixture was concentrated to give the product as a light yellow oil (150 mg, crude), which was purified by HPLC (Column: Phenomenex Gemini C18 250*50 10u; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Gradient 80%-90% B; Gradient time (min): 8) to give compound 42 (11 mg, 10%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.13-7.05 (m, 1H), 6.40-6.20 (m, 3H), 4.08-3.98 (m, 2H), 2.98 (s, 3H), 2.60-2.50 (m, 1H), 2.22-2.08 (m, 1H), 2.05-1.95 (m, 1H), 1.90-1.50 (m, 7H ), 1.50-1.35(m, 7H), 1.35-1.20(m, 8H), 1.20-1.00(m, 3H), 0.67(s, 3H).

LC/MS Rt=1.197 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for C28H41FNO2 [M+H] ⁺ 442, found 442.

Example 42. Synthesis connections 43

Step 1 (Compound 43): To a solution of B1 (100 mg, 0.251 mmol) in DMF (5 mL) were added 4-fluoro-N-methylaniline (37.6 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 16 h to give a yellow solution. The reaction mixture was concentrated to give a fluffy solid. The solid was purified by preparative HPLC (Column: Phenomenex Gemini 150*25mm*10μm; Conditions: water (0.05%HCl)-ACN; Gradient 60%-100% B; Gradient time (min): 10) to give compound 43 (30 mg, 27%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 6.95-6.86 (m, 2H), 6.58-6.47 (m, 2H), 4.05-3.95 (m, 2H), 2.97 (s, 3H), 2.60-2.52 (m, 1H), 2.18-2.07 (m, 1H), 1.96-1.51 (m, 9H), 1.51-1.02 (m, 17H ), 0.66 (s, 3H).

LC/MS Rt=0.971 min in 1.5 min chromatography, 5-95 AB, purity 100%, _{ESI MS calcd for C28H41FNO2 [} M ₊ H] ⁺ 442, found 442.

Example 43. Synthesis connections 44

The synthesis of C1 is disclosed in WO2015/180679.

Step 1 (C2). Liquid bromine (6.55 g, 41.0 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (54.6 mL, 3 M, 164 mmol) at 0 °C. When all the bromine had dissolved, the mixture was diluted with cold dioxane (15 mL) and slowly added to a stirred solution of C1 (5 g, 13.7 mmol) in dioxane (20 mL) and water (15 mL). The homogeneous yellow solution slowly decolorized and a white precipitate formed, and the reaction mixture was stirred at 25 °C for 5 h. The remaining oxidizing reagent was blocked with an aqueous solution of Na ₂ S ₂ O ₃ (30 mL), and the mixture was then heated to 80 °C until the solid dissolved. The solution was acidified with HCl (3 M, 40 mL) resulting in a solid precipitate. The solid was filtered and washed with water (3 x 100 mL) to give a solid which was dried under vacuum to give C2 (5 g, crude) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 11.89 (br.s, 1H), 4.13 (br.s, 1H), 3.46 (sq., J=7.0 Hz, 2H), 3.32-3.26 (m , 2H), 2.29 (t, J=9.2 Hz, 1H), 1.99-1.89 (m, 2H), 1.78-1.46 (m, 7H), 1.41-1.14 (m, 11H), 1, 11 (t, J=7.0 Hz, 3H), 1.07-0.91 (m, 3H), 0.62 (s, 3H).

Step 2 (Compound 44). To a solution of C2 (100 mg, 0.274 mmol) in DCM (3 mL) were added HATU (156 mg, 0.411 mmol) and _Et3N (137 mg, 1.36 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added 1,2,3,4-tetrahydroisoquinoline (54.7 mg, 0.411 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by HPLC (Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Initial B: 80 Final B: 100; Gradient Time (min): 8; 100% B Retention Time (min): 2; Flow Rate (mL/min): 25; Injections: 8) to afford compound 44 (65.0 mg, 50%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.26-7.02 (m, 4H), 4.88-4.65 (m, 2H), 4.00-3.65 (m, 2H), 3.56-3.36 (m , 4H), 2.90-2.66 (m, 3H), 2.35 (m, 1H), 1.80-1.56 (m, 9H), 1.56-0.96 (m, 17H ), 0.76-0.72 (m, 3H).

LC/MS Rt=0.971 min in 1.5 min chromatography, 5-95 AB, purity 100%, ESI MS calcd for C ₃₁ H ₄₆ NO ₃ [M+H] ⁺ 480, found 480.

Example 44. Synthesis connections 45 And connections 46

Step 1 (D2). To a solution of commercially available D1 (10 g, 46.6 mmol) in THF (60 mL) was added Lawesson's reagent (9.42 g, 23.3 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo. To the residue was added NaHCO ₃ (120 mL, sat.), and the mixture was stirred at 20 °C for 1 h. The mixture was filtered, the precipitate was washed with water (2 x 50 mL), and dried in vacuo to yield D2 (9.5 g, 89%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.49 (br., 2H), 4.65 (dd. J=3.6, 8.4 Hz, 1H), 3.70-3.30 (m, 2H), 2.70-1.80 (m, 4H), 1.46 (s, 9H).

LC/MS Rt=0.814 min in 2.0 min chromatography, 10-80, purity 100%, ESI MS calcd for C ₅ H ₁₁ N ₂ S [M+H-Me ₂ C=CH ₂ -CO ₂ ] ⁺ 131, found 131.

Step 2 (D3). To a solution of D2 (5 g, 21.7 mmol) in DME (250 mL) were added _KHCO3 (17.3 g, 173 mmol) and bromoacetone (8.91 g, 65.1 mmol). The mixture was stirred at 20 °C for 1 h. To the mixture were added pyridine (14.5 g, 184 mmol) and TFAA (18.2 g, 86.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. To the mixture was added _NaHCO3 (150 mL, sat.), and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with water ( ₂₀₀ mL), dried over _Na2SO4 , filtered, concentrated in vacuo and purified on a flash column (0~20% EtOAc in PE) to give D3 (3.6 g, 62%) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 6.73 (s, 1H), 5.38-5.00 (m, 1H), 3.69-3.37 (m, 2H), 2.41 (s, 3H), 2.38- 2.11 (m, 2H), 2.00-1.82 (m, 2H), 1.54-1.29 (m, 9H).

LC/MS Rt=1.059 min in 2.0 min chromatography, 10-80, purity 97.4% (220 nm), ESI MS calcd for C ₁₃ H ₂₁ N ₂ O ₂ S [M+H] ⁺ 269, found 269.

Step 3 (D4). To D3 (3.6 g, 13.4 mmol) was added HCl/dioxane (20 mL, 4 M). The mixture was stirred at 20 °C for 15 min. The mixture was concentrated in vacuo. The residue was dissolved in water (25 mL) and washed with MTBE (20 mL). The aqueous phase was basified with Na ₂ CO ₃ (sat.) until pH = 10. The mixture was extracted with MTBE (2 x 20 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give 5-methyl-2-(pyrrolidin-2-yl)thiazole , D4 (1 g, 90% purity, 40% yield) as a light brown oil.

¹ H NMR(400 MHz, CDCl₃) δ 6.73 (s, 1H), 4.52 (dd, J=6.4 Hz, 8.0 Hz, 1H), 3.18-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.40 (s, 3H), 2 .34-2.22 (m, 1H), 2.21-2.04 (br., 1H), 2.00-1.75 (m, 5H).

LC/MS Rt=0.544 min in 2.0 min chromatography, 0-30 AB, purity 100%, ESI MS calcd for C ₈ H ₁₃ N ₂ S [M+H] ⁺ 169, found 169.

Step 4 (Mixture of compound 45 and compound 46). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (312 mg, 0.822 mmol) and _Et3N (275 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added 5-methyl-2-(pyrrolidin-2-yl)thiazole (D4, 138 mg, 0.822 mmol) at 25 °C. After stirring at 25 °C for 10 h, the reaction was quenched with ice water (20 mL) and the reaction mixture was extracted with DCM (3×5 mL). _The combined organic phase was dried over anhydrous _Na2SO4 , filtered, concentrated to give a racemic mixture of compound 45 and compound 46 (200 mg) as an oil, which was further purified.

LC/MS Rt=0.902 min in 1.5 min chromatography, 5-95AB, ^{purity 65%, ESI MS calcd for C30H47N2O3S [M+H]+} _{515 , found 515} .

Step 5 (Compound 45 and Compound 46): A racemic mixture of compound 45 and compound 46 with impurities (200 mg, 0.388 mmol) was separated by SFC (Column: AD (250 mm * 30 mm, 5 μm), gradient: 45-45% B (A = 0.05% NH ₃ /H ₂ O, B = MeOH), flow rate: 60 mL/min) to give compound 45 (Peak 1, 33 mg, 16%) and compound 46 (Peak 2, 43 mg, 21%) as a solid.

SFC Peak 1: Rt=5.407 min and Peak 2 Rt=7.126 min in 10 min chromatography, AD_3_IPA_DEA_5_40_25ML. (Column: Chiralpak AD-3 150×4.6mm ID, 3μm Mobile phase: A: _CO2 B: isopropanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5ml/min; Column temperature: 35°C).

Compound 45

¹ H NMR(400 MHz, CDCl₃) δ 6.83-6.67 (m, 1H), 5.49-5.22 (m, 1H), 3.79-3.59 (m, 2H), 3.56-3.37 (m , 4H), 2.75-2.68 (m, 1H), 2.60-2.53 (m, 1H), 2.50-2.37 (m, 3H), 2.32-1.90 (m, 6H), 1.88-1.65 (m, 7H), 1.49-1.25 (m, 9H), 1.22-1.19 (m, 3H), 1.18-0 .99 (m, 4H), 0.98-0.93 (m, 1H), 0.83 (s, 3H).

LC/MS Rt=1.261 min in 2.0 min chromatography, 10-80AB, ^{purity 100%, ESI MS calcd for C30H47N2O3S [M+H]+} _{515 , found 515} .

SFC Rt=5.390 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25ML, 100% de. (Column: Chiralpak AD-3 150×4.6mm ID, 3μm Mobile phase: A: _CO2 B: isopropanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C).

Compound 46

¹ H NMR(400 MHz, CDCl₃) δ 6.80-6.64 (m, 1H), 5.60-5.35 (m, 1H), 3.86-3.73 (m, 1H), 3.64-3.34 (m , 5H), 2.85-2.55 (m, 2H), 2.49-2.36 (m, 3H), 2.33-2.15 (m, 3H), 2.08-1.94 (m, 2H), 1.89-1.58 (m, 8H), 1.51-1.33 (m, 7H), 1.32-1.02 (m, 10H), 0.74 (s , 3H).

LC/MS Rt=1.271 min in 2.0 min chromatography, 10-80AB, ^{purity 100%, ESI MS calcd for C30H47N2O3S [M+H]+} _{515 , found 515} .

SFC Rt=7.166 min in 10 min chromatography, AD_3_EtOH_DEA_5_40_25ML, 99.8% de. (Column: Chiralpak AD-3 150×4.6mm ID, 3μm Mobile phase: A: _CO2 B: isopropanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C).

Example 45. Synthesis connections 47

To a solution of C2 (200 mg, 0.548 mmol) in DMF (5 mL) were added HATU (312 mg, 0.822 mmol) and _Et3N (275 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added 4-fluoro-2,6-dimethylaniline (114 mg, 0.822 mmol) at 25 °C. After stirring at 50 °C for 10 h, the reaction was quenched with water (20 mL) and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with 3% aqueous LiCl solution (2×20 mL), dried over _{anhydrous Na2SO4} , filtered, concentrated and purified by flash chromatography on silica gel (0-40% EtOAc in PE) to give 50 mg of impure product, which was purified by preparative HPLC (Column: YMC-Actus Triart C18 100*30mm*5μm), gradient: 80-100% B (A=water (0.05%HCl), B=MeCN), flow rate: 25 mL/min) to give compound 47 (12 mg, 24%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 6.82-6.72 (m, 2H), 6.58-6.48 (m, 1H), 3.61-3.33 (m, 4H), 2.88-2.59 (m , 1H), 2.39-2.31 (m, 1H), 2.20 (s, 6H), 2.13-2.05 (m, 1H), 1.94-1.58 (m, 9H ), 1.52-1.35 (m, 7H), 1.30-1.06 (m, 9H), 0.81 (s, 3H).

LC/MS Rt=1.313 min in 2.0 min chromatography, 10-80AB, purity 100%, ESI MS _{calcd for C30H45FNO3 [} M ₊ H] ⁺ 486, found 486.

Example 46. Synthesis connections 48 And connections 49

Step 1 (Compound 48). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (312 mg, 0.822 mmol) and _Et3N (275 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added (R)-4-(1-aminoethyl)benzonitrile (120 mg, 0.822 mmol) at 25 °C. After stirring at 25 °C for 10 h, the reaction was quenched with water (20 mL) and the reaction mixture was extracted with EtOAc (3×5 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (0-60% EtOAc in PE) and preparative TLC (PE:EtOAc=1:1) to give compound 48 (150 mg, 55%) as a solid.

¹ H NMR(400 MHz, CDCl₃) 7.65-7.59 (m, 2H), 7.44-7.37 (m, 2H), 5.52-5.44 (m, 1H), 5.22-5.11 (m, 1H), 3.57-3.49 (m, 2H), 3.48-3.38 (m, 2H), 2.74 (s, 1H), 2.21-2.07 (m, 2H) , 1.95-1.88 (m, 1H), 1.87-1.62 (m, 7H), 1.51-1.32 (m, 9H), 1.32-1.24 (m, 3H), 1.23-1.18 (m, 4H), 1.17-1.02 (m, 4H), 0.68 (s, 3H).

LC/MS Rt=4.765 min in 7.0 min chromatography, 10-80AB, ^{purity 100%, ESI MS calcd for C31H45N2O3 [M+H]+} _{493 , found 493} .

Step 2 (E1). To a solution of compound 48 (120 mg, 0.275 mmol) in DCM (3 mL) were added imidazole (198 mg, 2.91 mmol) and TMSCl (236 mg, 2.18 mmol) at 20 °C. After stirring at 20 °C for 30 min, the reaction was quenched with water (10 mL) and the mixture was extracted with DCM (2 x 5 mL). The combined organic layers were washed with water (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give E1 (137 mg, crude) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.65-7.59 (m, 2H), 7.44-7.37 (m, 2H), 5.52-5.44 (m, 1H), 5.22-5.11 (m , 1H), 3.54-3.32 (m, 4H), 2.22-2.09 (m, 2H), 1.97-1.88 (m, 1H), 1.81-1.65 (m, 7H), 1.52-1.41 (m, 6H), 1.38-1.16 (m, 11H), 1.10-0.97 (m, 3H), 0.69 (s , 3H), 0.11 (s, 9H).

Step 3 (E2). To a solution of E1 (137 mg, 0.242 mmol) in DMF (3 mL) was added NaH (96.6 mg, 2.42 mmol, 60% pure) at 0 °C. After stirring at 0 °C under N ₂ for 10 min, MeI (515 mg, 3.63 mmol) was slowly added at 0 °C under N ₂ . After stirring at this temperature for 10 min, the reaction was quenched with water (10 mL) and the reaction mixture was extracted with EtOAc (2 x 5 mL). The combined organic phase was washed with LiCl (10 mL, 3% aqueous solution), dried over Na ₂ SO ₄ , filtered and concentrated to give E2 (140 mg, crude) as a brown oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.71-7.57 (m, 2H), 7.41-7.34 (m, 2H), 6.21-6.12 (m, 0.84 H), 5.41-5, 28 (m, 0.16H), 3.55-3.31 (m, 4H), 2.78-2.62 (m, 4H), 2.37-2.25 (m, 1H), 1 .82-1.65 (m, 9H), 1.53-1.39 (m, 8H), 1.36-1.29 (m, 5H), 1.15-1.04 (m, 6H) , 0.91-0.75 (m, 3H), 0.10 (s, 9H).

Step 4 (Compound 49). A solution of E2 (140 mg, 0.241 mmol) in TBAF (2.4 mL, 2.4 mmol, 1 M in THF) was heated at 30 °C for 30 min. The reaction was quenched with 50% NH ₄ Cl (10 mL) and the mixture was extracted with EtOAc (2 x 5 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography on silica gel (0-15% EtOAc in PE) to give compound 49 (18 mg, 15%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.71-7.57 (m, 2H), 7.41-7.34 (m, 2H), 6.21-6.12 (m, 0.84 H), 5.41-5, 28 (m, 0.16H), 3.59-3.33 (m, 4H), 2.79-2.56 (m, 5H), 2.36-2.21 (m, 1H), 1 .85-1.61 (m, 8H), 1.52-1.33 (m, 10H), 1.32-1.23 (m, 3H), 1.22-1.17 (m, 4H) , 1.16-1.06 (m, 3H), 0.91-0.75 (m, 3H).

LC/MS _Rt =1.126 min in 2.0 min chromatography, 30-90AB, purity 100%, ESI _MS calcd for _C32H47N2O3 [M ₊ H] ⁺ 507, found 507.

Example 47. Synthesis connections 50

Step 1 (Compound 50). To a solution of C2 (100 mg, 0.274 mmol) in DCM (3 mL) were added HATU (156 mg, 0.411 mmol) and TEA (137 mg, 1.36 mmol) at 25 °C. After stirring at 25 °C for 10 min, piperidine (34.9 mg, 0.411 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 1 h and quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC (Instrument: BQ; Method: YMC-Actus Triart C18 Column 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Initial B: 80; Final B: 100; Gradient Time (min): 8; 100% B Retention Time (min): 2; Flow Rate (mL/min): 25; Injections: 7) to give compound 50 (78 mg, 66%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.65-3.38 (m, 8H), 2.75-2.65 (m, 2H), 2.38-2.25 (m, 1H), 1.86-1.56 (m , 12H), 1.50-1.00 (m, 19H), 0.72 (s, 3H).

LC/MS Rt=1.104 min in 2 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for C ₂₇ H ₄₆ NO ₃ [M+H] ⁺ 432, found 432.

Example 48. Synthesis connections 51

Step 1 (Compound 51). To a solution of C2 (100 mg, 0.274 mmol) and 4-fluoro-2-methylaniline (41.0 mg, 0.328 mmol) in DCM (3 mL) were added EDCI (78.7 mg, 0.411 mmol) and DMAP (16.7 mg, 0.137 mmol). The mixture was stirred at 30 °C for 3 h. The reaction was quenched with water (5 mL) and the reaction mixture was extracted with DCM (2×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by HPLC (Column: Xtimate C18 150*25mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient: 60%~90% B; Flow rate: 30 mL/min) to give compound 51 (23 mg, 18%) as a solid.

^1H NMR (400 MHz, _CDC13 ) δ 7.78-7.72 (m, 1H), 6.92-6.85 (m, 2H), 6.72 (s, 1H), 3.58 -3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.35-2.21 (m, 5H), 2.09-2.02 (m, 1H), 1 .88-1.71 (m, 6H), 1.69-1.62 (m, 2H), 1.52-1.34 (m, 8H), 1.31-1.09 (m, 9H) , 0.77 (s, 3H).

LC/MS Rt=1.123 min in 2.0 min chromatography, 30-90AB, 100% purity (HPLC), ESI MS calc. for C ₂₉ H ₄₃ FNO ₃ [M+H] ⁺ 472, found 472.

Example 49. Synthesis of compound 52

Step 1 (C3) : To a solution of C2 (1 g, 2.74 mmol) in toluene (20 mL) were added 1,2-di(pyridin-2-yl) (1.2 g, 5.48 mmol) and triphenylphosphine (1.43 g, 5.48 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was purified by silica gel chromatography (PE/EtOAc=5/1) to give C3 (800 mg, 64%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.62-8.61 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (d, J=8 Hz, 1H), 7.28-7.27 (m, 1H), 3.53 (sq., J=7 Hz, 2H), 3.43 (sq.,J=9.3 Hz, 2H), 2.79-2.68 (m, 2H), 2.28-2.16 (m, 2H), 1.94-1.60 (m, 8H), 1, 50-1.33 (m, 7H), 1.30-1.03 (m, 9H), 0.74 (s, 3H).

Step 2 (Compound 52): To a solution of C2 (100 mg, 0.218 mmol) in DCM (3 mL) was added AgOTf (56 mg, 0.218 mmol) followed by the addition of 1,2,3,4-tetrahydroquinoline (43.5 mg, 0.327 mmol) at 25 °C. After stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (15 mL). The combined organic layers were washed with 1M HCl (10 mL), brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give an oil (95 mg), which was purified by HPLC ( _Column : YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient: 85% B~100% B; Flow rate: 25 mL/min) to give compound 52 (16 mg, 17%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.23-7.02 (m, 4H), 4.42-4.22 (m, 1H), 3.54-3.48 (m, 2H), 3.43-3.34 (m , 2H), 3.32-3.12 (m, 2H), 2.79-2.59 (m, 3H), 2.34-2.20 (m, 1H), 2.13-2.03 (m, 1H), 1.82-1.63 (m, 6H), 1.52-1.35 (m, 6H), 1.34-1.24 (m, 4H), 1.22-1 .14 (m, 5H), 1.10-0.83 (m, 5H), 0.73 (s, 3H).

LC/MS Rt=1.190 min in 2.0 min chromatography, 30-90AB, ^{purity 100%, ESI MS calcd for C31H46NO3 [M+H]+} _{480 , found} 480.

Example 50. Synthesis connections 53

Step 1 (Compound 53): To a solution of C3 (100 mg, 0.218 mmol) in DCM (3 mL) was added AgOTf (56 mg, 0.218 mmol), followed by the addition of 2-amino-5-fluorobenzonitrile (44.5 mg, 0.327 mmol) at 25 °C. After stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (15 mL). The combined organic layers were washed with 1M HCl (10 mL), brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give an oil (90 mg), which was purified by HPLC ( _Column : YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient: 75%B~100%B; Flow rate: 25 mL/min) to give compound 53 (18 mg, 20%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.46-8.40 (m, 1H), 7.45 (s, 1H), 7.34-7.26 (m, 2H), 3.57-3.50 (m, 2H), 3.48-3.38 (m, 2H), 2.71 (s, 1H), 2.43-2.36 (m, 1H), 2.33-2.21 (m, 1H), 2. 16-2.09 (m, 1H), 1.92-1.72 (m, 6H), 1.66-1.59 (m, 2H), 1.52-1.38 (m, 7H), 1.34-1.25 (m, 3H), 1.24-1.17 (m, 4H), 1.16-1.07 (m, 2H), 0.75 (s, 3H).

¹⁹ F NMR(400 MHz, CDCl₃) δ -116.43 (s).

LC/MS _Rt =1.094 min in 2.0 min chromatography, 30-90AB, purity 100%, ESI MS _calcd for _C29H40FN2O3 [M ₊ H] ⁺ 483, found 483.

Example 51. Synthesis connections 54

Step 1 (Compound 54): To a solution of C3 (100 mg, 0.218 mmol) in DCM (3 mL) was added AgOTf (56 mg, 0.218 mmol), followed by the addition of 4-amino-3-methylbenzonitrile (43.2 mg, 0.327 mmol) at 25 °C. After stirring the reaction mixture at 25 °C for 1 h, the reaction mixture was filtered and the filter cake was washed with DCM (15 mL). The combined organic layers were washed with 1M HCl (10 mL), brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give an oil (93 mg), which was purified by HPLC ( _Column : YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient: 75%B~100%B; Flow rate: 25 mL/min) to give compound 54 (12 mg, 13%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.35 (d,J=8.4 Hz, 1H), 7.53-7.48 (m, 1H), 7.46 (s, 1H), 6.96 (s, 1H), 3.57-3.50 (m, 2H), 3.47-3.38 (m, 2H), 2.75 (s, 1H), 2.40-2.24 (m, 5H), 2.06-1.99 (m, 1H) , 1.91-1.72 (m, 6H), 1.68-1.60 (m, 2H), 1.50-1.36 (m, 7H), 1.32-1.18 (m, 6H), 1.18-1.04 (m, 3H), 0.75 (s, 2H), 0.77-0.72 (m, 1H).

LC/MS Rt=1.129 min in 2.0 min chromatography, 30-90AB, ^{purity 100%, ESI MS calcd for C30H43N2O3 [M+H]+} _{479 , found 479} .

Example 52. Synthesis connections 55

Step 1 (F2). To a solution of commercially available F1 (20 g, 80.2 mmol) in DCM (200 mL) were added 2,2-dimethoxyethanamine (8.43 g, 80.2 mmol), HOBt (14 g, 104 mmol), EDCI (19.9 g, 104 mmol), and TEA (40.5 g, 401 mmol) at 25 °C. The mixture was stirred at 25 °C for 19 h. The mixture was filtered. The filtrate was washed with water (2 x 150 mL), brine (2 x 150 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo to afford F2 (27 g, crude) as an oil.

Step 2 (F3) To a solution of F2 (17 g, 50.5 mmol) in acetone (200 mL) was added aqueous HCl (151 mL, 3 M) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was extracted with EtOAc (3 x 250 mL). The organic phase was washed with water (3 x 600 mL), saturated NaHCO ₃ (3 x 500 mL), brine (3 x 450 mL), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to give F3 (5.57 g) as an oil.

Step 3 (F4): To a stirred solution of F3 (5.57 g, 19.1 mmol) and perchloroethane (9.04 g, 38.2 mmol) in dichloromethane (200 mL) was added _PPh3 (10 g, 38.2 mmol). The mixture was stirred at 0 °C for 15 min, then _Et3N (5.51 mL, 38.2 mmol) was added and the mixture was stirred at 25 °C for 18 h. The mixture was washed with water (2×150 mL), brine (2×150 mL), dried over _Na2SO4 , filtered, concentrated in _vacuo to give the crude product, which was purified by flash chromatography on silica gel (0-65% EtOAc in PE) to give F4 (2.7 g, 52%) as a yellowish-white oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.75-7.45 (s, 1H), 7.10-6.98 (m, 2H), 5.20-4.95 (m, 3H), 3.75-3.45 (m , 2H), 2.40-2.20 (m, 3H), 2.00-1.95 (m, 1H)

Step 4 (F5): To a solution of F4 (1.3 g, 4.77 mmol) in AcOH (5 mL) was added HBr (10 mL, 35% in AcOH) at 25 °C. The mixture was stirred at 25 °C for 4 h. MTBE (25 mL) was added and a solid was obtained. The mixture was filtered. The filter cake was washed with MTBE (15 mL) and dried under vacuum at 50 °C to give F5 (800 mg, 77%) as a solid.

¹ H NMR(400 MHz, methanol-d ₄ ) δ 8.03 (s, 1H), 7.27 (s, 1H), 5.05-4.80 (m, 1H), 3.60-3.45 (m, 2H), 2.60- 2.55 (m, 1H), 2.45-2.35 (m, 1H), 2.31-2.20 (m, 2H)

Step 5 (Compound 55). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (312 mg, 0.822 mmol) and _Et3N (276 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added (S)-2-(pyrrolidin-2-yl)oxazole hydrobromide (180 mg, 0.822 mmol) at 25 °C over 18 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (50 mL), brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated to give the crude _material . The crude material was purified by silica gel chromatography with PE/EtOAc=0/1-1/1 to give compound 55 (200 mg) as a fluffy solid. Compound 55 was further purified by preparative HPLC (Conditions: water (0.05% ammonium hydroxide v/v)-ACN, Column: Phenomenex Gemini C18 250*50mm*10μm, Gradient time: 8 min) to give compound 55 (100 mg, 50%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.62-7.50 (m, 1H), 7.14-6.99 (m, 1H), 5.27-5.11 (m, 1H), 3.93-3.29 (m , 7H), 2.77-2.49 (m, 2H), 2.31-1.99 (m, 5H), 1.84-1.60 (m, 8H), 1.49-1.32 (m, 7H), 1.25-1.17 (m, 6H), 1.16-1.03 (m, 3H), 0.85-0.76 (m, 3H)

LC/MS Rt ^{=0.977 min in 2.0 min chromatography, 30-90AB, 100% purity; ESI MS calcd for C29H45N2O4[M+H]+} _{485 , found 485} .

SFC Rt=1.488 min in 3.0 min chromatography, AD-H_3UM_4_5_40_4ML_3MIN.M, 100% de. (Column: Chiralpak AD-3 50*4.6mm ID, 3μm; Mobile phase: A: _CO2 B: isopropanol (0.05% DEA); Gradient: maintaining 5% for 0.2 min, then from 5% to 40% B in 1.4 min and maintaining 40% for 1.05 min, then 5% B for 0.35 min; Flow rate: 4 ml/min Column temperature: 40°C).

Example 53. Synthesis connections 56 And connections 57

Step 1 (G2). To a solution of titanium(IV) isopropoxide (2.51 g, 8.67 mmol) in methanamine (611 mg, 2 M in MeOH) was added commercially available 1-(4-fluorophenyl)propan-1-one ( G1 , 1 g, 6.57 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. NaBH ₄ (248 mg, 6.57 mmol) was added to the mixture. The mixture was stirred at 25 °C for 10 min. The mixture was poured into saturated NH ₄ Cl (10 mL) and water (10 mL). The reaction mixture was filtered and washed with PE (3×10 mL). The filtrate was concentrated to give G2 (400 mg, 36%) as an oil, which was used in the next step without further purification.

Step 2 (Mixture of compounds 56 and 57). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (312 mg, 0.822 mmol) and Et ₃ N (276 mg, 2.73 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, 1-(4-fluorophenyl)-N-methylpropan-1-amine ( G2 , 137 mg, 0.822 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 40 °C for 10 h. The residue was quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to give a mixture of compound 56 and 57 (300 mg, crude) as solids, which were further purified as described below in step 3.

Step 3 (Compound 56 and Compound 57): A mixture of compounds 56 and 57 (300 mg, crude) was purified by silica gel chromatography eluting with PE:EtOAc=3/1 to afford compound 56 (35 mg, 12%) as a solid and compound 57 (46 mg, 15%) as a solid.

Compound 56

¹ H NMR(400 MHz, CDCl₃) δ 7.28-7.21 (m, 2H), 7.08-6.94 (m, 2H), 5.97-5.85 (m, 0.9H), 5.08-4.99 (m, 0.1H), 3.57-3.49 (m, 2H), 3.47-3.36 (m, 2H), 2.74-2.64 (m, 4H), 2.39 -2.25 (m, 1H), 2.01-1.90 (m, 1H), 1.88-1.60 (m, 10H), 1.51-1.05 (m, 17H), 0 .96 (t, J=7.28, 3H), 0.94 (s, 0.4H), 0.80 (s, 2.6H).

LC/MS Rt=5.531 min in 7 min chromatography, 10-80AB, purity 98%, ESI MS _calcd for _C32H49FNO3 [M ₊ H] ⁺ 514, found 514.

SFC Rt=4.251 min in 10 min chromatography, OD_3_EtOH_DEA_5_40_25ML, 98%de. (Column: Chiralcel OD-3 150×4.6mm ID, 3 μm Mobile phase: A: _CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 ml/min; Column temperature: 35°C).

Compound 57

¹ H NMR(400 MHz, CDCl₃) δ 7.29-7.23 (m, 2H), 7.19-7.15 (m, 0.2H), 7.08-6.96 (m, 1.8H), 5.94-5 .75 (m, 0.9H), 5.02-4.94 (m, 0.1H), 3.57-3.48 (m, 2H), 3.47-3.36 (m, 2H) , 2.79-2.64 (m, 5H), 2.36-2.10 (m, 1H), 2.03-1.96 (m, 1H), 1.86-1.61 (m, 8H), 1.50-0.97 (m, 18H), 0.95-0.88 (m, 3H), 0.87 (s, 0.4H), 0.80 (s, 2.6H).

LC/MS Rt=5.485 min in 7 min chromatography, 10-80AB, purity 98%, ESI MS _calcd for _C32H49FNO3 [M ₊ H] ⁺ 514, found 514.

SFC Rt=2.890 min in 10 min chromatography, OD_3_EtOH_DEA_5_40_25ML, 99%de. (Column: Chiralcel OD-3 150×4.6mm ID, 3 μm Mobile phase: A: _CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 ml/min; Column temperature: 35°C).

Example 54. Synthesis connections 58 And connections 59

Step 1 (H2). To a solution of commercially available H1 (3 g, 19.7 mmol) in MeOH (100 mL) were added _AcONH4 (15.1 g, 196 mmol) and _NaBH3CN (6.18 g, 98.4 mmol) at 20 °C. The mixture was stirred at 20 °C for 19 h. Water (100 mL) was added, yielding a solid. The mixture was filtered. The filtrate was extracted with EtOAc (2 x 80 mL). _The combined organic phase was washed with water (2 x 100 mL), brine (2 x 80 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo to give H2 (2.15 g, 71%) as an off-white oil, which was used in the next step without further purification.

Step 2 (Compound 58 and Compound 59). To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (312 mg, 0.822 mmol) and TEA (276 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added 1-(4-fluorophenyl)propan-1-amine H2 (125 mg, 0.822 mmol) at 25 °C. The reaction mixture was stirred at 40 °C for 10 h. The residue was quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel chromatography eluting with PE:EtOAc=3/1 to afford compound 58 (100 mg, 37%, Rf=0.6 in PE/EtOAc=3/1) as a solid and compound 59 (100 mg, 37% Rf=0.5 in PE/EtOAc=3/1) as a solid.

Compound 58 (100 mg) was further purified twice by silica gel chromatography and then SFC (Column: Chiralcel OJ-3 150×4.6mm ID, 3 μm Mobile phase: A: _CO2B :ethanol (0.05% DEA) Gradient: 5% to 40% B over 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 mL/min; Column temperature: 35°C) to afford compound 58 (23 mg, yield) as a solid.

Compound 59 (100 mg) was purified twice by SFC (Column: Chiralcel OJ-3 150×4.6 mm ID, 3 μm Mobile phase: A: _CO2 B: ethanol (0.05% DEA) Gradient: 5% to 40% B over 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min Flow rate: 2.5 mL/min; Column temperature: 35°C) to afford compound 59 (17 mg, yield) as a solid.

Compound 58

¹ H NMR(400 MHz, CDCl₃) δ 7.26-7.21 (m, 2H), 7.05-6.98 (m, 2H), 5.46-5.40 (m, 1H), 4.88 (q, J=7.53 Hz, 1H), 3.53 (q, J=7.03 Hz, 2H), 3.43 (q, J=9.54, 2H), 2.73 (s, 1H), 2.22-2.03 (m, 2H), 1.99-1.92 (m, 1H), 1.87-1.61 (m, 9H), 1.51-1.02 (m, 17H), 0.89 (t, J=7.53, 3H), 0.70 (s, 3H).

LC/MS Rt=1.334 min in 2.0 min chromatography, 10-80AB, purity 100%, ESI MS _{calcd for C31H47FNO3 [} M ₊ H] ⁺ 500, found 500.

SFC Rt=2.890 min in 10 min chromatography, OJ_3_EtOH_DEA_5_40_25ML, 98%de. (Column: Chiralcel OJ-3 150×4.6mm ID, 3μm Mobile phase: A: _CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5 ml/min; Column temperature: 35°C).

Compound 59

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.21 (m, 2H), 7.04-6.96 (m, 2H), 5.49-5.40 (m, 1H), 4.85 (sq., J= 7.36 Hz, 1H), 3.53 (sq., J=6.86 Hz, 2H), 3.42 (sq., J=9.12 Hz, 2H), 2.72 (s, 1H) , 2.22-2.07 (m, 2H), 1.86-1.70 (m, 7H), 1.68-1.62 (m, 2H), 1.49-0.95 (m, 18H), 0.88 (t, J=7.4 Hz, 3H), 0.49 (s, 3H).

LC/MS Rt=1.322 min in 2.0 min chromatography, 10-80AB, purity 100%, ESI MS _{calcd for C31H47FNO3 [} M ₊ H] ⁺ 500, found 500.

SFC Rt=2.668 min in 10 min chromatography, OJ_3_EtOH_DEA_5_40_25ML, 95%de. (Column: Chiralcel OJ-3 150×4.6mm ID, 3μm Mobile phase: A: _CO2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5ml/min; Column temperature: 35°C).

Example 55. Synthesis connections 60

Step 1 (I2). To a solution of commercially available I1 (20 g, 80.2 mmol) in DCM (200 mL) were added 2,2-dimethoxyethanamine (8.43 g, 80.2 mmol), HOBt (14 g, 104 mmol), EDCI (19.9 g, 104 mmol), and TEA (40.5 g, 401 mmol) at 25 °C. The mixture was stirred at 25 °C for 19 h. The mixture was filtered, concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0-70% EtOAc in PE) to give I2 (20 g, 74%) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.32 (s, 5H), 5.20-5.00 (m, 2H), 3.55-3.20 (m, 10H), 2.40-1.80 (m, 5H)

Step 2 (I3). To a solution of I2 (9.9 g, 29.4 mmol) in acetone (200 mL, 29.4 mmol) was added HCl (176 mL, 1 M) at 25 °C. The mixture was stirred at 25 °C for 18 h. The reaction mixture was combined with another portion prepared from 100 mg of I2 . The reaction mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phase was washed with water (3 x 300 mL) and brine (2 x 200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give I3 (2.4 g, crude) as an oil.

Step 3 (I4). To a stirred solution of I3 (2.4 g, 8.26 mmol) and perchloroethane (3.9 g, 16.5 mmol) in dichloromethane (100 mL) was added _PPh3 (4.32 g, 16.5 mmol). The mixture was stirred at 0 °C for 15 min. TEA (1.66 g, 16.5 mmol) was then added and the mixture was stirred at 25 °C for 18 h. The mixture was washed with water (2 x 80 mL), brine (2 x 80 mL), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0-65% EtOAc in PE) to give I4 (630 mg, 32%) as an oil, which was used directly in the next step.

Step 4 (I5). To a solution of I4 (530 mg, 1.94 mmol) in AcOH (3 mL) was added HBr (6 mL, 35% in AcOH) at 25 °C. The mixture was stirred at 25 °C for 2 h. MTBE (15 mL) was added to give a solid. The mixture was filtered. The filter cake was washed with MTBE (15 mL) and dried under vacuum at 50 °C to give I5 (430 mg, crude) as a solid.

¹ H NMR(400 MHz, methanol-d ₄ ) δ 8.05 (s, 1H), 7.28 (s, 1H), 5.05-4.85 (m, 2H), 3.60-3.45 (m, 2H), 2.60- 2.50 (m, 1H), 2.45-2.35 (m, 1H), 2.30-2.21 (m, 2H)

Step 5 (Compound 60) To a solution of 2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (313 mg, 1.30 mmol) and _Et3N (276 mg, 2.73 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. To the reaction mixture was added (R)-2-(pyrrolidin-2-yl)oxazole hydrobromide I5 (180 mg, 0.822 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (50 mL), brine (50 mL ₎ , dried over anhydrous _Na2SO4 , filtered and concentrated to give the crude product, which was purified by silica gel chromatography eluted with PE:EtOAc=0:1-1:1 to give compound 60 (190 mg) as a solid. The product was further purified by preparative HPLC (Conditions: water (0.05% ammonium hydroxide v/v)-ACN, Column: Phenomenex Gemini C18 250*50mm*10μm, Gradient time: 8 min) to give compound 60 (98 mg) as a solid. The solid was re-purified by SFC (Column: AD (250mm*30mm, 10μm), Conditions: 0.1% _{NH3H2O IPA} , Gradient: 45%, Flow rate (mL/min): 80mL/min, 25°C) to give compound 60 (67 mg, 25%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.60-7.50 (m, 1H), 7.10-6.98 (m, 1H), 5.33-5.23 (m, 1H), 3.86-3.70 (m , 1H), 3.66-3.58 (m, 1H), 3.55-3.50 (m, 2H), 3.46-3.38 (m, 2H), 2.74-2.42 (m, 2H), 2.30-2.07 (m, 4H), 2.04-1.94 (m, 2H), 1.86-1.66 (m, 6H), 1.51-1 .32 (m, 8H), 1.28-1.04 (m, 10H), 0.77-0.62 (m, 3H).

LC/MS Rt ^{=0.977 min in 2.0 min chromatography, 30-90AB, 100% purity; ESI MS calcd for C29H45N2O4[M+H]+} _{485 , found 485} .

SFC Rt=1.961 min in 3 min chromatography, AD-H_3UM_4_5_40_4ML, 100%de. (Column: Chiralpak AD-3 50*4.6mm ID, 3μm; Mobile phase: A: _CO2B :isopropanol(0.05%DEA); Gradient: maintaining 5% for 0.2 min, then from 5% to 40% B in 1.4 min and maintaining 40% for 1.05 min, then 5% B for 0.35 min; Flow rate: 4ml/min; Column temperature: 40°C).

Example 56. Synthesis connections 61 And connections 62

Step 1 (J2). Ti(iPrO) ₄ (5.31 g, 18.7 mmol) was added to methanamine in MeOH (14.4 mL, 2 M) followed by commercially available J1 (2 g, 14.4 mmol). After stirring at 25 °C for 3 h, _NaBH4 (544 mg, 14.4 mmol) was added. The mixture was stirred at 25 °C for 18 h and quenched with water (15 mL). A solid formed and was filtered. The filtrate was extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with water (2 x 40 mL), brine (2 x 40 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give J2 (2.9 g, crude) as an oil, which was used immediately.

Step 2. (Compound 61 and Compound 62) To a solution of C2 (200 mg, 0.548 mmol) in DCM (5 mL) were added HATU (312 mg, 0.822 mmol) and TEA (276 mg, 2.73 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, 1-(4-fluorophenyl)-N-methylethanamine J2 (134 mg, 0.876 mmol) was added at 25 °C. The reaction mixture was stirred at 25 °C for 18 h, diluted with EtOAc (30 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude material. The crude material was purified by silica gel chromatography with PE/EtOAc=0/1-10/1 to afford compound 61 (50 mg, Rf=0.50 in PE/EtOAc=2/1) and compound 62 (50 mg, Rf=0.45 in PE/EtOAc=2/1) as a solid.

Compound 61 was further purified by SFC (Column: AD (250mm*30mm, 5μm), Conditions: 0.1% _{NH3H2O IPA} , Gradient: 35%, Flow Rate (mL/min): 60mL/min, 25°C) to give compound 61 (25 mg, 9%) as a solid.

Compound 62 with impurities (50 mg, 0.100 mmol) was triturated with hexane (3 mL) to give compound 62 (40 mg, 14%) as a solid.

Compound 61

¹ H NMR(400 MHz, CDCl₃) δ 7.26-7.22 (m, 2H), 7.09-6.97 (m, 2H), 6.17-6.11 (m, 0.9H), 5.28 (s, 0 ,1H), 3.56-3.50 (m, 2H), 3.46-3.38 (m, 2H), 2.74-2.67 (m, 5H), 2.57 (s, 0 ,5H), 2.36-2.27 (m, 1H), 1.84-1.70 (m, 6H), 1.47-1.42 (m, 6H), 1.40-1.32 (m, 4H), 1.30-1.18 (m, 8H), 1.16-1.09 (m, 3H), 0.89 (s, 0.6H), 0.79 (s, 3H).

LC/MS Rt=1.173 min in 2.0 min chromatography, 30-90AB, purity _{100%; ESI MS calcd for C31H47FNO3 [} M ₊ H] ⁺ 500, found 500.

SFC Rt=5.128 min in 10 min chromatography, AD_3_IPA_DEA_5_40_25ML, 98.36% de. (Column: Chiralpak AD-3 150×4.6mm ID, 3μm Mobile phase: A: _CO2 B: isopropanol (0.05% DEA) Gradient: from 5% to 40% B in 5 min and maintaining 40% for 2.5 min, then 5% B for 2.5 min; Flow rate: 2.5ml/min; Column temperature: 35°C)

Compound 62

¹ H NMR(400 MHz, CDCl₃) δ 7.26-7.22 (m, 1.6H), 7.17-7.11 (m, 0.4H), 7.06-6.98 (m, 2H), 6.15-6 .09 (m, 0.7H), 5.36-5.28 (m, 0.2H), 3.56-3.50 (m, 2H), 3.47-3.37 (m, 2H) , 2.82-2.65 (m, 5H), 2.40-2.24 (m, 1H), 1.89-1.68 (m, 5H), 1.67-1.57 (m, 4H), 1.50-1.17 (m, 16H), 1.16-1.04 (m, 3H), 0.82 (s, 3H).

LC/MS Rt=1.178 min in 2.0 min chromatography, 30-90AB, purity _{100%; ESI MS calcd for C31H47FNO3 [} M ₊ H] ⁺ 500, found 500.

Example 57. Synthesis connections 63

The synthesis of K1 is disclosed in WO2016/123056.

Step 1 (K2). To a solution of K1 (1 g, 3.13 mmol) in MeOH (10 mL) were added HBr (125 mg, 0.626 mmol, 40% in water) and _Br2 (500 mg, 3.19 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous _NaHCO3 (10 mL), treated with water (20 mL), extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo to give K2 (1.2 g) as a solid, which was used directly in the next step.

Step 2 (Compound 63). To a solution of K2 (100 mg, 0.251 mmol) in DMF (5 mL) were added N-methylaniline (32.2 mg, 0.301 mmol) and TEA (76.1 mg, 0.753 mmol) at 25 °C. The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was purified by preparative HPLC (Column: Gemini 150*25 mm, 5 μm; Conditions: water (0.05% HCl)-ACN; Gradient 27%-52% B; Flow rate (mL/min): 30) to give compound 63 (4 mg, 4%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.36-7.29 (m, 2H), 7.17-7.08 (m, 2H), 7.04-6.98 (m, 1H), 4.21-4.11 (m , 2H), 3.18 (s, 3H), 2.56-2.48 (m, 1H), 2.19-2.09 (m, 1H), 1.90-1.74 (m, 3H ), 1.69-1.63 (m, 2H), 1.52-1.24 (m, 10H), 1.20 (s, 3H), 1.13-0.92 (m, 6H), 0.73-0.61 (m, 2H), 0.55 (s, 3H)

LC/MS Rt=2.147 min in 3.0 min chromatography, 10-80AB, purity 100%, _ESI MS calcd for _C28H42NO2 [M ₊ H] ⁺ 424, found 424.

Example 58. Synthesis connections 64

Step 1 (Compound 64). To a solution of K2 (60 mg, 0.151 mmol) in DMF (2 mL) was added DIPEA (25.3 mg, 0.196 mmol). The mixture was stirred for 10 min at 20 °C. Aniline (18.2 mg, 0.196 mmol) was added to the mixture. The mixture was stirred for another 16 h at 20 °C. The mixture was poured into water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Column: Phenomenex Gemini C18 250*50 mm*10 μm, Gradient: 70-100% B, Conditions: water (0.05% ammonium hydroxide v/v)-ACN, Flow rate: 30 mL/min) to give compound 64 (10 mg, 16.1%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.21(t, J=8 Hz, 2H), 7.76-7.69 (m, 1H), 6.62-6.58 (m, 2H), 4.70 (br.s, 1H), 4.41-3.86 (m, 2H), 2.62-2.55 (m, 1H), 2.29-2.19 (m, 1H), 2.01-1.92 ( m, 1H), 1.88-1.64 (m, 7H), 1.47-1.16 (m, 10H), 1.13-0.96 (m, 6H), 0.79-0. 64 m, 5H.

LC/MS Rt=1.173 min in 2 _min chromatography, 30-90AB, purity 95%, ESI MS calcd for _C27H40NO2 [M ₊ H] ⁺ 410, found 410.

Example 59. Synthesis connections 65

The synthesis of L1 is disclosed in WO2015/27227.

Step 1 (L2). To a solution of L1 (1.2 g, 2.77 mmol) in MeOH (10 mL) were added HBr (110 mg, 0.554 mmol, 40% in water) and _Br2 (442 mg, 2.82 mmol) at 25 °C. After stirring at 25 °C for 16 h, the reaction was quenched with saturated aqueous _NaHCO3 (10 mL), treated with water (20 mL), extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo to give L2 (1.4 g) as a solid, which was used directly in the next step.

Step 2 (Compound 65) To a solution of L2 (100 mg, 0.219 mmol) in DMF (5 mL) were added N-methylaniline (28 mg, 0.262 mmol) and TEA (66.4 mg, 657 mmol) at 25 °C. The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was purified by preparative HPLC (Column: Gemini 150*25 mm, 5 μm; Conditions: water (0.05% HCl)-ACN; Gradient 62%-87% B; Flow rate (mL/min):30) to give compound 65 (3 mg, 3%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.21-7.17 (m, 2H), 6.76-6.70 (m, 1H), 6.66-6.60 (m, 2H), 4.13-3.95 (m , 2H), 3.53-3.50 (s, 1H), 3.43-3.35 (m, 3H), 3.01 (s, 3H), 2.65-2.52 (m, 1H ), 2.22-2.13 (m, 1H), 2.05-1.95 (m, 2H), 1.75-1.63 (m, 3H), 1.52-1.45 (m , 5H), 1.26-1.14 (m, 15H),1.00-0.93 (m, 1H), 0.88-0.77 (m, 2H), 0.67 (s, 3H).

LC/MS Rt=1.254 min in 2.0 min chromatography, 30-90AB, purity 95%, ESI MS _calcd for _C31H48NO3 [M ₊ H] ⁺ 482, found 482.

Example 60. Synthesis connections 66

Step 1 (Compound 66). To a solution of DIPEA (18.2 mg, 0.141 mmol) in DMF (1.5 mL) was added aniline (20.3 mg, 0.218 mmol) at 10 °C under N ₂ . After stirring at 10 °C for 30 min, L2 (50 mg, 0.109 mmol) in DMF (1.5 mL) was added. The reaction mixture was stirred at 40 °C for 16 h. To the reaction mixture was added another portion of DIPEA (36.5 mg, 0.283 mmol) and aniline (40.6 mg, 0.436 mmol). The reaction mixture was heated to 50 °C and stirred at this temperature for another 16 h. The reaction mixture was treated with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to give the crude material. The crude material was purified by preparative HPLC (Conditions: Water (0.05% ammonium hydroxide v/v-ACN), Column: Phenomenex Gemini C18 250*50mm*10μm, Gradient time: 8 min). The solvent was removed to give compound 66 (19 mg, 37%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.19 (t, 2H), 6.72 (t, 1H), 6.60 (d, 2H), 4.00-3.86 (m, 2H), 3.52-3.49 ( m, 1H), 3.41-3.35 (m, 3H), 2.57 (br.t, 1H), 2.29-2.19 (m, 1H), 2.07-1.92 ( m, 2H), 1.71 (b.d., 4H), 1.65-1.59 (m, 3H), 1.51-1.46 (m, 4H), 1.39-1.24 ( m, 5H), 1.23-1.19 (m, 5H), 1.15 (t, 4H), 1.12-1.06 (m, 1H), 1.03-0.94 (m, 1H), 0.65 (s, 3H).

LC/MS Rt=2.391 min in 3 min chromatography, 30-90CD, purity 97.8%, ESI MS _calcd for _C30H46NO3 [M ₊ H] ⁺ 468, found 468.

Example 61. Synthesis connections 67 And connections 68

Step 1 (M2). To a mixture of M2 (5 g, 17.4 mmol) and CsF (1.32 g, 8.70 mmol) in THF (50 mL) was added dropwise _TMSCF3 (6.17 g, 43.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. To the mixture was added TBAF (52 mL, 1 M in THF, 52 mmol). The mixture was stirred at 25 °C for another 2 h. The mixture was poured into water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1~3/1) to give impure M2 (4.6 g) as a solid. The crude product was recrystallized from MeCN (3 mL) at 25~50°C to give M2 (2.64 g, 40%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.16-5.08 (m, 1H), 2.40-2.13 (m, 3H), 2.05-1.74 (m, 6H), 1.73-1.42 (m , 12H), 1.30-1.04 (m, 6H), 0.88 (s, 3H).

Step 2 (M3). To a solution of M2 (1 g, 2.80 mmol) in THF (30 mL) was added 9-BBN dimer (2 g, 8.19 mmol) at 0 °C under N ₂ . The solution was stirred at 65 °C for 1 h. After cooling the mixture to 0 °C, NaOH solution (6 mL, 5 M, 30 mmol) was added very slowly. H ₂ O ₂ (4 g, 35.2 mmol, 30% in water) was added slowly and the internal temperature was maintained below 10 °C. The mixture was stirred at 60 °C under N ₂ for 1 h. The mixture was cooled to 30 °C and water (30 mL) was added. The reaction mixture was extracted with EtOAc (30 mL). The organic layer was washed with brine (2×20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give M3 (1.43 g, crude) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 3.88-3.65 (m, 3H), 1.96-1.76 (m, 6H), 1.73-1.38 (m, 10H), 1.27-1.02 (m , 11H), 0.67 (C, 3H).

Step 3 (M4). To a solution of M3 (1.43 g, 3.81 mmol) in DCM (15 mL) was slowly added DMP (3.23 g, 7.62 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 _h . The mixture was poured into saturated _Na2S2O3 (30 _mL ) and extracted with DCM (2×30 mL). The combined organic layer was washed with brine (2×30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by column (PE/EtOAc=5/1~3/1) to give M4 (570 mg, 40%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 2.57-2.51 (m, 1H), 2.20-1.93 (m, 8H), 1.86-1.44 (m, 13H), 1.81-1.06 (m , 6H), 0.62 (s, 3H).

Step 4 (M5). Liquid bromine (1.91 g, 12.0 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (16.0 mL, 3 M, 48.2 mmol) at 0 °C. When all the bromine had dissolved, the mixture was diluted with cold dioxane (4.5 mL) and slowly added to a stirred solution of M4 (1.5 g, 4.02 mmol) in dioxane (6 mL) and water (4.5 mL). The homogeneous yellow solution slowly decolorized and a white precipitate formed. The reaction mixture was stirred at 25 °C for 5 h. The remaining oxidizing reagent was blocked with aqueous Na ₂ S ₂ O ₃ (30 mL) and the mixture was then heated to 80 °C until the solid dissolved. The solution was acidified with aqueous HCl (3 M, 30 mL) and the solid precipitated. The solid was filtered and washed with water (3 x 50 mL) to give a solid which was dried with toluene (2 x 40 mL) under vacuum to give M5 (1.1 g, 73%) as a solid.

¹ H NMR(400 MHz, DMSO-d ₆ ) δ 11.89 (br.s, 1H), 5.73 (s, 1H), 2.29 (t, J=9.4 Hz, 1H), 1.99-1.87 (m, 4H), 1.85-1.51 (m, 7H), 1.49-1.32 (m, 5H), 1, 30-1.15 (m, 4H), 1.12-0.96 (m, 3H), 0.64 (s, 3H).

Step 5 (Compound 67). To a solution of M5 (200 mg, 0.534 mmol) in DCM (3 mL) were added commercially available ( S )-4-(1-aminoethyl)benzonitrile hydrochloride (146 mg, 0.801 mmol), TEA (269 mg, 2.66 mmol), and HATU (304 mg, 0.801 mmol). The mixture was stirred at 25 °C for 1 h. The mixture was washed with water (1 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (Instrument: FB; Column: Phenomenex Gemini C18 250*50mm*10μm; Conditions: water (0.05% ammonium hydroxide v/v)-ACN; Initial B: 58; Final B: 88; Gradient Time (min): 8; 100% B Retention Time (min): 2; Flow Rate (mL/min): 30; Injections: 7) to afford compound 67 (170 mg, 63%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.62 (d,J=8.0 Hz, 2H), 7.42 (d,J=8.4 Hz, 2H), 5.53 (d,J=7.2 Hz, 1H), 5.20-5.08 (m, 1H), 2.21-1.89 (m, 5H), 1.86-1.61 (m, 8H), 1, 55-1.39 (m, 8H), 1.30-1.04 (m, 7H), 0.55 (s, 3H).

LC/MS Rt=1.257 min in 2 min chromatography, 10-80AB, purity 100%, ESI MS calcd for C ₂₉ H ₃₈ F ₃ N ₂ O ₂ [M+H] ⁺ 503, found 503.

HPLC Rt=6.04 min in 10 min chromatography, 10-80, 100% de

Step 6 (Compound 68). To a solution of compound 67 (120 mg, 0.238 mmol) in DMF (1 mL) was added NaH (9.51 mg, 60%, 0.238 mmol). The mixture was stirred at 20 °C for 15 min. Then MeI (33.7 mg, 0.238 mmol) was added and the reaction mixture was stirred at 20 °C for 15 min. The reaction was quenched with water (5 mL) and the mixture was extracted with EtOAc (2 mL). The organic layer was separated, concentrated in vacuo and purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give compound 68 (10 mg, 8%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.63 (d,J=8.4 Hz, 2H), 7.42 (d,J=8.0 Hz, 2H), 6.16 (d,J=7.6 Hz, 1H), 3.36 (s, 3H), 2.80-2.67 (m, 4H), 2.39-2.24 (m, 1H), 2.10-1, 98 (m, 1H), 1.98-1.88 (m, 1H), 1.81-1.62 (m, 8H), 1.52-1.02 (m, 15H), 0.82 ( s, 3H).

LC/MS Rt=1.254 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₃₁ H ₄₂ F ₃ N ₂ O ₂ [M+H] ⁺ 531, found 531.

Example 62. Synthesis connections 69 And connections 70

Step 1 (N2). A solution of commercially available 4-acetylbenzonitrile N1 (1 g, 6.88 mmol) in MeNH ₂ (20.6 mL, 41.2 mmol, 2M in EtOH) was stirred at 20 °C for 16 h. NaBH ₄ (1.30 g, 34.4 mmol) was added and the mixture was stirred at 20 °C for 2 h, blocked with 50% NH ₄ Cl (50 mL) and extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (50 mL), dried over _Na2SO4 , filtered, concentrated and purified by silica _gel chromatography (0-20% EtOAc in PE) to give the impure compound (900 mg, 82%) as an oil, which was used directly in the next step.

¹ H NMR(400 MHz, CDCl₃) δ 7.66-7.58 (m, 2H), 7.46-7.40 (m, 2H), 3.75-.3.67 (m, 1H), 2.42-2.36 ( m, 1H), 2.29 (s, 3H), 1.37-1.31 (m, 3H).

Step 2. (Compound 69 and Compound 70) To a solution of M2 (160 mg, 0.427 mmol) in DCM (5 mL) were added HATU (249 mg, 0.640 mmol), TEA (215 mg, 2.13 mmol), and 4-(1-(methylamino)ethyl)benzonitrile N2 (136 mg, 0.854 mmol). After stirring at 25 °C for 1 h, the reaction was quenched with water (20 mL), and the reaction mixture was extracted with DCM (3×5 mL). The combined organic phase was washed with HCl (2×20 mL, 2 M), dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (PE/EtOAc=2/1) to give compound 69 (60 mg) and compound 70 (35 mg, 16%) as oil.

60 mg of compound 69 was separated by SFC (Column: AD(250mm*30mm,5μm), gradient: 50-50% B (A=0.05% _NH3 / _H2O , B=MeOH), flow rate: 60 mL/min) to give compound 69 with impurity (35 mg), which was further separated by SFC (Column: AD(250mm*30mm,5μm), gradient: 50-50% B (A=0.05% _NH3 / _H2O , B=MeOH), flow rate: 60 mL/min) to give pure compound 69 (16 mg, 7%) as a solid.

Compound 69

¹ H NMR(400 MHz, CDCl₃) δ 7.72-7.57 (m, 2H), 7.42-7.33 (m, 2H), 6.22-6.12 (m, 0.9H), 5.37-5.28 (m, 0.1H), 2.78-2.57 (m, 4H), 2.37-2.24 (m, 1H), 2.13-1.99 (m, 2H), 1.97 -1.88 (m, 1H), 1.87-1.64 (m, 8H), 1.56-1.41 (m, 8H), 1.37-1.06 (m, 7H), 0 .92-0.75 (m, 3H).

LC/MS _Rt =3.583 min in 7.0 min chromatography, 30-90AB, 100% _{purity, ESI MS calcd for C30H40F3N2O2 [ M +} H] ⁺ 517, found 517.

Compound 70

¹ H NMR(400 MHz, CDCl₃) δ 7.68-7.60 (m, 2H), 7.41-7.36 (m, 1.5H), 7.31-7.27 (m, 0.5H), 6.20-6 .11 (m, 0.8H), 5.41-5.32 (m, 0.2H), 2.77-2.68 (m, 4H), 2.43-2.44 (m, 1H) , 2.08-1.89 (m, 3H), 1.85-1.61 (m, 9H), 1.53-1.44 (m, 6H), 1.41-1.24 (m, 4H), 1.24-1.02 (m, 4H), 0.81 (s, 3H).

LC/MS _Rt =3.489 min in 7.0 min chromatography, 30-90AB, 100% _{purity, ESI MS calcd for C30H40F3N2O2 [ M +} H] ⁺ 517, found 517.

Example 63. Synthesis connections 71 And 72

Step 1 (Compound 71). To a solution of M2 (200 mg, 0.534 mmol) in DCM (5 mL) were added HATU (312 mg, 0.801 mmol), _Et3N (268 mg, 2.66 mmol), and (R)-4-(1-aminoethyl)benzonitrile (117 mg, 0.801 mmol). After stirring at 25 °C for 1 h, the reaction was quenched with water (20 mL) and the reaction mixture was extracted with DCM (3×5 mL). _The combined organic phase was dried over _Na2SO4 , filtered, concentrated and purified by preparative HPLC (Column: YMC-Actus Triart C18 100*30mm*5μm), gradient: 75-100% B (A=water (0.05%HCl), B=MeCN), flow rate: 25 mL/min) to give compound 71 (200 mg, 75%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.65-7.59 (m, 2H),7.44-7.39 (m, 2H), 5.52-5.45 (m, 1H), 5.21-5.12 (m , 1H), 2.20-2.10 (m, 2H), 2.08-1.99 (m, 2H), 1.97-1.89 (m, 2H), 1.87-1.78 (m, 3H), 1.77-1.58 (m, 5H), 1.54-1.45 (m, 6H), 1.35-1.05 (m, 8H), 0.69 (s , 3H).

LC/MS Rt=1.287 min in 2.0 min chromatography, 10-80AB, purity 99%, ESI MS calcd for C ₂₉ H ₃₈ F ₃ N ₂ O ₂ [M+H] ⁺ 503, found 503.

Example 64. Synthesis connections 73

Step 1 (O2): To a solution of O1 (50 g, 157 mmol) in MeOH (500 mL) was added 4-methylbenzenesulfonic acid (2.70 g, 15.7 mmol) at 25 °C. The mixture was stirred at 65 °C for 1 h. The reaction mixture was cooled to 25 °C and TEA (2.16 mL, 15.7 mmol) was added. The mixture was stirred for 0.5 h. The precipitate was collected by filtration and washed with methanol (2 x 100 mL) to give O2 (50 g, crude) as a white solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.25-3.05 (m, 6H), 2.60-2.40 (m, 1H), 2.20-2.05 (m, 4H), 2.00-1.95 (m , 1H), 1.90-1.80 (m, 1H), 1.75-1.50 (m, 6H), 1.49-1.05 (m, 12H), 1.04-0.95 (m, 1H), 0.78 (s, 3H), 0.59 (s, 3H).

Step 2 (O3): To a solution of bromo(methyl)triphenylphosphorane (73.2 g, 205 mmol) in THF (500 mL) was added t-BuOK (23.0 g, 205 mmol) at 25 °C. The mixture was heated to 45 °C and stirred for 1 h. O2 (50 g, 137 mmol) was added. The mixture was stirred at 45 °C for 2 h. The reaction was quenched with NH ₄ Cl (200 mL) and the mixture was extracted with THF (3 x 100 mL). The organic layer was washed with brine (200 mL), dried over Na ₂ SO ₄ and filtered to give a product mixture including O3 (50 g, 500 mL), which was used in the next step without further purification.

Step 3 (O4): To a solution of the mixture containing O3 (50 g, 138 mmol) in THF (500 mL) was added aqueous HCl (207 mL, 1 M in water). The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered: and the filter cake was dissolved in DCM (200 mL) and washed with brine (100 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give O4 (39 g, 90%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.84 (s, 1H), 4.70 (s, 1H), 2.45-2.20 (m, 3H), 2.15-2.00 (m, 3H), 1.90- 1.65 (m, 8H), 1.60-1.50 (m, 2H), 1.45-1.05 (m, 8H), 1.00 (s, 3H) 0.90-0.85 (m, 1H), 0.80-0.75 (m, 1H), 0.58 (s, 3H).

Step 4 (O5): To a solution of O4 (27 g, 85.8 mmol) in THF (200 mL) were added CsF (25.9 g, 171 mmol) and _TMSCF3 (24.3 g, 171 mmol). The mixture was stirred at 10 °C for 1 h. To the mixture were added water (10 mL) and TBAF, _3H2O (30 g). The mixture was stirred at 30 °C for another 2 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (500 mL), washed with water (2×500 mL), dried over _Na2SO4 , filtered, concentrated in vacuo and purified on _a flash column (DCM/EtOAc (1:1) in PE, 0~10%) to give O5 (27 g, 82%) and by-product O5A (3.5 g, 11%) as solids.

O5:

¹ H NMR(400 MHz, CDCl₃) δ 4.84 (s, 1H), 4.70 (s, 1H), 2.12-1.94 (m, 3H), 1.89-1.78 (m, 2H), 1.75 ( s, 3H), 1.72-1.60 (m, 5H), 1.58-1.48 (m, 2H), 1.45-1.09 (m, 10H), 1.01-0, 89 (m, 1H), 0.85 (s, 3H), 0.78-0.68 (m, 1H), 0.56 (s, 3H).

Step 5 (O6). To a solution of O5 (1 g, 2.6 mmol) in DCM (30 mL) and MeOH (30 mL) was added _NaHCO3 (1 g, 11.9 mmol). Ozone gas (1 atm) was bubbled through the mixture at -78 °C until the mixture turned blue (approximately 2 min). _N2 gas was then bubbled through the mixture for an additional 5 min until the mixture became colorless. _Me2S (1.3 g, 20.9 mmol) was added to the mixture and the mixture was stirred at 15 °C for 16 h. The mixture was filtered and concentrated in vacuo, triturated with MeCN (10 mL) to give O6 (0.8 g, 80%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 2.52 (t,J=8.8 Hz, 1H), 2.21-2.13 (m, 1H), 2.11 (s, 3H), 2.07-1.97 (m, 1H), 1.85-1, 52 (m, 10H), 1.47-1.11 (m, 9H), 1.03-0.89 (m, 1H), 0.86-0.76 (m, 4H), 0.61 ( s, 3H).

Step 6 (O7). To a solution of O6 (0.8 g, 2.06 mmol) in MeOH (10 mL) were added HBr (82.2 mg, 0.412 mmol, 40% in water) and _Br2 (329 mg, 2.10 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO3 (10 _mL ), treated with water (20 mL), and the reaction mixture was extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated in vacuo to give O7 (0.9 g, 94%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.95-3.90 (m, 2H), 2.90-2.75 (m, 1H), 2.25-2.10 (m, 1H), 1.95-1.85 (m , 1H), 1.80-1.50 (m, 10H), 1.45-1.15 (m, 9H), 1.00-0.75 (m, 5H), 0.65 (s, 3H ).

Step 7 (Compound 73). To a solution of DIPEA (21.4 mg, 0.166 mmol) in DMF (3 mL) was added _PhNH2 (23.8 mg, 0.256 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. O7 (60 mg, 0.128 mmol) was added. The reaction mixture was stirred at 40 °C for 10 h. The reaction was quenched with water (5 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was triturated with _H2O (10 mL) at 25°C to give compound 73 (20 mg, crude) as a solid, which was purified by HPLC (Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05% HCl)-ACN; Gradient 80%-100% B; Gradient time (min): 9.5) to give compound 73 (9 mg, 15%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.19 (t,J=8.0 Hz, 2H), 6.72 (t,J=8.0 Hz, 1H), 6.60 (d,J=8.0 Hz, 2H), 4.69 (s, 1H), 4.02-3.85 (m, 2H), 2.61-2.53 (m, 1H), 2.30-2, 18 (m, 1H), 2.03-1.92 (m, 1H), 1.83-1.60 (m, 9H), 1.46-1.16 (m, 10H), 1.04- 0.92 (m, 1H), 0.84-0.77 (m, 4H), 0.64 (s, 3H).

LC/MS Rt=1.228 min in 2.0 min chromatography, 30-90AB, 100% _purity , ESI MS _calcd for _C28H39F3NO2 [M ₊ H] ⁺ 478, found 478.

Example 65. Synthesis connections 74

Step 1 (Compound 74). To a solution of DIPEA (21.4 mg, 0.166 mmol) in DMF (3 mL) was added PhNHMe (27.3 mg, 0.256 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h. O3 (60 mg, 0.128 mmol) was added. The reaction mixture was stirred at 40 °C for 20 h and quenched with water (5 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was triturated with _H2O (10 mL) at 25°C to give compound 74 (21 mg, crude) as a solid. The crude product was purified by HPLC (Instrument: BQ; Method: Column YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient 80%-100% B; Gradient time (min): 9.5) to give compound 74 (8 mg, 38%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.23-7.17 (m, 2H), 6.71 (t, J=8.0 Hz, 1H), 6.60 (d,J=8.0 Hz, 2H), 4.11-3.96 (m, 2H), 2.99 (s, 3H), 2.64-2.57 (m, 1H), 2.22-2, 08 (m, 1H), 1.99-1.94 (m, 1H), 1.86-1.57 (m, 9H), 1.46-1.19 (m, 9H), 1.18- 0.89 (m, 2H), 0.85-0.76 (m, 4H), 0.67 (s, 3H)

LC/MS Rt=1.227 min in 2.0 min chromatography, 30-90AB, purity 100% ESI calcd for C ₂₉ H ₄₁ F ₃ NO ₂ [M+H] ⁺ 492 found 492

Example 66. Synthesis connections 75

The synthesis of P1 is disclosed in WO2016/123056.

To a solution of DIPEA (18.8 mg, 146 μmol) in DMF (3 mL) was added N-methylaniline (24.2 mg, 226 μmol) at 10 °C under N ₂ atmosphere at 10 °C. The mixture was stirred at this temperature for 30 min. Then P1 (50 mg, 0.113 mmol) was added. The mixture was heated at 60 °C for 16 h. The mixture was concentrated to give a light yellow oil, which was purified by HPLC (Column: Xtimate C18 150*25mm*5μm; Conditions: water (0.05% HCl)-ACN; Gradient 63%-88% B; Gradient time (min): 9.5) to give compound 75 (7.00 mg, 13%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.35-7.20 (m, 2H), 7.05-6.86 (m, 3H), 4.08-4.03 (m, 2H), 3.58-3.47 (m , 1H), 3.32 (s, 3H), 3.20-3.12 (m, 1H), 3.11 (s, 3H), 2.54 (br.s, 1H), 2.20- 2.03 (m, 1H), 1.90 (s, 3H), 1.82-1.33 (m, 12H), 1.33-1.06 (m, 10H), 0.58 (s, 3H).

LC/MS Rt=0.943 min in 1.5 min chromatography, 5-95 AB, _purity 100%, ESI MS calcd for _C30H46NO3 [M ₊ H] ⁺ 468, found 468.

Example 67. Synthesis connections 76

Step 1 (Compound 76) To a solution of P1 (100 mg, 0.226 mmol) in DMF (5 mL) were added aniline (25.2 mg, 0.271 mmol) and TEA (68.6 mg, 0.678 mmol) at 25 °C under N ₂ atmosphere. The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was purified by preparative HPLC (Column: Gemini 150*25 mm, 5 μm; Conditions: water (0.05% HCl)-ACN; Gradient 66%-91% B; Gradient time (min): 30) to give compound 76 (15 mg, 15%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 7.40-7.33 (m, 4H), 7.24-7.18 (m, 1H), 4.24-4.18 (m, 2H), 3.53-3.48 (m , 1H), 3.31 (s, 3H), 3.18-3.13 (m, 1H), 2.55-2.45 (m, 1H), 2.22-2.12 (m, 1H ), 1.92-1.84 (m, 3H), 1.80-1.71 (m, 3H), 1.63-1.40 (m, 10H), 1.28-1.15 (m , 10H), 0.58 (s, 3H).

LC/MS Rt=2.014 min in 3.0 min chromatography, 10-80AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₄ NO ₃ [M+H] ⁺ 454, found 454.

Example 68. Synthesis connections 77

The synthesis of Q1 is disclosed in WO2015/27227 A1.

To a solution of Q1 (80 mg, 0.1614 mmol) in DMF (1 mL) was added DIPEA (52.1 mg, 0.4035 mmol). The mixture was stirred at 20 °C for 10 min. Aniline (37.5 mg, 0.4035 mmol) was added to the reaction mixture. After stirring at 20 °C for 12 h, the mixture was poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by HPLC (Column: Phenomenex Gemini C18 250*50mm*10μm, Gradient: 78-88% B, Conditions: water (0.05% ammonium hydroxide v/v)-ACN, Flow rate: 30 mL/min) to give compound 77 (35 mg, 43%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.22-7.17 (m, 2H), 6.76-6.70 (m, 1H), 6.62-6.59 (m, 2H), 3.28-3.23 (m , 1H), 4.68 (br.s, 1H), 4.0-3.87 (m, 2H), 3.50-3.48 (m, 1H), 3.31 (s, 3H), 2.61-2.54 (m, 1H), 2.29-1.68 (m, 11H), 1.65-1.21 (m, 12H), 0.65 (s, 3H).

LC/MS Rt=2.273 min in 3 min chromatography, 30-90CD, purity 100%, ESI MS calcd for C ₂₉ H ₄₁ F ₃ NO ₃ [M+H] ⁺ 508, found 508.

Example 69. Synthesis connections 78

The synthesis of R1 is disclosed in WO2015/27227 A1.

Step 1 (R2). Liquid bromine (1.9 g, 0.61 mL, 11.9 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (9 mL, 4 M, 36 mmol) at 0 °C. When all the bromine had dissolved, the mixture was diluted with cold dioxane (0.75 mL) and slowly added to a stirred solution of R1 (500 mg, 1.2 mmol) in dioxane (1 mL) and water (0.75 mL). The homogeneous yellow solution slowly became colorless and a white precipitate formed. The reaction mixture was stirred at 25 °C for 16 h. The remaining oxidizing reagent was blocked with an aqueous solution of Na ₂ S ₂ O ₃ (1.5 mL), and the mixture was then heated at 80 °C until the solid dissolved. Acidification of the solution with hydrochloric acid (3 N) resulted in the precipitation of a white precipitate. The solid was filtered and washed with water (3 x 20 mL) to give a solid which was dried under vacuum to give R2 (600 mg, crude) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.70 (s, 1H), 3.59-3.44 (m, 1H), 3.26-3.15 (m, 4H), 2.34-2.23 (m, 1H), 2.07-1.32 (m, 17H), 1.27-0.98 (m, 6H), 0.68-0.56 (m, 3H).

LC/MS _Rt =0.948 min in 2 min chromatography, 30-90AB, purity ₉₇ %, ESI MS _{calcd for C22H32F3O4 [} MH] ^- 417, found 417.

Step 2 (Compound 78). To R2 (60 mg, 0.14 mmol) in DCM (3 mL) were added HATU (81.3 mg, 0.21 mmol) and Et ₃ N (72.3 mg, 0.71 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, aniline (21.2 mg, 0.228 mmol) was added at 25 °C. The reaction mixture was stirred at 40 °C for 10 h and treated with water (10 mL). The mixture was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC (Column: Xtimate C18 150*25mm*5μm), Conditions: water (0.225%FA)-ACN, Gradient: 75-95% B, Gradient time: 13 min, 100% B Retention time: 2.5 min, Flow rate: 25 ml/min) to give compound 78 (21 mg, 29%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.54-7.46 (m, 2H), 7.36-7.29 (m, 2H), 7.13-7.06 (m, 1H), 6.93 (s, 1H), 3.54-3.48 (m, 1H), 3.30 (s, 3H), 3.29-3.25 (m, 1H), 2.34-2.23 (m, 2H), 2. 17-2.08 (m, 1H), 2.07-1.96 (m, 4H), 1.89-1.61 (m, 7H), 1.51-1.42 (m, 3H), 1.41-1.04 (m, 7H), 0.75 (s, 3H).

LC/MS Rt=1.101 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₈ H ₃₉ F ₃ NO ₃ [M+H] ⁺ 494, found 494.

Example 70. Synthesis connections 79

Step 1 (Compound 79). To R2 (100 mg, 0.23 mmol) in DCM (3 mL) were added HATU (135 mg, 0.35 mmol) and Et ₃ N (120 mg, 1.19 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, N-methyl-1-phenylmethanamine (46 mg, 0.38 mmol) was added at 25 °C. The reaction mixture was stirred at 40 °C for 10 h and treated with water (10 mL). The mixture was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by HPLC (Column: Xtimate C18 150*25mm*5μm), Conditions: water (0.225%FA)-ACN, Gradient: 70-100% B, Gradient time: 13 min, 100% B Retention time: 2.5 min, Flow rate: 25 ml/min) to give compound 79 (46 mg, 37%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.39-7.28 (m, 2H), 7.25-7.17 (m, 2H), 7.16-7.08 (m, 1H), 5.08-4.89 (m , 1H), 4.37-4.21 (m, 1H), 3.56-3.48 (m, 1H), 3.31 (s, 3H), 3.29-3.23 (m, 1H ), 3.01-2.91 (m, 3H), 2.83-2.67 (m, 1H), 2.41-2.27 (m, 1H), 2.15-1.86 (m , 4H), 1.84-1.59 (m, 7H), 1.54-1.18 (m, 10H), 1.16-0.98 (m, 1H), 0.80 (s, 3H).

LC/MS Rt=1.110 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₃₀ H ₄₃ F ₃ NO ₃ [M+H] ⁺ 522, found 522.

Example 71. Synthesis connections 80

Step 1 (Compound 80). To R2 (100 mg, 0.23 mmol) in DCM (3 mL) were added HATU (135 mg, 0.35 mmol) and Et ₃ N (120 mg, 1.19 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, cyclohexamine (37.6 mg, 0.38 mmol) was added at 25 °C. The reaction mixture was stirred at 25 °C for 10 h and treated with water (10 mL). The mixture was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by trituration with MeCN (5 mL) to give compound 80 (49 mg, 40%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.16-5.07 (m, 1H), 3.87-3.73 (m, 1H), 3.54-3.47 (m, 1H), 3.30 (s, 3H), 3.29-3.24 (m, 1H), 2.23-1.86 (m, 9H), 1.79-1.62 (m, 8H), 1.55-1.33 (m, 8H ), 1.29-1.02 (m, 9H), 0.66 (s, 3H).

LC/MS Rt=1.107 min in 2 min chromatography, 30-90AB, purity 97%, ESI MS calcd for C ₂₈ H ₄₅ F ₃ NO ₃ [M+H] ⁺ 500, found 500.

Example 72. Synthesis connections 81 And connections 82

The synthesis of S1 is disclosed in Russian Chemical Bulletin, 2013 , Vol. 62, 9 p., 2086-2087.

Step 1 (S2). To a solution of S1 (5.00 g, 13.9 mmol) in THF (100 mL) was added Pd/C (wet, 1.5 g). The mixture was stirred under _H2 (15 psi (103.4 kPa)) at 25 °C for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to give S2 (4.80 g, 96%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.03-3.80 (m, 4H), 3.74 (s, 2H), 2.74-2.66 (m, 1H), 2.40-1.98 (m, 5H), 1.98-1.56 (m, 6H), 1.56-1.05 (m, 12H), 1.01 (s, 3H), 0.78 (s, 3H).

Step 2 (S3). A solution of trimethylsulfonium iodide (5.42 g, 26.6 mmol) and NaH (1.06 g, 26.6 mmol, 60% purity) in DMSO (50 mL) was stirred at 25 °C for 1.0 h under N ₂ . A solution of S2 (4.80 g, 13.3 mmol) in DMSO (20 mL) was added to the reaction mixture, and the mixture was stirred at 60 °C for 4 h. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give S3 (4.80 g, 48%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.89-3.86 (m, 4H), 2.63-2.55 (m, 2H), 2.44-2.33 (m, 1H), 2.07-1.56 (m , 8H), 1.50-1.05 (m, 11H), 1.05-0.93 (m, 7H), 0.93-0.78 (m, 2H), 0.76 (s, 3H ).

Step 3 (S4). To anhydrous ethanol (100 mL) was added Na (2.94 g, 128 mmol) in five portions. The mixture was stirred at 25 °C for 2 h. The reaction mixture was added S3 (4.8 g, 12.8 mmol) in THF (50 mL) and then stirred at 60 °C for 5 h. After cooling the reaction mixture to 0 °C, the reaction was quenched with H ₂ O (100 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give S4 (4.80 g, 89%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.06-3.85 (m, 3H), 3.76-3.65 (m, 1H), 3.58-3.40 (m, 2H), 3.26-3.18 (m , 1H), 2.08-1.56 (m, 8H), 1.56-1.05 (m, 21H), 1.05-0.78 (m, 5H), 0.73 (s, 3H ).

Step 4 (Compound 81). To a solution of S4 (4.80 g, 11.4 mmol) in methanol (50 mL) was added dropwise hydrogen chloride (22.8 mL, 1 M in H ₂ O) at 25 °C. The mixture was stirred at 25 °C for 10 min. The mixture was poured into water (50 mL). The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give the impure product as a solid, which was re-purified by silica gel chromatography to give compound 81 (600 mg) as a light yellow oil, which was triturated with MeCN (10 mL) at 25 °C for 2 h to give compound 81 (500 mg, 10%) as a light yellow oil.

The structure of compound 81 was confirmed by the NOE method.

¹ H NMR(400 MHz, CDCl₃) δ 3.58-3.49 (sq.,J=6.8 Hz,J=14 Hz, 2H), 3.47-3.36 (sq., J=8.8 Hz,J=20.8 Hz, 2H), 2.72 (s, 1H), 2.57-2.48 (t, J=8.8 Hz, 1H), 2.18-2.13 (m, 1H), 2.10 (s, 3H), 2.04-1.78 (m, 3H), 1.74-1, 58 (m, 4H), 1.55-1.32 (m, 8H), 1.31-1.12 (m, 8H), 1.04-0.96 (m, 1H), 0.93 ( s, 3H), 0.58 (s, 3H).

LC/MS Rt=1.113 min in 2 min chromatography, 30-90AB, ^{purity 100%, ESI MS calcd for C24H39O2[M+HH2O]+} _{359 , found 359} .

Step 5 (S5). Liquid bromine (848 mg, 0.271 mL, 5.31 mmol) was slowly added to a vigorously stirred aqueous solution of sodium hydroxide (5.30 mL, 4 M, 21.2 mmol) at 0 °C. When all the bromine had dissolved, the mixture was diluted with cold (0 °C) dioxane (2 mL) and slowly added to a stirred solution of compound 81 (200 mg, 0.531 mmol) in dioxane (2 mL) and water (1.5 mL). The homogeneous yellow solution slowly decolorized and a white precipitate formed. The reaction mixture was stirred at 25 °C for an additional 16 h. The remaining oxidizing reagent was blocked with an aqueous solution of Na ₂ S ₂ O ₃ (1.5 mL), and the mixture was then heated at 80 °C until the solid dissolved. Oxidation of the solution with aqueous hydrochloric acid (3 N) resulted in the formation of a white precipitate. The solid was filtered and washed with water (3 x 20 mL) to give a solid which was dried under vacuum to give S5 (380 mg, crude) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 3.58-3.50 (m, 2H), 3.46-3.38 (m, 2H), 2.42-2.34 (m, 1H), 2.04 (s, 1H), 1.96-1.30 (m, 14H), 1.26-1.10 (m, 11H), 1.03-0.90 (m, 4H), 0.71 (s, 3H).

Step 6 (Compound 82). To a solution of S5 (200 mg, 0.528 mmol) in DCM (3 mL) were added HATU (301 mg, 0.792 mmol) and _Et3N (266 mg, 2.63 mmol) at 25 °C. After stirring at 25 °C for 10 min, N-methyl-1-phenylmethanamine (95.9 mg, 0.792 mmol) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 1.5 h and quenched with ice water (10 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (2×10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated, the resulting residue was purified by flash chromatography on silica gel (0~25% EtOAc in PE) to give compound 82 (100 mg) as a solid _. Compound 82 was redissolved in EtOAc (20 mL) and washed with _H2O (3×20 mL), dried over _Na2SO4 , filtered, concentrated in vacuo to give compound 82 (78 mg, 31%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.38-7.29 (m, 2H), 7.25-7.21 (m, 2H), 7.16-7.09 (m, 1H), 5.08-4.88 (m , 1H), 4.37-4.22 (m, 1H), 3.58-3.49 (m, 2H), 3.47-3.33 (m, 2H), 2.99-2.91 (m, 3H), 2.88-2.64 (m, 2H), 2.38-2.26 (m, 1H), 1.98-1.66 (m, 6H), 1.52-0 .98 (m, 17H), 1.04-0.96 (m, 1H), 0.94 (s, 3H), 0.78 (s, 3H).

LC/MS Rt=1.172 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₃₁ H ₄₈ NO ₃ [M+H] ⁺ 482, found 482.

Example 73. Synthesis connections 83

The synthesis of T1 is disclosed in WO2015/180679.

Step 1 (Compound 83): To a solution of DIPEA (37.8 mg, 0.293 mmol) in DMF (3 mL) was added N-methylaniline (48.4 mg, 0.452 mmol) at 25 °C under N ₂ atmosphere. After stirring at 25 °C for 30 min, T1 (100 mg, 226 mmol) was added. The mixture was stirred at 50°C for 16 hours and concentrated to give a light yellow oil, which was purified by HPLC (Column: YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05% HCl)-ACN; Gradient 80%-100% B; Gradient time (min): 9.5) to give compound 83 (32.0 mg, 30%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.18 (m, 2H), 6.75-6.68 (m, 1H), 6.62-6.59 (m, 2H), 4.11-3.98 (m , 2H), 3.58-3.38 (m, 4H), 3.00 (s, 3H), 2.72 (br.s, 1H), 2.62-2.56 (m, 1H), 2.22-2.05 (m, 1H), 2.00-1.92 (m, 1H), 1.85-1.53 (m, 7H), 1.53-1.33 (m, 7H ), 1.33-1.02 (m, 10H), 0.67 (s, 3H).

LC/MS Rt=1.031 min in 1.5 min chromatography, 5-95 AB, _purity 100%, ESI MS calcd for _C30H46NO3 [M ₊ H] ⁺ 468, found 468.

Example 74. Synthesis connections 84

Step 1 (Compound 84). To a solution of DIPEA (37.8 mg, 293 μmol) in DMF (3 mL) was added aniline (42.0 mg, 452 μmol) at 25 °C under N ₂ atmosphere. After stirring at 25 °C for 30 min. T1 (100 mg, 0.226 mmol) was added. The mixture was stirred at 50 °C for 16 h and concentrated to give a light yellow oil, which was purified by HPLC (Column: YMC-Actus Triart C18 100*30mm*5μm; Conditions: water (0.05% HCl)-ACN; Gradient 75%-100% B; Gradient time (min): 8) to give compound 84 (22.0 mg, 21%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.13 (m, 2H), 6.75-6.68 (m, 1H), 6.62-6.53 (m, 2H), 4.69 (br.s, 1H ), 4.00-3.85 (m, 2H), 3.58-3.35 (m, 4H), 2.73 (s, 1H), 2.62-2.53 (m, 1H), 2.28-2.15 (m, 1H), 1.98-1.90 (m, 1H), 1.85-1.53 (m, 7H), 1.53-1.31 (m, 7H ), 1.31-0.98 (m, 10H). 0.84 (s, 3H).

LC/MS Rt=0.989 min in 1.5 min chromatography, 5-95 AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₄ NO ₃ [M+H] ⁺ 454, found 454.

Example 75. Synthesis connections 85

Step 1 (Compound 85). To a solution of T2 (50 mg, 0.113 mmol) in DMF (5 mL) were added N-methylaniline (14.4 mg, 0.135 mmol) and TEA (34.3 mg, 0.339 mmol) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 18 h to give a yellow solution. The solution was poured into saturated aqueous LiCl (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a loose solid. The solid was purified by HPLC (Column: Xtimate C18 150*25mm*5μm; Conditions: water (0.05%HCl)-ACN; Gradient 70%-100% B; Gradient time (min): 10) to give compound 85 (31.0 mg, 59%) as a loose solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.13 (m, 2H), 6.74-6.65 (m, 1H), 6.59-6.54 (m, 2H), 4.10-3.95 (m , 2H), 3.55-3.45 (m, 2H), 3.22 (s, 2H), 3.00 (s, 3H), 2.65-2.54 (m, 1H), 2. 30-1.50 (m, 8H), 1.50-1.05 (m, 14H), 1.05-0.70 (m, 3H), 0.70-0.65 (m, 5H).

LC/MS Rt=1.029 min in 1.5 min chromatography, 5-95 AB, _purity 100%, ESI MS calcd for _C30H46NO3 [M ₊ H] ⁺ 468, found 468.

Example 76. Synthesis connections 86

Step 1 (Compound 86). To a solution of T2 (50 mg, 0.113 mmol) in DMF (5 mL) were added aniline (12.5 mg, 0.135 mmol) and TEA (34.3 mg, 0.339 mmol) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 18 h to give a yellow solution. The mixture was poured into saturated aqueous LiCl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic phase was washed with brine (2×50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to give a fluffy solid, which was purified by HPLC (Column: Xtimate C18 150*25mm*5μm; Conditions: water (0.05% HCl)-ACN; Gradient 70%-100% B; Gradient time (min): 10) to give compound 86 (7.00 mg, 14%) as a fluffy solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.25-7.10 (m, 2H), 6.74-6.65 (m, 1H), 6.59-6.52 (m, 2H), 4.68-4.63 (m , 1H), 4.02-3.82 (m, 2H), 3.55-3.42 (m, 2H), 3.21 (s, 2H), 2.62-2.52 (m, 1H ), 2.30-2.15 (m, 1H), 2.10-2.05 (m, 1H), 1.98-1.50 (m, 7H), 1.50-0.92 (m , 15H), 0.90-0.65 (m, 3H), 0.65 (s, 3H).

LC/MS Rt=1.019 min in 2.0 min chromatography, 5-95 AB, purity 100%, ESI MS calcd for C ₂₉ H ₄₄ NO ₃ [M+H] ⁺ 454, found 454.

Example 77. Synthesis connections 87 And connections 88

Step 1 (U2). To a solution of commercially available dehydroisoandrosterone U1 (47 g, 162 mmol) in MeOH (200 mL) and THF (200 mL) was added Pd/C (5 g, <1% water), and the solution was hydrogenated under 30 psi (206.8 kPa) of hydrogen at 25°C for 48 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford U2 (45 g, 91%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.65-3.54 (m, 1H), 2.49-2.38 (m, 1H), 2.13-1.99 (m, 1H), 1.97-1.88 (m , 1H), 1.87-1.76 (m, 3H), 1.74-1.63 (m, 2H), 1.59-1.07 (m, 12H), 1.03-0.94 (m, 2H), 0.89-0.79 (m, 6H), 0.74-0.63 (m, 1H).

Step 2 (U3). To a solution of U2 (160 g, 550 mmol) and silica gel (300 g) in DCM (2 L) was added PCC (237 g, 1100 mmol) at 25 °C. The mixture was stirred for 1 h. The solution was filtered and the filter cake was washed with DCM (500 mL). The filtrate was diluted with PE (2 L) and stirred with silica gel (100 g) for 30 min. The silica gel was filtered and washed with DCM (300 mL). The combined filtrate was concentrated in vacuo to give U3 (150 g, crude) as a solid.

¹ H NMR(CDCl₃,400M Hz) δ 2.50-2.20 (m, 4H), 2.25-1.90 (m, 4H), 1.85-1.80 (m, 2H), 1.75-1, 65 (m, 1H), 1.60-1.45 (m, 3H), 1.45-1.20 (m, 6H), 1.05-0.90 (m, 4H), 0.89- 0.75 (m, 4H).

Step 3 (U4). A suspension of LiCl (6.14 g, 145 mmol, anhydrous) in THF (600 mL, anhydrous) was stirred at 10 °C for 30 min under N ₂ . FeCl ₃ (12.3 g, 76.2 mmol, anhydrous) was added at 10 °C. The mixture was cooled to -30 °C. To the mixture was added MeMgBr (92.3 mL, 3 M in diethyl ether) dropwise at -30 °C. The mixture was stirred at -30 °C for 10 min. U3 (20 g, 69.3 mmol) was added at -30 °C. The mixture was stirred at -15 °C for 2 h. To the mixture was added citric acid (400 mL, 10% aq.). The mixture was extracted with EtOAc (3×200 mL). The combined organic phase was washed with brine (300 mL) _, dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography eluting with (PE/EtOAc=1/10~1/5) to give U4 (18.5 g, 88%) as a solid.

¹ H NMR(400MHz, CDCl₃) δ 2.45-2.39 (m, 1H), 2.12-2.00 (m, 1H), 1.98-1.88 (m, 1H), 1.84-1.74 (m , 2H), 1.72-1.64 (m, 1H), 1.61-1.42 (m, 7H), 1.33-1.22 (m, 8H), 1.20 (s, 3H ), 1.08-0.95 (m, 1H), 0.86 (s, 3H), 0.84-0.79 (m, 1H), 0.77 (s, 3H)

Step 5 (Compound 87). To a solution of aniline (61 mg, 0.656 mmol) in DCE (2 mL) were added U4 (100 mg, 0.328 mmol) and HOAc (39.3 mg, 0.656 mmol). The mixture was stirred at 15 °C for 10 min. Then NaBH(OAc) ₃ (127 mg, 0.656 mmol) was added. The reaction mixture was stirred at 15 °C for 16 h. The reaction was quenched with saturated aqueous NaHCO ₃ (20 mL) and the mixture was extracted with DCM (3×10 mL). _The combined organic phase was dried over _Na2SO4 , filtered, concentrated and purified by silica gel chromatography (0-10% EtOAc in (PE and _NH3 / _H2O , v:v=100:1) to afford impure compound 87 (20 mg) as a solid, which was triturated with hexane (3 mL). The mixture was filtered and the filter cake was washed with hexane (3×1 mL) to afford pure compound 87 (12 mg, 10%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.17-7.07 (m, 2H), 6.66-6.58 (m, 3H), 3.64-3.52 (m, 1H), 3.46-3.31 (m , 1H), 2.29-2.15 (m, 1H), 1.81-1.58 (m, 4H), 1.53-1.36 (m, 6H), 1.35-1.23 (m, 5H), 1.21-1.07 (m, 8H), 1.00-0.89 (m, 1H), 0.82-0.72 (m, 7H).

LC/MS Rt=0.918 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C26H40NO [M ₊ H] ⁺ 382, found 382.

Step 6 (Connection 88). To a solution of compound 87 (500 mg, 1.31 mmol) in THF (10 mL) were added acetic acid (157 mg, 2.62 mmol) and paraformaldehyde (486 mg, 5.24 mmol). After stirring at 25 °C for 2.5 h, sodium cyanoborohydride (205 mg, 3.27 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h and quenched with water (30 mL), the reaction mixture was extracted with EtOAc (2 x 30 mL). The organic layers were washed with brine (2 x 40 mL), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo to give a residue, which was purified by chromatography on silica gel eluted (PE/EtOAc = 10/1 to 4/1) to give compound 88 (37 mg, 12%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.23-7.17 (m, 2H), 6.91-6.85 (m, 1H), 6.74-6.67 (m, 2H), 3.76-3.67 (m , 1H), 2.88-2.80 (m, 3H), 2.02-1.62 (m, 5H), 1.62-1.56 (m, 1H), 1.53-1.43 (m, 4H), 1.42-1.31 (m, 2H), 1.31-1.22 (m, 6H), 1.21-1.16 (m, 5H), 1.15-1 .04 (m, 1H), 1.03-0.86 (m, 1H), 0.83-0.77 (m, 4H), 0.75 (s, 3H).

LC/MS Rt=0.734 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C27H42NO [M ₊ H] ⁺ 396, found 396.

Example 78. Synthesis connections 89

The synthesis of U4 is disclosed in WO2016/61527.

Step 1 (Compound 89). To a solution of U4 (200 mg, 0.656 mmol) in toluene (3 mL) were added 4-fluoroaniline (145 mg, 1.31 mmol) and 4-methylbenzenesulfonic acid (112 mg, 0.656 mmol) at 15 °C under N ₂ . The mixture was heated under reflux at 110 °C for 16 h. After cooling to 15 °C, NaBH ₄ (49.5 mg, 1.31 mmol) was added. The mixture was poured into water (15 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0~15% EtOAc in PE) to afford compound 89 (11 mg, 4%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 6.87-6.79 (m, 2H), 6.60-6.50 (m, 2H), 3.49-3.37 (m, 1H), 3.36-3.25 (m , 1H), 2.28-2.11 (m, 1H), 1.75-1.62 (m, 3H), 1.60-1.55 (m, 1H), 1.54-1.44 (m, 4H), 1.43-1.32 (m, 2H), 1.31-1.22 (m, 5H), 1.21-1.14 (m, 7H), 1.14-1 .06 (m, 1H), 1.03-0.86 (m, 1H), 0.84-0.69 (m, 7H).

LC/MS Rt=1.066 min in 2 min chromatography, 30-90AB, ^{purity 100%, ESI MS calcd for C26H39FNO [M+H] +} _{400 ,} found 400.

Example 79. Synthesis connections 90

Step 1. (Compound 90). A solution of U4 (200 mg, 0.656 mmol), 3-fluoroaniline (109 mg, 0.984 mmol), 4-methylbenzenesulfonic acid (56.4 mg, 0.328 mmol) in toluene (5 mL) was stirred at 110 °C for 12 h. After cooling to 25 °C, NaBH ₄ (49.5 mg, 1.31 mmol) and 5 mL MeOH were added. The mixture was stirred at 25 °C for 30 min, poured into water (20 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by HPLC (Column: Phenomenex Synergi C18 150*30mm*4μm, gradient: 95-95% B (A=0.05%HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to give compound 90 (16 mg, 6%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 7.06-7.00 (m, 1H), 6.38-6.28 (m, 3H), 3.74-3.67 (m, 1H), 3.37-3.30 (m , 1H), 2.26-2.16 (m, 1H), 1.77-1.63 (m, 3H), 1.62-1.57 (m, 2H), 1.54-1.34 (m, 7H), 1.32-1.08 (m, 11H), 1.04-0.85 (m, 2H), 0.83-0.74 (m, 6H).

LC/MS Rt=1.309 min in 2.0 min chromatography, 30-90 AB, purity 96.5%, ESI MS _calcd for _C26H39FNO [M+H] ⁺ 400, found 400.

Example 80. Synthesis connections 91

Step 1 (Compound 91). A solution of U4 (200 mg, 0.656 mmol), 2-fluoroaniline (109 mg, 0.984 mmol), 4-methylbenzenesulfonic acid (56.4 mg, 0.328 mmol) in toluene (5 mL) was stirred at 110 °C for 12 h. After cooling to 25 °C, NaBH ₄ (49.5 mg, 1.31 mmol) and 5 mL MeOH were added. The mixture was stirred at 25 °C for 30 min, poured into water (30 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by HPLC (Column: Phenomenex Synergi C18 150*30mm*4μm, gradient: 93-93% B (A=0.05%HCl-ACN, B=acetonitrile), flow rate: 25 mL/min) to give compound 91 (6 mg, 2%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 6.95-6.90 (m, 2H), 6.79-6.74 (m, 1H), 6.56-6.52 (m, 1H), 3.85-3.81 (m , 1H), 3.42-3.35 (m, 1H), 2.27-2.17 (m, 1H), 1.76-1.64 (m, 2H), 1.62-1.32 (m, 10H), 1.30-1.06 (m, 11H), 1.05-0.86 (m, 2H), 0.83-0.66 (m, 6H).

LC/MS Rt=1.393 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C26H39FNO [M ₊ H] ⁺ 400, found 400.

Example 81. Synthesis connections 92, connections 93 And connections 94

Step 1 (Compound 92) A solution of U4 (3 g, 9.85 mmol), phenylmethanamine (4.22 g, 39.4 mmol), NaBH(OAc) ₃ (5.21 g, 24.6 mmol), HOAc (2.36 g, 39.4 mmol) in 1,2-dichloroethane (30 mL) was stirred at 25 °C for 12 h. Saturated _Na2CO3 solution (10 mL) was added to _the mixture and stirred for 10 min. The mixture was poured into water (20 mL) and extracted with DCM (2×100 _mL ). The combined organic layers were washed with brine (200 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EtOAc=1:1) to give compound 92 (2.3 g, 59%) as a solid. Compound 92 (100 mg, 0.252 mmol) was re-purified by preparative HPLC (Column: Gemini 150*25mm, 5μm, gradient: 85-100%, Conditions: water (10 mM NH ₄ HCO ₃ )-ACN, flow rate: 30 mL/min) to give compound 92 (13 mg, 13%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 7.41-7.39 (m, 2H), 7.33 (t, J=8 Hz, 2H), 7.28-7.24 (m, 1H), 3.99-3.81 (m, 2H), 2.58 (m, 1H), 2.02-1.91 ( m, 2H), 1.66-1.48 (m, 5H), 1.46-1.10 (m, 15H), 1.07-0.82 (m, 7H), 0.77-0. 68 (m, 4H).

LC/MS Rt=0.783 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C27H42NO [M ₊ H] ⁺ 396, found 396.

Step 2 (Compound 93). To a solution of compound 92 (2.3 g, 5.81 mmol) in MeOH (30 mL) was added Pd/C (0.5 g, <1% water). The solution was then hydrogenated under 50 psi (344.7 kPa) of hydrogen at 25 °C for 3 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to give compound 93 (1.5 g, 85%) as a solid. Compound 93 (100 mg, 0.327 mmol) was purified by silica gel chromatography (DCM/MeOH=10/1) to give compound 93 (14 mg, 14%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 2.67-2.62 (m, 1H), 2.04-1.95 (m, 1H), 1.72-1.64 (m, 2H), 1.62-1.60 (m , 1H), 1.56-1.46 (m, 4H), 1.40-1.09 (m, 16H), 1.01-0.85 (m, 3H), 0.79-0.71 (m, 4H), 0.62 (s, 3H).

LC/MS Rt=4.746 min in 7.0 min chromatography, 30-90 CD, purity 100%, ESI MS calcd for _C20H36NO [M ₊ H] ⁺ 306, found 306

Step 3 (Compound 94). To a solution of compound 93 (200 mg, 0.65 mmol) and TEA (164 mg, 1.63 mmol) in DCM (2 mL) was added benzoyl chloride (182 mg, 1.3 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 15 h under N ₂ atmosphere. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel column (EtOAc/PE=3/1) to give compound 94 (120 mg, 45%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.76-7.74 (m, 2H), 7.52-7.47 (m, 1H), 7.45-7.41 (m, 2H), 5.95-5.92 (m , 1H), 4.14-4.07 (m, 1H), 2.26-2.18 (m, 1H), 1.78-1.66 (m, 3H), 1.63-1.58 (m, 1H), 1.53-1.23 (m, 13H), 1.2-1.16 (m, 5H), 1.02-0.92 (m, 2H), 0.87-0 .76 (m, 7H).

LC/MS Rt=1.355 min in 2.0 min chromatography, 30-90 AB, purity 100%, _ESI MS calcd for _C27H40NO2 [M ₊ H] ⁺ 410, found 410.

Example 82. Synthesis connections 95

Step 1 (Compound 95). To a solution of compound 93 (200 mg, 0.65 mmol) and DMAP (198 mg, 1.63 mmol) in DCM (3 mL) was added acetic anhydride (132 mg, 1.3 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=3/1) to afford compound 95 (60 mg, 26% yield) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 5.25-5.23 (m, 1H), 3.91-3.84 (m, 1H), 2.15-2.07 (m, 1H), 1.97 (s, 3H), 1.71-1.62 (m, 3H), 1.54-1.44 (m, 4H), 1.42-1.04 (m, 16H), 0.99-0.88 (m, 1H ), 0.81-0.73 (m, 4H), 0.67 (s, 3H).

LC/MS Rt=0.869 min in 2 _min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C22H38NO2 [M ₊ H] ⁺ 348, found 348.

Example 83. Synthesis connections 96

Step 1 (Compound 96). To a solution of compound 93 (200 mg, 0.65 mmol) and TEA (164 mg, 1.63 mmol) in DCM (3 mL) was added benzenesulfonyl chloride (229 mg, 1.3 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (10 mL) and extracted with DCM (2×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column (PE/EtOAc=5/1~3/1) to give V1 (80 mg, 40%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 7.88-7.86 (m, 2H), 7.58-7.48 (m, 3H), 4.37-4.34 (m, 1H), 3.09-3.06 (m , 1H), 1.85-1.72 (m, 1H), 1.63-1.39 (m, 11H), 1.38-1.33 (m, 1H), 1.23-1.15 (m, 8H), 0.95-0.75 (m, 6H), 0.72 (s, 3H), 0.65 (s, 3H).

LC/MS _Rt =1.251 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C26H40NO3S [M ₊ H] ⁺ 446, found 446.

Step 2 (Compound 96). To a solution of V1 (40 mg, 0.090 mmol) and _Cs2CO3 (58.3 mg, 0.179 mmol) in DMF (2 mL) was added iodomethane (19 mg, 0.134 mmol) at 25 _° C. The mixture was stirred at 25 °C for 16 h. The mixture was poured into water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/ ₁ to 3/1) to afford compound 96 (32 mg, 78%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.80-7.78 (m, 2H), 7.57-7.48 (m, 3H), 3.75-3.70 (m, 1H), 2.78 (s, 3H), 1.91-1.89 (m, 1H), 1.66-1.53 (m, 4H), 1.51-1.43 (m, 3H), 1.39-1.09 (m, 15H ), 1.02-0.86 (m, 2H), 0.79-0.74 (m, 7H).

LC/MS Rt=1.221 min in 2.0 min chromatography, 30-90 AB, purity 98.5% _{, ESI MS calcd for C27H40NO2S [ MH2O} +H] ⁺ 442, found 442 _.

Example 84. Synthesis connections 97 And connections 98

Step 1 (Compound 97). To a solution of compound 93 (100 mg, 0.327 mmol) and DIEA (105 mg, 0.817 mmol) in DCM (2 mL) was added methanesulfonyl chloride (74.9 mg, 0.654 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE/EtOAc=2/1) to give compound 97 (50 mg, 40%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 4.13-4.11 (m, 1H), 3.28-3.21 (m, 1H), 2.95 (s, 3H), 2.22-2.12 (m, 1H), 1.83-1.78 (m, 1H), 1.70-1.59 (m, 3H), 1.55-1.35 (m, 7H), 1.29-1.09 (m, 11H ), 1.05-0.87 (m, 2H), 0.81-0.73 (4H), 0.69 (s, 3H).

LC/MS Rt=0.869 min in 2.0 min chromatography, 30-90 AB, ^purity 98.8% _{, ESI MS calcd for C21H36NO2S [ MH2O} +H] ₊ 366, found 366.

Step 2 (Compound 98): To a solution of compound 97 (40 mg, 0.90 mmol) and _Cs2CO3 (84.7 mg, 260 μmol) in DMF (2 mL) was added iodomethane (29.5 mg, 0.208 mmol) at 25 _° C. After stirring at 25 °C for 16 h, the mixture was poured into water (10 mL) and filtered. The filter cake was concentrated to give compound 98 (35 mg, 85%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 3.65-3.60 (m, 1H), 2.87 (s, 3H), 2.77 (s, 3H), 1.92-1.81 (m, 2H), 1.75- 1.57 (m, 4H), 1.53-1.43 (m, 4H), 1.36-1.12 (m, 13H), 1.06-0.89 (m, 2H), 0. 77-0.73 (m, 7H).

ESI MS calc. for C ₂₂ H ₄₀ NO ₃ S [M+H] ⁺ 398, found 398.

Example 85. Synthesis connections 99

Step 1 (U5). A solution of U4 (3 g, 9.85 mmol), N-methyl-1-phenylmethanamine (4.77 g, 39.4 mmol), NaBH(OAc) ₃ (5.21 g, 24.6 mmol) and HOAc (2.36 g, 39.4 mmol) in 1,2- _{dichloroethane} (30 mL) was stirred at 60 °C for 12 h. Then saturated aqueous _Na2CO3 solution (10 mL) was added to the mixture and the mixture was stirred for 10 min. The mixture was poured into water (20 mL) and extracted with DCM (2 _× 100 mL). The combined organic layers were washed with brine (200 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EtOAc=1/1) to give U5 (0.5 g, 12%) as a solid.

The structure was determined based on a similar reductive amination described in the literature (Steroids, 2011, 1098-1102).

¹ H NMR(400 MHz, CDCl₃) δ 7.34-7.28 (m, 4H), 7.23-7.20 (m, 1H), 3.64-3.36 (m, 2H), 2.18-2.14 (m , 1H), 2.08-2.02 (m, 4H), 1.98-1.89 (m, 1H), 1.69-1.61 (m, 2H), 1.56-1.34 (m, 7H), 1.32-1.04 (m, 12H), 0.98-0.86 (m, 5H), 0.78-0.71 (m, 4H).

Step 2 (U6). To a solution of U5 (500 mg, 1.22 mmol) in THF/MeOH (10 mL, 1/1) was added Pd/C (0.5 g, water <1%) at 25 °C. The solution was hydrogenated under 50 psi (344.7 kPa) of hydrogen at 25 °C for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford U6 ( 300 mg, 60%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 2.45-2.43 (m, 4H), 2.02-1.99 (m, 1H), 1.82-1.80 (m, 1H), 1.68-1.64 (m , 1H), 1.63-1.43 (m, 9H), 1.60-1.36 (m, 6H), 1.35-1.11 (m, 5H), 1.03-0.82 (m, 3H), 0.77-0.74 (m, 4H), 0.69 (s, 3H).

Step 3 (Compound 99). To a solution of U6 (100 mg, 0.31 mmol) and TEA (69.2 mg, 0.69 mmol) in DCM (3 mL) was added methyl chloroformate (58.9 mg, 0.62 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (10 mL) and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1~3/1) to give compound 99 (27 mg, 23%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 4.07-3.95 (m, 1H), 3.68 (s, 3H), 2.86 (s, 3H), 1.90-1.31 (m, 1H), 1.77- 1.63 (m, 4H), 1.53-1.43 (m, 4H), 1.39-1.15 (m, 13H), 1.10-0.81 (m, 3H), 0. 79-0.73 (m, 4H), 0.69 (s, 3H).

LC/MS Rt=1.259 min in 2.0 min chromatography, 30-90 AB, purity 99.3%, _ESI MS calcd for _C23H40NO3 [M ₊ H] ⁺ 378, found 378.

Example 86. Synthesis connections 100

The synthesis of W1 is disclosed in WO2014/169833.

Step 1 (Compound 100). To a solution of W1 (0.24 g, 0.83 mmol) in THF (10 mL) was added PhLi (11 mL, 1.5 M in ether, 16.5 mmol). The mixture was stirred at 65 °C for 4 h. After cooling, NH ₄ Cl (10 mL, sat.) was added. The mixture was extracted with EtOAc (20 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo, purified by silica gel chromatography (PE/EtOAc=6/1 to 5/1) to give compound 100 (120 mg) as a light brown oil. The crude material was dissolved in MeCN (20 mL) and water (5 mL) was added. The mixture was concentrated in vacuo to give a brown oil. The residue was dissolved in DCM (3 mL) and concentrated in vacuo to give compound 100 (83 mg, 27%) as a fluffy solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.40-7.28 (m, 5H), 2.47-2.32 (m, 1H), 2.18-2.05 (m, 1H), 1.86 (br.s, 1H ), 1.80-1.60 (m, 5H), 1.53-1.41 (m, 5H), 1.34-1.20 (m, 10H), 1.13-0.92 (m , 7H), 0.48-0.37 (m, 1H).

LC/MS Rt=0.975 min in 2.0 min chromatography, 30-90AB, purity 98.2%, _ESI MS calcd for _C25H33 [M+H- _2H2O ] ⁺ 333, found 333.

Example 87. Synthesis connections 101

Step 1 (W2). To a solution of W1 (5 g, 17.2 mmol) and 2,6-dimethylpyridine (4.59 g, 42.9 mmol) in DCM (100 mL) was added dropwise tert-butyldimethylsilyl trifluoromethanesulfonate (9.09 g, 34.4 mmol) at 0 °C. After stirring at 25 °C for 16 h, the reaction was quenched with water (100 mL) and the reaction mixture was extracted with EtOAc (2×100 mL). The combined organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100-200 mesh, PE/EtOAc=10/1) to give W2 (6 g, 86%) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 2.50-2.40 (m, 1H), 2.16-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.82-1.70 (m , 4H), 1.70-0.95 (m, 18H), 0.95-0.60 (m, 1H), 0.95-0.75 (m, 12H), 0.07 (s, 6H ).

Step 2 (W3). To KHMDS (9.88 mL, 1 M in THF) was added a solution of W2 (2 g, 4.94 mmol) in THF (10 mL) at 0 °C. After warming to 20 °C and stirring at 20 °C for 30 min, a solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.64 g, 7.41 mmol) in THF (15 mL) was added at 0 °C. The mixture was warmed to 20 °C and stirred at 20 °C for 17 h. The reaction was then quenched with water (20 mL) and the mixture was extracted with EtOAc (2×20 mL). The combined organic phase was washed with brine (2×30 mL), dried over _{Na2SO4 ,} filtered, concentrated in vacuo to give the crude product, which was purified by flash chromatography on silica gel (0-10% EtOAc in PE, 60 min) to give W3 (1.47 g, 56%) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 5.56 (s, 1H), 2.25-2.17 (m, 1H), 2.01-1.95 (m, 1H), 1.82-1.60 (m, 7H), 1.55-1.05 (m, 15H), 0.96 (s, 3H), 0.90-0.80 (m, 9H), 0.08 (s, 6H).

Step 3 (W4). To a mixture of W3 (200 mg, 0.372 mmol) was added phenylboric acid (58.8 mg, 0.48 mmol) and Pd(dppf) _Cl2 (28.3 mg, 0.0372 mmol) in THF (4 mL), NaOH (0.24 mL, 2 M in water). The mixture was degassed under vacuum and purged with _N2 . The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2×10 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give W4 (232 mg, crude) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.45-7.38 (m, 2H), 7.35-7.28 (m, 1H), 7.25-7.20 (m, 2H), 5.91-5.87 (m ,1H), 2.28-2.19 (m, 1H), 2.10-1.95 (m, 2H), 1.89-1.62 (m, 7H), 1.59-1.48 (m, 4H), 1.48-1.37 (m, 5H), 1.37-1.18 (m, 6H), 1.02 (s, 3H), 1.02-0.70 (m , 8H), 0.07 (s, 6H).

Step 5 (W5). To a mixture of W4 (232 mg, 0.499 mmol) in THF (2 mL) was added TBAF (332 mg, 0.998 mmol) at 80 °C. After stirring at 80 °C for 18 h, the mixture was cooled to 15 °C, treated with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to afford W5 (160 mg, 94% yield over 2 steps) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.40-7.35 (m, 2H), 7.35-7.25 (m, 1H), 7.25-7.18 (m, 2H), 5.91-5.87 (m ,1H), 2.41-2.38 (m, 1H), 2.25-2.12 (m, 1H), 2.11-1.95 (m, 2H), 1.95-1.81 (m, 3H), 1.80-1.61 (m, 3H), 1.61-1.52 (m, 1H), 1.52-1.48 (s, 3H), 1.48-1 .32(m, 3H), 1.32-1.15 (m, 5H), 1.02 (s, 3H), 0.92-0.82 (m, 3H).

Step 6 (Compound 101). To a solution of W5 (130 mg, 0.37 mmol) in EtOAc (15 mL) was added Pd/C (wet, 10%, 0.1 g) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ three times. The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 0.5 h to give a black suspension. The mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to give compound 101 (33 mg, 25%) as a solid.

The structure of compound 101 was confirmed by X-ray crystallography.

¹ H NMR(400 MHz, CDCl₃) δ 7.31-7.27 (m, 2H), 7.24-7.15 (m, 3H), 2.81-2.75 (m, 1H), 2.12-2.03 (m , 1H), 2.01-1.91 (m, 1H), 1.91-1.78 (m, 4H), 1.71-1.61 (m, 2H), 1.61-1.52 (m, 3H), 1.52-1.41 (m, 4H), 1.41-1.38 (s, 2H), 1.38-1.21 (m, 6H), 1.21-1 .09 (m, 2H), 1.05-0.79 (m, 2H), 0.46 (s, 3H).

LC/MS Rt=1.398 min in 2 min chromatography, 30-90AB, purity 100%, _ESI MS calcd for _C25H35 [M+ _HH2O ] ⁺ 335, found 335.

Example 88. Synthesis connections 102

Step 1 (X1). To a mixture of W3 (200 mg, 0.372 mmol), p-methylphenylboric acid (65.6 mg, 0.48 mmol), and Pd(dppf) _Cl2 (28.3 mg, 0.0372 mmol) in THF (4 mL) was added NaOH (0.24 mL, 2 M in water). The mixture was degassed under vacuum and purged with _N2 . The reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2 _× 5 mL), the concentrated layers were washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give X1 (240 mg, with impurities) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.30-7.25 (m, 2H), 7.12-7.08 (m, 2H), 5.89-5.85 (m, 1H), 2.33 (s, 3H), 2.33-2.15(m, 1H), 2.11-1.95(m, 2H), 1.90-1.61(m, 6H), 1.61-1.58(m, 1H ), 1.53-1.46 (m, 3H), 1.46-1.41 (m, 2H), 1.41-1.35 (m, 2H), 1.35-1.30 (m , 2H), 1.30-1.21 (m, 7H), 1.21-1.08 (m, 1H), 1.01 (s, 3H), 0.90-0.81(m, 6H), 0.07 (s, 6H).

Step 2 (X2). To a mixture of X1 (232 mg, 0.484 mmol) in THF (2 mL) was added TBAF (322 mg, 0.968 mmol) at 80 °C. After stirring at 80 °C for 18 h, the mixture was cooled to 15 °C, treated with water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% _EtOAc in PE) to afford X2 (100 mg, 56% yield over 2 steps) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.32-7.25 (m, 2H), 7.12-7.08 (m, 2H), 5.87-5.84 (m, 1H), 2.33 (s, 3H), 2.22-2.10 (m, 1H), 2.09-1.91 (m, 2H), 1.91-1.81 (m, 3H), 1.79-1.55 (m, 4H ), 1.55-1.40 (m, 5H), 1.40-1.12 (m, 9H), 1.00 (s, 3H), 0.90-0.80 (m, 1H).

Step 3 (Compound 102). To a solution of X2 (100 mg, 0.274 mmol) in EtOAc (5 mL) was added Pd/C (wet, 10%, 0.1 g) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ three times. The mixture was stirred under H ₂ (15 psi (103.4 kDa)) at 15 °C for 0.5 h to give a black suspension. The mixture was filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to give compound 102 (17 mg, 17%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.12-7.05 (m, 4H), 2.69-2.60 (m, 1H), 2.32 (s, 3H), 2.11-2.01 (m, 1H), 2.00-1.72 (m, 5H), 1.71-1.52 (m, 4H), 1.52-1.42 (m, 3H), 1.42-1.32 (m, 4H ), 1.32-1.15(m, 7H), 1.15-0.90 (m, 3H), 0.46 (s, 3H).

LC/MS Rt=1.472 min in 2 min chromatography, 30-90AB, purity 98%, _ESI MS calcd for _C26H37 [M+ _HH2O ] ⁺ 349, found 349.

Example 89. Synthesis connections 103

Step 1 (Y1). To a mixture of W3 (200 mg, 0.372 mmol), pyridin-4-ylboronic acid (59.3 mg, 0.483 mmol), and NaOH (0.241 mL, 2 M in water) in THF (4 mL) was added Pd(dppf) _Cl2 (5 mg, 0.00656 mmol) under _N2 . The suspension was stirred at 80 °C for 1 h and then cooled to room temperature. The reaction mixture was block with sat. _NaHCO3 (3 mL). The mixture was extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give Y1 (210 mg, with impurities) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 8.53-8.45 (d, 2H), 7.31-7.20 (d, 2H), 6.20-6.10 (m, 1H), 2.32-2.20 (s , 1H), 2.12-1.98 (m, 2H), 1.87-1.59 (m, 6H), 1.59-1.42 (m, 4H), 1.42-1.38 (m, 6H), 1.38-1.12 (m, 9H), 1.03 (s, 3H), 0.91-0.81 (m, 5H), 0.06 (s, 6H).

Step 2 (Y2). To a mixture of Y1 (210 mg, impurity) in THF (2 mL) was added TBAF (328 mg, 0.985 mmol). The reaction solution was stirred at 80 °C for 18 h. Water (5 mL) was added. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified on a flash column (0~30% EtOAc in PE) to afford Y2 (56 mg, 32% yield over 2 steps) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.55-8.45 (m, 2H), 7.31-7.20 (m, 2H), 6.19-6.15 (m, 1H), 2.30-2.20 (m , 1H), 2.10-1.99 (m, 2H), 1.91-1.80 (m, 3H), 1.80-1.60 (m, 3H), 1.58-1.39 (m, 7H), 1.39-1.12 (m, 9H), 1.03 (s, 3H).

Step 3 (Compound 103): To a mixture of Y2 (56 mg, 0.159 mmol) in EtOAc (5 mL) of Pd/C (100 mg, 5%, wet) was added Pd/C (100 mg, 5%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 15 h to give a black suspension, which was filtered and concentrated to give compound 103 (10 mg) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.52-8.40 (m, 2H), 7.16-7.08 (m, 2H), 2.69-2.60 (m, 1H), 2.11-2.05 (m , 1H), 2.05-1.90 (m, 1H), 1.90-1.75 (m, 4H), 1.71-1.52 (m, 4H), 1.52-1.45 (m, 3H), 1.38-1.22 (m, 7H), 1.22-0.95 (m, 5H), 0.92-0.81 (m, 2H), 0.45 (s , 3H).

LC/MS Rt=0.570 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C24H36NO [M ₊ H] ⁺ 354, found 354.

Example 90. Synthesis connections 104

Step 1 (Z1). To a mixture of W3 (200 mg, 0.372 mmol), pyrimidin-5-ylboric acid (69.1 mg, 0.558 mmol), and _Na2CO3 (0.372 mL, 2 M in water) in THF (10 mL) was added Pd( _PPh3 ) _2Cl2 (5 _mg , 0.00712 mmol). The mixture was degassed under vacuum and purged with _N2 . The reaction mixture was stirred at 80 _° C for 5 h, cooled to room temperature, block with _saturated aqueous NaHCO3 (3 mL), and extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0%-15% EtOAc in PE) to give Z1 (140 mg, 81%) as an oil.

The structure of compound 104 was confirmed by X-ray crystallography.

¹ H NMR(400 MHz, CDCl₃) δ 9.06 (s, 1H), 8.72 (s, 2H), 6.12-6.08 (m, 1H), 2.35-2.25 (s, 1H), 2.12- 1.95 (m, 2H), 1.87-1.51 (m, 7H), 1.62-1.42 (m, 4H), 1.42-1.38 (m, 4H), 1. 38-1.12 (m, 7H), 1.00 (s, 3H), 0.91-0.81 (m, 8H), 0.06 (s, 6H).

Step 2 (Z2). To a mixture of Z1 (140 mg, impurity) in THF (2 mL) was added TBAF (199 mg, 0.598 mmol). The resulting solution was stirred at 80 °C for 18 h. Water (5 mL) was added. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to afford Z2 (70 mg, 67%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 9.06 (s, 1H), 8.72 (s, 2H), 6.11-6.05 (m, 1H), 2.32-2.15 (m, 1H), 2.10- 1.95 (m, 2H), 1.91-1.72 (m, 4H), 1.72-1.62 (m, 2H), 1.61-1.59 (m, 1H), 1. 57-1.42 (m, 5H), 1.42-1.25 (m, 8H), 1.25-1.15 (m, 2H), 1.00 (s, 3H).

Step 3 (Compound 104): To a mixture of Z2 (100 mg, 0.283 mmol) in EtOAc (5 mL) was added Pd/C (100 mg, 5%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 15 h to give a black suspension, which was filtered and concentrated to give compound 104 (31 mg, 31%) as a solid.

¹ H NMR(400 MHz, CDCl₃) 9.06 (s, 1H), 8.58 (s, 2H), 2.70-2.60 (m, 1H), 2.15-1.98 (m, 2H), 1.91-1 .78 (m, 4H), 1.75-1.60 (m, 2H), 1.61-1.42 (m, 6H), 1.42-1.31 (m, 7H), 1.31 -1.22 (m, 3H), 1.22-1.08 (m, 3H), 0.51 (s, 3H).

LC/MS Rt=1.017 min in 2 min chromatography, 30-90AB, purity 100% _{, ESI MS calcd for C23H35N2O [} M ₊ H] ⁺ 355, found 355.

Example 91. Synthesis connections 105

Step 1 (AA1). To a mixture of W3 (200 mg, 0.372 mmol), (3-cyanophenyl)borinic acid (70.9 mg, 0.483 mmol), and NaOH (0.241 mL, 2 M in water) in THF (4 mL) was added Pd(dppf) _Cl2 (5 mg). The mixture was degassed under vacuum and purged with _N2 . After stirring at 80 °C for 1 h, the reaction mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give AA1 (150 mg, 82%) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.60-7.57 (d, 1H), 7.52-7.47 (d, 1H), 7.41-7.33 (t, 1H), 6.03-5.95 (m, 1H), 2.30-2.20 (m, 1H), 2.08-1.97 (m, 1H), 1.89-1.59 (m, 7H ), 1.59-1.38 (m, 6H), 1.38-1.11 (m, 9H), 1.01 (s, 3H), 0.91-0.78 (m, 9H), 0.06 (s, 6H).

Step 2 (AA2). To a mixture of AA1 (150 mg) in THF (2 mL) was added TBAF (203 mg, 0.612 mmol). The reaction mixture was stirred at 80 °C for 18 h to give a black oil. Water (5 mL) was added. The mixture was extracted with EtOAc (2 x 10 mL), the combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to give AA2 (80 mg, 70%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.63 (s, 1H), 7.60-7.57 (d, 1H), 7.52-7.47 (d, 1H), 7.41-7.33 (m, 1H), 6.03-5.95 (m, 1H), 2.30-2.20 (m, 1H), 2.08-1.93 (m, 2H), 1.91-1.80 (m, 3H ), 1.80-1.57 (m, 4H), 1.57-1.32 (m, 5H), 1.32-1.12 (m, 7H), 1.01 (s, 3H), 0.99-0.80 (m, 3H).

Step 3 (Compound 105) To a mixture of AA2 (80 mg, 0.213 mmol) in EtOAc (5 mL) was added Pd/C (100 mg, 10%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 20 min to give a black suspension, which was filtered and concentrated to give compound 105 (17 mg, 21%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.51-7.47 (m, 2H), 7.44-7.41 (m, 1H), 7.39-7.32 (m, 1H), 2.79-2.61 (m , 1H), 2.10-1.93 (m, 2H), 1.89-1.74 (m, 4H), 1.71-1.60 (m, 2H), 1.59-1.45 (m, 4H), 1.45-1.37 (m, 4H), 1.37-1.19 (m, 6H), 1.19-0.78 (m, 5H), 0.44 (s , 3H).

LC/MS Rt=1.269 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for C ₂₆ H ₃₄ N [M+HH ₂ O] ⁺ 360, found 360,

Example 92. Synthesis connections 106

Step 1 (BB1). To a mixture of W3 (200 mg, 0.372 mmol), pyridin-3-ylboronic acid (68.5 mg, 0.588 mmol) _, and _Na2CO3 (0.74 mL, 2 M in water) in 1,4-dioxane (3 mL) was added Pd(dppf) _Cl2 (5 mg, 0.00656 mmol) under _N2 . After stirring at 80 °C for 1 h, the reaction mixture was blocked with _saturated NaHCO3 (3 mL) and extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give BB1 (150 mg, 87%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.69-8.60 (m, 1H), 8.49-8.40 (m, 1H), 7.69-7.61 (m, 1H), 7.25-7.15 (m , 1H), 6.05-5.93 (m, 1H), 2.30-2.20 (m, 1H), 2.09-1.95 (m, 2H), 1.87-1.73 (m, 4H), 1.73-1.60 (m, 2H), 1.60-1.45 (m, 3H), 1.45-1.30 (m, 5H), 1.30-1 .14 (m, 7H), 1.00 (s, 3H), 0.92-0.82 (m, 9H), 0.06 (c, 6H).

Step 2 (BB2). To a mixture of BB1 (150 mg) in THF (2 mL) was added TBAF (214 mg, 0.644 mmol). The reaction mixture was stirred at 80 °C for 18 h. Water (5 mL) was added to the reaction mixture. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give BB2 (89 mg, 79%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.69-8.60 (m, 1H), 8.49-8.40 (m, 1H), 7.69-7.61 (m, 1H), 7.26-7.18 (m , 1H), 6.00-5.93 (m, 1H), 2.30-2.20 (m, 1H), 2.09-1.95 (m, 2H), 1.92-1.81 (m, 3H), 1.81-1.61 (m, 3H), 1.61-1.39 (m, 6H), 1.39-1.13 (m, 10H), 1.00 (s , 3H).

Step 3 (Compound 106): To a mixture of BB2 (79 mg, 0.224 mmol) in EtOAc (5 mL) was added Pd/C (100 mg, 5%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 15 h to give a black suspension, which was filtered and concentrated to give compound 106 (10 mg, 21%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.50-8.40 (m, 2H), 7.55-7.49 (m, 1H), 7.25-7.18 (m, 1H), 2.73-2.65 (m , 1H), 2.13-1.97 (m, 2H), 1.92-1.77 (m, 4H), 1.61-1.55 (m, 4H), 1.55-1.42 (m, 4H), 1.42-1.31 (m, 5H), 1.31-1.17 (m, 5H), 1.17-0.90 (m, 3H), 0.47 (s , 3H).

LC/MS Rt=0.640 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C24H36NO [M ₊ H] ⁺ 354, found 354.

Example 93. Synthesis connections 107

Step 1 (CC1). To a mixture of W3 (200 mg, 0.372 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-doxaborolane (101 mg, 0.502 mmol) and NaOH (0.241 mL, 2 M in water) in THF (4 mL) was added Pd(dppf) _Cl2 (5 mg) under _N2 . The mixture was stirred at 80 °C for 15 h and cooled to room temperature. The reaction mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine (10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give CC1 (170 mg, 97%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.87-5.80 (m, 1H), 5.68-5.64 (m, 1H), 4.28-4.15 (m, 2H), 3.90-3.70 (m , 2H), 2.39-2.28 (m, 1H), 2.22-2.18 (m, 3H), 1.90-1.79 (m, 5H), 1.69-1.51 (m, 4H), 1.49-1.30 (m, 5H), 1.30-1.09 (m, 8H), 1.04-0.78 (m, 12H), 0.06 (s , 6H).

Step 2 (CC2). To a mixture of CC1 (170 mg) in THF (2 mL) was added TBAF (240 mg, 0.722 mmol). The reaction mixture was stirred at 80 °C for 18 h. Water (5 mL) was added to the reaction mixture, which was then extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to afford CC2 (70 mg, 55%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 5.87-5.80 (m, 1H), 5.68-5.64 (m, 1H), 4.28-4.15 (m, 2H), 3.90-3.76 (m , 2H), 2.39-2.28 (m, 1H), 2.28-2.07 (m, 3H), 1.90-1.79 (m, 4H), 1.79-1.61 (m, 2H), 1.61-1.39 (m, 9H), 1.39-1.09 (m, 8H), 0.92 (s, 3H).

Step 3 (Compound 107): To a mixture of CC2 (70 mg, 0.196 mmol) in EtOAc (5 mL) was added Pd/C (100 mg, 5%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 15 h to give a black suspension, which was filtered and concentrated to give compound 107 (37 mg, 52%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.97-3.87 (m, 2H), 3.41-3.28 (m, 2H), 1.94-1.73 (m, 6H), 1.66-1.51 (m , 5H), 1.50-1.33 (m, 8H), 1.33-1.19 (m, 8H), 1.19-0.98 (m, 6H), 0.68 (s, 3H ).

LC/MS Rt=1.297 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C24H39O [M _{+ HH2O} ] ⁺ 343, found 343.

Example 94. Synthesis connections 108

Step 1 (DD1). To a mixture of W3 (200 mg, 0.372 mmol) in THF (10 mL) were added 2-pyridylzinc bromide (0.966 mL, 0.5 M) and Pd( _PPh3 ) ₄ (21.4 mg, 0.0186 mmol) under _N2 . The reaction mixture was stirred at 80°C for 15 h, then the mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give DD1 (170 mg, 99%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 7.60-7.52 (m, 1H), 7.39-7.32 (m, 1H), 7.09-7.03 (m , 1H), 6.37-6.32 (m, 1H), 2.40-2.30 (m, 1H), 2.30-2.19 (m, 1H), 2.10-1.99 (m, 1H), 1.90-1.62 (m, 6H), 1.52-1.29 (m, 9H), 1.29-1.18 (m, 7H), 1.11 (s , 3H), 0.91-0.80 (m, 8H), 0.06 (s, 6H).

Step 2 (DD2). To a mixture of DD1 (170 mg) in THF (2 mL) was added TBAF (242 mg, 0.728 mmol). The reaction mixture was stirred at 80 °C for 18 h to give a black oil. Water (5 mL) was added to the oil. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to give DD2 (90 mg, 71%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 7.60-7.52 (m, 1H), 7.41-7.34 (m, 1H), 7.12-7.03 (m , 1H), 6.40-6.30 (m, 1H), 2.42-2.32 (m, 1H), 2.28-2.19 (m, 1H), 2.09-1.99 (m, 1H), 1.92-1.79 (m, 3H), 1.79-1.62 (m, 3H), 1.62-1.42 (m, 5H), 1.42-1 .32 (m, 5H), 1.32-1.17 (m, 6H), 1.11 (s, 3H).

Step 3 (Compound 108): To a mixture of DD2 (30 mg, 0.085 mmol) in EtOAc (5 mL) was added Pd/C (50 mg, 5%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi) at 15 °C for 15 h to give a black suspension, which was filtered and concentrated to give compound 108 (11 mg, 34%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 8.58-8.52 (m, 1H), 7.61-7.51 (m, 1H), 7.18-7.05 (m, 2H), 2.89-2.82 (m , 1H), 2.50-2.39 (m, 1H), 2.01-1.52 (m, 8H), 1.52-1.43 (m, 3H), 1.43-1.29 (m, 6H), 1.29-1.19 (m, 5H), 1.19-0.91 (m, 4H), 0.46 (s, 3H).

LC/MS Rt=0.653 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C24H36NO [M ₊ H] ⁺ 354, found 354.

Example 95. Synthesis connections 109

Step 1 (EE1). To a mixture of W3 (200 mg, 0.372 mmol) in THF (4 mL) were added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (93.7 mg, 0.483 mmol) and Pd(dppf) _2Cl2 (5 mg) under _N2 . After stirring at 80 °C for 15 h, the reaction mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2 _× 5 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give EE1 (160 mg, 95%) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 5.81-5.75 (m, 1H), 5.54-5.52 (m, 1H), 2.54-2.37 (m, 4H), 2.21-2.10 (m , 1H), 1.91-1.58 (m, 7H), 1.58-1.45 (m, 3H), 1.45-1.31 (m, 6H), 1.31-1.09 (m, 9H), 0.94-0.72 (m, 12H), 0.06 (s, 6H).

Step 2 (EE2). To a mixture of EE1 (160 mg) in THF (2 mL) was added TBAF (233 mg, 0.702 mmol). After stirring at 80 °C for 18 h, the resulting black oil was treated with water (5 mL) and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to give EE2 (90 mg, 75%) as an oil.

Step 3 (Compound 109): To a solution of EE2 (90 mg) in EtOAc (5 mL) was added Pd/C (100 mg, 5%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 15 h to give a black suspension, which was filtered and concentrated to give compound 109 (33 mg, 36%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 1.91-1.80 (m, 3H), 1.80-1.73 (m, 3H), 1.73-1.62 (m, 3H), 1.62-1.50 (m , 5H), 1.50-1.42 (m, 3H), 1.42-1.34 (m, 5H), 1.34-1.31 (m, 1H), 1.31-1.21 (m, 5H), 1.18-1.08 (m, 4H), 1.08-0.91 (m, 4H), 0.91-0.80 (m, 1H), 0.63 (s , 3H).

LC/MS Rt=1.564 min in 2 min chromatography, 30-90AB, purity 100%, ESI MS calcd for _C24H39 [M _{+ HH2O} ] ⁺ 327, found 327.

Example 96. Synthesis connections 110

Step 1 (FF1). To a mixture of W3 (200 mg, 0.372 mmol), (4-cyanophenyl)borinic acid (70.9 mg, 0.483 mmol), and Pd(dppf) _Cl2 (5 mg, 0.00656 mmol) in THF (4 mL) was added NaOH (0.241 mL, 2 M in water). The reaction mixture was stirred at 80 °C under _N2 for 1 h, then cooled to room temperature, treated with _saturated aqueous NaHCO3 (3 mL), and extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated. The product was purified by flash chromatography on silica gel (0%-5% EtOAc in PE) to give FF1 (230 mg, with impurities) as an oil.

Step 2 (FF2). To a mixture of FF1 (230 mg, impure) in THF (2 mL) was added TBAF (307 mg, 0.921 mmol). The reaction mixture was heated to 80 °C and stirred for 18 h to give a dark black oil, which was triturated with water (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0~30% EtOAc in PE) to give FF2 (106 mg, 76% yield over 2 steps) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.62-7.53 (m, 2H), 7.49-7.41 (m, 2H), 6.12-6.01 (m, 1H), 2.34-2.19 (m , 1H), 2.21-1.96 (m, 2H), 1.91-1.81 (m, 3H), 1.80-1.60 (m, 3H), 1.60-1.13 (m, 16H), 1.03 (s, 3H).

Step 3 (Compound 110). To a solution of FF2 (30 mg, 0.0798 mmol) in EtOAc (5 mL) was added Pd/C (wet, 10%, 40 mg) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ three times. The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 0.5 h to give a black suspension. The reaction mixture was filtered and concentrated to give compound 110 (12 mg, 40%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.59-7.53 (m, 2H), 7.32-7.28 (m, 2H), 2.81-2.67 (m, 1H), 2.12-1.95 (m , 2H), 1.89-1.78 (m, 4H), 1.71-1.60 (m, 2H), 1.55-1.42 (m, 3H), 1.42-1.38 (m, 4H), 1.37-1.31(m, 3H), 1.31-1.24 (m, 6H), 1.20-1.11 (m, 1H), 1.11-1 .02 (m, 1H), 1.02-0.90 (m, 1H), 0.44 (s, 3H).

LC/MS Rt=1.275 min in 2 min chromatography, 30-90AB, ^{purity 99%, ESI MS calcd for C26H34N [M+HH2O]+} _{360 , found} 360.

Example 97. Synthesis connections 111

Step 1 (GG1). To a mixture of W3 (200 mg, 0.372 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.483 mmol) and NaOH (0.241 mL, 0.482 mmol, 2 M in water) in THF (4 mL) was added Pd(dppf) _Cl2 (5 mg). The mixture was degassed under vacuum and purged with _N2 . After stirring at 80 °C for 1 h, the reaction mixture was quenched with _saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (2×5 mL). _The combined organic layers were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0% to 30% EtOAc in PE) to give GG1 (180 mg, with impurities) as an oil.

¹ H NMR(400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.35 (s, 1H), 5.75-5.71 (m, 1H), 3.85 (s, 3H), 2.20-2.12 ( m, 1H), 2.02-1.87 (m, 2H), 1.87-1.72 (m, 4H), 1.72-1.52 (m, 4H), 1.52-1. 39 (m, 6H), 1.39-1.12 (m, 12H), 0.97-0.81 (m, 7H), 0.06 (s, 6H).

Step 2 (GG2). To a mixture of GG1 (180 mg, with impurities) in THF (2 mL) was added TBAF (255 mg, 0.766 mmol). The reaction mixture was stirred at 80 °C for 18 h to give a black oil. Water (5 mL) was added to the oil. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0~10% EtOAc in PE) to give GG2 (100 mg, 76% over 2 steps) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.35 (s, 1H), 5.81-5.70 (m, 1H), 3.87 (s, 3H), 2.32-2.12 ( m, 1H), 2.02-1.91 (m, 2H), 1.91-1.80 (m, 3H), 1.80-1.63 (m, 2H), 1.61-1. 38 (m, 7H), 1.38-1.34 (m, 1H), 1.34-1.12 (m, 9H), 0.90 (s, 3H).

Step 3 (Compound 111): To a mixture of GG2 (80 mg, 0.213 mmol) in EtOAc (5 mL) was added Pd/C (100 mg, 10%, wet) under N ₂ . The mixture was stirred under H ₂ (15 psi (103.4 kPa)) at 15 °C for 20 min to give a black suspension, which was filtered and concentrated to give compound 111 (17 mg, 22%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.30 (s, 1H), 7.11 (s, 1H), 3.85 (s, 3H), 2.58-2.41 (m, 1H), 2.06-1.92 ( m, 1H), 1.89-1.60 (m, 6H), 1.55 (s, 3H), 1.51-1.36 (m, 5H), 1.36-1.23 (m, 6H), 1.23-0.95 (m, 5H), 0.91-0.81 (m, 1H), 0.47 (s, 3H).

LC/MS Rt=1.075 min in 2 min chromatography, 30-90AB, purity 100% _, ESI MS calcd for _C23H37N2O [M ₊ H] ⁺ 357, found 357.

Example 98. Synthesis connections 112

Step 1 (HH1). To a solution of U4 (2 g, 6.56 mmol) in MeOH (20 mL) was added _NaBH4 (495 mg, 13.1 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then the mixture was stirred at 15 °C for an additional 48 h. The reaction mixture was quenched with saturated aqueous _NH4Cl (20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0~15% _EtOAc in PE) to afford HH1 (1.5 g, 75%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 3.65-3.57 (m, 1H), 2.09-2.01 (m, 1H), 1.83-1.74 (m, 1H), 1.73-1.31 (m , 12H), 1.30-1.12 (m, 10H), 1.11-0.84 (m, 3H), 0.77-0.74 (m, 3H), 0.73-0.69 (m, 3H).

Step 2 (Compound 112). To a solution of HH1 (200 mg, 0.652 mmol) in THF (2 mL) was added NaH (77.8 mg, 1.95 mmol, 60%) portionwise at 0 °C. The mixture was stirred at 25 °C for 30 min. Then (bromomethyl)benzene (167 mg, 0.978 mmol) was added dropwise to the solution. The mixture was stirred at 25 °C for 1 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 112 (30 mg, 12%) as a solid.

¹ H NMR(400 MHz, CDCl₃) δ 7.36-7.30 (m, 4H), 7.24-7.21 (m, 1H), 4.54 (s, 2H), 3.43-3.39 (m, 1H), 2.01-1.90 (m, 2H), 1.69-1.57 (m, 2H), 1.51-1.08 (m, 18H), 0.99-0.85 (m, 3H ), 0.82 (s, 3H), 0.76 (s, 3H), 0.74-0.69 (m, 1H).

LC/MS Rt=1.344 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C27H39O [ _MH2O +H] ⁺ 379, found 379 _.

Example 99. Synthesis connections 113

Step 1 (I2). A mixture of I1 (500 mg, 1.84 mmol), 10% Pd/carbon (50 mg), and concentrated hydrobromic acid (0.02 mL) in tetrahydrofuran (5 mL) was hydrogenated at 1 atm for 24 h, then the mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. Recrystallization from acetone gave I2 (367 mg, 73%).

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 2.58 (t, 1H, J=14 Hz), 2.45 (dd, 1H, J=19 Hz, 9 Hz), 0.98 (s, 3H)

Step 2 (I3). To a solution of I2 (274 mg, 1.0 mmol) in methanol (4 mL) at room temperature was added iodine (0.1 mmol). After stirring at 60 °C for 12 h, the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20 mL) and washed with saturated aqueous NaHCO ₃ solution (15 mL), brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography on alkaline alumina (petroleum ether/ethyl acetate = 9:1) to give compound I3 (280 mg, 88%).

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 3.19 (s, 3H), 3.13 (s, 3H), 2.43 (dd, 1H, J=19.2 Hz, 8.8 Hz), 0.83 (s, 3H).

Step 3 (I4). To a suspension of methyltriphenylphosphonium bromide (10.26 g, 28.84 mmol) in THF (30 mL) was added KOt-Bu (3.23 g, 28.80 mmol). The reaction mixture was heated to 60 °C for 1 h, then I3 (3.23 g, 9.6 mmol) was added to the mixture. The solution was stirred at 60 °C for 15 h. The reaction mixture was diluted with EtOAc (500 mL). The resulting mixture was washed with brine (300 mL) and evaporated in vacuo. Then, the crude residue was purified by silica gel chromatography (PE:EtOAc=3:1) to give I4 as a solid (2.1 g, 65%).

Step 4 (I5). To a solution of I4 (1 g, 3.1 mmol) in THF (20 mL) was added 2M HCl (2 mL). The solution was stirred at room temperature for 1 h, then the reaction mixture was extracted with EtOAc (100 mL), washed with brine (100 mL) and evaporated in vacuo . The crude residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give I5 as a solid (710 mg, 2.6 mmol, 83%).

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 4.65 (s, 1H), 4.63 (s, 1H), 0.82 (s, 3H).

Step 5 (I6). To a stirred suspension of trimethylsulfonium iodide (6.4 g, 23.5 mmol) in DMSO (10 mL) was added NaH (60%; 800 mg, 31.5 mmol). After stirring at room temperature for 1 h, a suspension of compound I5 (870 mg, 3.2 mmol) in DMSO (5 mL) was added dropwise. After 15 h, the reaction mixture was poured into ice water and extracted with EtOAc (300 mL), washed with brine (100 mL), dried and evaporated in vacuo. The crude residue was then purified by silica gel chromatography (PE:EtOAc=10:1) to give a mixture of I6 and its C-3 isomer as a solid (695 mg, 10%).

Step 6 (I7). To a solution of I6 and its C-3 isomer (129 mg, 0.45 mmol) in THF (10 mL) was added LiAlH ₄ (50 mg, 1.35 mmol). The mixture was stirred at room temperature for 1 h, then the reaction mixture was blocked with H ₂ O (5 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and evaporated in vacuo, and the resulting crude residue was purified by chromatography (PE:EtOAc=3:1) to give I7 as a solid (62 mg, 48%).

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 4.63 (s, 1H), 4.61 (s, 1H), 1.25 (s, 3H), 0.82 (s, 3H).

Step 7 (I8). To a solution of I7 (86 mg, 0.3 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath then slowly blocked with 10% aqueous NaOH (1 mL) followed by the addition of 30% aqueous _H2O2 (1 _mL ). After stirring at room temperature for one h, the mixture was extracted with _EtOAc ( ₃ ×100 mL). The combined organic layers were washed with 10% aqueous _Na2S2O3 (100 mL), brine (100 mL), dried over _MgSO4 , filtered and concentrated to give crude I8 as a solid (83 mg, 91%). The crude product was used in the next step without further purification.

Step 8 (I9): To a solution of I8 (150 mg, 0.49 mmol) in DCM (10 mL) was added PCC (320 mg, 1.47 mmol), and the reaction solution was stirred at room temperature for 2 h. Then, the reaction mixture was filtered through a pad of celite, evaporated under vacuum, and the crude residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give I9 as a solid (80 mg, 53%).

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 9.77 (s, 1H), 2.31 (t, 1H, J = 9 Hz), 1.27 (s, 3H), 0.75 (s, 3H).

Step 9 (Compound 113). Trifluoroethylamine hydrochloride (90 mg, 0.66 mmol) and _NaNO2 (50 mg, 0.79 mmol) _were dissolved in _CH2Cl2 /water (3 mL/0.1 mL) and stirred for one hour in a sealed Schlenk vessel cooled in an ice bath. The mixture was then further cooled to -78 °C in a dry ice/acetone bath and stirred for 10 min, then I9 (0.1 g, 0.33 mmol) and _ZrCl4 (100 mg, 0.43 mmol, 1.3 equiv) were added to the mixture. After 45 min, the resulting mixture was blocked with MeOH (3 mL) followed by addition of saturated aqueous _NaHCO3 (20 mL), extracted _{with CH2Cl2} (3×20 mL), dried over _MgSO4 and evaporated in vacuo. The crude residue was purified by silica gel column chromatography (pentane/diethyl ether = 10:1) to afford compound 113 (12 mg, 9%) as a solid.

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 3.20 (m, 2H), 2.57 (1H, t, J=9 Hz), 2.22-2.15 (m, 1H), 1.27 (s, 3H), 0.65 (s, 3H).

¹⁹ FNMR (376.5 M Hz, CDCl ₃ ), δ (ppm), - 62.28

Example 100. Synthesis connections 114 And connections 115

Step 1 (Compound 114 and Compound 115). To a stirred solution of 2,4,5-trimethyloxazole (0.37 g, 3.3 mmol) in 10 mL THF was added LDA (2.0 M; 0.82 mL, 1.64 mmol) at -78 °C. After stirring at -78 °C for 30 min, a solution of I9 (0.1 g, 0.33 mmol) in 2 mL THF was added dropwise at -78 °C. After stirring at -78 °C for 1 h, the reaction mixture was poured into ice-water. The mixture was extracted with EtOAc (3 x 100 mL), washed with brine (3 x 100 mL), dried (MgSO ₄ ), filtered and evaporated in vacuo. The resulting crude residue was purified by preparative HPLC to afford compound 114 (54 mg, 35% yield) as a solid and compound 115 (22 mg, 16.1% yield) as a solid.

Compound 114

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 4.0 (1H, t, J=7 Hz), 3.68 (s, 1H), 2.94 (1H, d, J=13 Hz), 2.70 (dd, 1H, J=16 Hz, 10 Hz), 2.20 (s, 3H), 2.03 (s, 3H), 1.26 (s, 3H), 0.72 (s, 3H).

Compound 115

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 3.96 (1H, t, J = 7 Hz), 3.40-3.60 (1H, br), 2.82 (1H, d, J = 13 Hz), 2.62 (dd, 1H, J = 16 Hz, 9 Hz), 2.20 (s, 3H), 2.03 (s, 3H), 1.26 (s, 3H), 0.78 (s, 3H).

Example 101. Synthesis connections 116 And connections 117

Step 1 (Compound 116 and Compound 117): To a stirred solution of 2,4,5-trimethylthiazole (0.21 g, 1.64 mmol) in 10 mL THF was added nBuLi (2.5 M; 0.66 mL, 1.64 mmol) at -78 °C. After stirring at -78 °C for 30 min, a solution of I9 (0.1 g, 0.33 mmol) in 2 mL THF was added dropwise at -78 °C. After stirring at -78°C for 1 h, the reaction mixture was poured into ice water and extracted with EtOAc (3 x 100 mL), washed with brine (3 x 100 mL), dried (MgSO ₄ ), filtered and evaporated in vacuo, then purified by preparative HPLC to give compound 116 (44 mg, 31% yield) as a solid and compound 117 (27 mg, 19% yield) as a solid.

Compound 116

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 4.10 (br, 1H), 3.97 (t, 1H, J = 8.6 Hz), 3.14 (dd, 1H, J = 15.3 Hz, J = 2.8 Hz), 2.88 (dd, 1H, J = 14.8 Hz, J = 9.6 Hz), 2.30 (s, 3H), 2.27 (s, 3H), 1.25 (s, 3H), 0.72 (s, 3H).

Compound 117

¹ H NMR (500 MHz, CDCl ₃ ), δ (ppm), 3.91 (t, 1H, J = 8.4 Hz), 3.03 (dd, 1H, J = 14.4 Hz, J = 1.9 Hz), 2.78 (dd, 1H, J = 14.4 Hz, J = 7.8 Hz), 2.30 (s, 3H), 2.27 (s, 3H), 1.25 (s, 3H), 0.77 (s, 3H).

Example 102. Synthesis connections 118.

The synthesis of 1A is described in WO 2015/010054.

Step 1: Hydroxylamine hydrochloride (154 mg, 2.2 mmol) was added to a solution of compound 1A (350 mg, 1.09 mmol) in anhydrous pyridine (10 mL). The solution was allowed to stir at 20 °C for 12 h. The reaction mixture was poured into water (20 mL). The solid was collected and dried to give compound 1B (280 mg, 76%) as a near solid.

¹ H NMR: (400 MHz, CDCl₃) δ 6.82 (br., 1H), 3.92-3.85 (m, 1H), 3.31-3.22 (m, 4H), 2.47-2.37 (m, 2H) , 1.90-1.52 (m, 6H), 1.45-0.94 (m, 12H), 0.87 (s, 3H), 0.82 (s, 3H), 0.78-0 .67 (m, 1H).

Step 2: A solution of _KHCO3 (500 mg, 5 mmol) in _H2O (5 mL) was added to a solution of NBS (440 mg, 2.5 mmol) in dioxane (5 mL). The suspension was allowed to stir at room temperature for 0.25 h, and a solution of compound 1B (280 mg, 0.835 mmol) in dioxane (10 mL) was added dropwise. The reaction mixture quickly turned pale green and was stirred at room temperature for 10 h. The solution was cooled to 0 °C and _NaBH4 (220 mg, 5.85 mmol) was added portionwise. Large amounts of gas evolution were observed and the reaction mixture was stirred overnight, gradually warming to room temperature. The reaction was quenched with saturated aqueous _NH4Cl (20 mL). The resulting suspension was partitioned between water (20 mL) and EtOAc (50 mL), and the organic layer was separated. The aqueous layer was then extracted with EtOAc (3 x 20 mL), and the organic extracts were combined, washed with brine (20 mL), dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 118 (70 mg, 24%) as an off-white powder.

¹ H NMR: (400 MHz, CDCl₃) δ 4.36 (t,J=8.8 Hz, 1H), 3.99-3.92 (m, 1H), 3.37-3.30 (m, 4H), 2.60-2.48 (m, 1H), 2, 12-2.02 (m, 2H), 1.95-1.62 (m, 5H), 1.50-1.38 (m, 3H), 1.37-1.23 (m, 8H), 1.03-0.94 (m, 1H), 0.93 (s, 3H), 0.80-0.75 (m, 1H), 0.71 (s, 3H).

Example 103. Synthesis connections 119.

The synthesis of 2A is described in WO 2015/010054.

Step 1: Hydroxylamine hydrochloride (178 mg, 2.58 mmol) was added to 2A (300 mg, 0.86 mmol) in anhydrous pyridine (3 mL). The solution was allowed to warm to room temperature over 12 h. Water was added slowly, then a near-solid precipitated. The solid was filtered and evaporated to dryness. 2B ( 200 mg, 64%) was collected. It was used in the next step without purification.

¹ H NMR: (400 M Hz, methanol-d4) δ 3.83-3.80 (m, 1H), 3.81-3.70 (m, 1H), 2.44-2.43 (m, 3H), 1 .95-1.11 (m, 12H), 1.09 (s, 3H), 1.03 (s, 3H), 1.02-0.98 (m, 1H), 0.88-0.81 (m, 1H).

Step 2: A solution _{of K2CO3} (330 mg, 3.3 mmol) in _H2O (3 mL) was added to a solution of NBS (290 mg, 1.65 mmol) in dioxane (2 mL). The suspension was stirred at room temperature for 15 min, and 2B (200 mg, 0.55 mmol) in dioxane (3 mL) was added dropwise. The reaction mixture quickly turned pale green and was stirred at room temperature for 10 h. The solution was cooled to 0 °C and _NaBH4 (146.3 mg, 3.85 mmol) was added portionwise. Large amounts of gas evolution were observed, and the reaction mixture was stirred overnight, gradually warming to room temperature. The reaction was quenched with saturated aqueous _NH4Cl (30 mL) and the reaction mixture was extracted with _EtOAc (3×50 mL). The organic extracts were combined, washed with brine (100 mL), dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 119 (73 mg, 35%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.33-4.30 (m, 1H), 3.96-3.95 (m, 1H), 3.71-3.31 (m, 1H), 3.34-3.30 (m , 4H), 3.23 (s, 3H), 2.55-2.51 (m, 2H), 2.10-1.92 (m, 1H), 1.89-1.74 (m, 5H ), 1.54-1.10 (m, 9H), 1.08 (s, 3H), 0.98-0.91 (m, 1H), 0.89 (s, 3H), 0.79- 0.76 (m, 1H).

Example 104. Synthesis connections 120 And 121.

The synthesis of 3A is described in WO 2015/010054.

Step 1: Hydroxylamine hydrochloride (509 mg, 7.32 mmol) was added to 3A (800 mg, 2.38 mmol) in anhydrous pyridine (5 mL). The solution was stirred at room temperature for 12 h. The mixture was extracted with EtOAc (50 mL) and H ₂ O (40 mL). The organic phase was washed with HCl (80 mL, 0.5 M), dried over Na ₂ SO ₄ and evaporated to give crude product 3B (700 mg, 84%) as a near solid.

Step 2: A solution of _K2CO3 (1.20 g, 11.96 mmol) _{in H2O} (8 mL) was added to a solution of NBS (1.05 g, 5.97 mmol) in dioxane (3 mL). The suspension was stirred at room temperature for 15 min, and 3B (700 mg, 1.99 mmol) in dioxane (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 10 h. The solution was cooled to 0 °C, and _NaBH4 (529.34 mg, 13.93 mmol) was added portionwise. Large amounts of gas evolution were observed, and the reaction mixture was stirred overnight, gradually warming to room temperature. The reaction was quenched with saturated aqueous _NH4Cl (30 mL) and the reaction mixture was extracted with _EtOAc (3×50 mL). The organic extracts were combined, washed with brine (100 mL), dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 120 (400 mg, 55%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.41-4.33 (m, 1H), 4.30-4.28 (m, 1H), 3.97-3.90 (m, 1H), 3.36-3.35 (m , 4H), 2.56-2.52 (m, 1H), 2.25-2.21 (m, 1H), 2.08-2.00 (m, 2H), 1.89-1.53 (m, 4H), 1.51-1.20(m, 8H), 1.17-1.10 (m, 4H), 1.09-1.07 (m, 1H), 1.10-0 .94 (m, 4H), 0.83-0.79 (m, 1H).

Step 3: To a stirred solution of compound 120 (250 mg, 0.68 mmol) in _CH2Cl2 (3 mL) were added _Ac2O (69.54 mg, 0.68 mmol) and DMAP (17 mg, _0.14 mmol). Then _Et3N (137.5 mg, 1.36 mmol) was added. The mixture was stirred at room temperature for 3 h. The mixture was treated with water and extracted _{with CH2Cl2} (2×50 mL), and the organic layer was washed with brine (100 mL), dried over _{anhydrous Na2SO4} , then concentrated to give crude product 3C (200 mg, 80%), which was used in the next step without purification.

Step 4: To a stirred solution of 3C (200 mg, 0.49 mmol) in _CH2Cl2 (3 _mL ) was added PCC (211 mg, 0.98 mmol). The mixture was stirred at room temperature for 12 h. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 5:1) to give 3D (130 mg, 65%) as a near solid.

Step 5: To a stirred solution of 3D (130 mg, 0.32 mmol) in MeOH (3 mL) and H ₂ O (1 mL) was added LiOH (60.8 mg, 1.60 mmol). The mixture was stirred at 50 °C for 4 h. The solvent was removed and the residue was treated with water then extracted with EtOAc (2 x 50 mL). The organic phase was washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , then evaporated to give the crude product, which was purified by preparative HPLC to give compound 121 (41 mg, 18%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.57-4.52 (m, 1H), 4.30-4.28 (m, 1H), 3.93-3.92 (m, 1H), 3.37 (s, 3H), 3.28-3.27 (m, 1H), 2.78-2.74 (m, 1H), 2.64-2.57 (m, 2H), 2.46-2.43 (m, 1H ), 2.25-2.19 (m, 1H), 1.90-1.73 (m, 6H), 1.53-1.48 (m, 2H), 1.33-1.20 (m , 3H), 1.18-1.10 (m, 5H), 0.68 (s, 3H).

Example 105. Synthesis connections 5 And 6.

The synthesis of 4A is described in WO 2015/010054.

Step 1: A solution of 4A (2.0 g, 6.57 mmol) in EtOH (20 mL) was treated with 5 drops of fuming H ₂ SO ₄ at room temperature. After 1 h, the reaction mixture was quenched with aqueous NaHCO ₃ (10 mL). The resulting solution was extracted with 2×100 mL ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 6:1) to afford 4B (800 mg, 35%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.44-4.41 (m, 1H), 3.94-3.93 (m, 1H), 3.61-3.57 (m, 1H), 3.45-3.454 (m, 1H ), 3.42-3.41 (m, 1H), 2.50-2.44 (m, 1H), 2.09-1.83 (m, 7H), 1.61-1.58 (m , 3H), 1.45-1.20 (m, 14H), 1.18-1.12 (m, 4H), 1.10 (s, 3H), 1.06-1.02 (m, 1H ), 0.83-0.80 (m, 1H).

Step 2: Hydroxylamine hydrochloride (458 mg, 6.60 mmol) was added to 4B (770 mg, 2.20 mmol) in anhydrous pyridine (5 mL). The solution was stirred at room temperature for 12 h. The mixture was extracted with EtOAc (100 mL) and H ₂ O (80 mL). The organic phase was washed with HCl (80 mL, 0.5 M), dried over Na ₂ SO ₄ and evaporated to give crude product 4C (720 mg, 90%) as a near solid.

Step 3: A solution _{of K2CO3} (1.15 g, 11.5 mmol) in _H2O (5 mL) was added to a solution of NBS (1.0 g, 5.73 mmol) in dioxane (3 mL). The suspension was stirred at room temperature for 15 min, and 4C (700 mg, 1.91 mmol) in dioxane (3 mL) was added dropwise. The reaction was stirred at room temperature for 10 h. The solution was cooled to 0 °C, and _NaBH4 (508.46 mg, 13.37 mmol) was added portionwise. Large amounts of gas evolution were observed, and the reaction mixture was stirred overnight, gradually warming to room temperature. The reaction was quenched with saturated aqueous _NH4Cl (30 mL) and the reaction mixture was extracted with _EtOAc (3×50 mL). The organic extracts were combined, washed with brine (100 mL), dried over anhydrous _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 5 (350 mg, 48%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.41-4.40 (m, 1H), 4.33-4.28 (m, 1H), 4.00-3.90 (m, 1H), 3.62-3.60 (m , 1H), 3.45-3.42 (m, 1H), 3.40-3.38 (m, 1H), 2.56-2.53 (m, 1H), 2.25-2.21 (m, 1H), 2.10-2.00 (m, 2H), 1.89-1.70 (m, 4H), 1.54-1.19 (m, 8H), 1.18-1 .15 (m, 7H), 1.12-1.10 (m, 1H), 1.05-0.98 (m, 4H), 0.83-0.79 (m, 1H).

Step 4: To a stirred solution of compound 122 (350 mg, 0.92 mmol) in _CH2Cl2 (3 mL) were added _Ac2O (93.6 mg, 0.92 mmol) and DMAP (22.5 mg, 0.18 mmol). Then _Et3N (196.2 mg, _1.94 mmol) was added. The mixture was stirred at room temperature for 3 h. The mixture was treated with water and extracted _{with CH2Cl2} (2×50 mL), and the organic layer was washed with brine (100 mL), dried over anhydrous _{Na2SO4 ,} then concentrated to give crude 4D (147 mg, 38%), which was used in the next step without purification.

Step 5: To a stirred solution of 4D (110 mg, 0.26 mmol) in _CH2Cl2 (3 _mL ) was added PCC (112 mg, 0.52 mmol). The mixture was stirred at room temperature for 12 h. The mixture was filtered and the filtrate was concentrated to give the crude product, which was purified by flash chromatography (petroleum ether:ethyl acetate=5:1) to give 4E (88 mg, 81%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.92-4.90 (m, 1H), 4.56-4.52 (m, 1H), 3.67-3.63 (m, 1H), 3.45-3.40 (m , 2H), 2.78-2.75 (m, 1H), 2.64-2.61 (m, 2H), 2.46-2.42 (m, 1H), 2.26-2.19 (m, 1H), 2.05 (s, 3H), 1.91-1.70 (m, 5H), 1.51-1.20 (m, 6H), 1.18-1.15 (m , 6H), 1.104-1.00 (m, 1H), 0.90-0.80 (m, 2H), 0.68(s, 3H).

Step 6: To a stirred solution of 4E (88 mg, 0.21 mmol) in MeOH (2 mL) and H ₂ O (1 mL) was added LiOH (40 mg, 1.68 mmol). The mixture was stirred at 50 °C for 4 h. The solvent was removed and the residue was treated with water, then extracted with EtOAc (2 x 30 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , evaporated to give the crude product, which was purified by flash chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to give compound 123 (28 mg, 34%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 4.57-4.52 (m, 1H), 3.91-3.90 (m, 1H), 3.75-3.70 (m, 1H), 3.39-3.34 (m , 2H), 2.74-2.69 (m, 1H), 2.66-2.61 (m, 2H), 2.45-2.42 (m, 1H), 1.90-1.77 (m, 5H), 1.41-1.36 (m, 1H), 1.33-1.20 (m, 6H), 1.18-1.15 (m, 8H), 1.33- 1.20 (m, 3H), 0.90-0.81 (m, 1H), 0.68 (s, 3H).

Example 106. Synthesis connections 124 And 125.

The synthesis of 5A is described in WO 2015/010054.

Step 1 : Benzoyl chloride (0.8 g, 5.7 mmol) was added to a solution of mixture 5A (0.6 g, 2 mmol) in pyridine (5 mL). The mixture was then stirred at 20 °C for 2 h. Then, aqueous NaHCO ₃ solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated in vacuo to give mixture 5B (0.9 g, crude) as a light yellow oil.

¹ H NMR:(400 MHz, CDCl₃) δ 8.10-8.00 (m, 2H), 7.58-7.52 (m, 1H), 7.49-7.40 (m, 2H), 5.09-5.00 (m , 1H), 2.49-2.39 (m, 1H), 2.20-1.45 (m, 14H), 1.40-0.75 (m, 15H).

To a solution of 5B (0.9 g, crude) in THF (4 mL) and MeOH (6 mL) _{was added CeCl3,7H2O (} 0.87 g, 2.2 mmol). The mixture was stirred at 0°C for 15 min. Then _NaBH4 (90 mg, 2.4 mmol) was added portionwise at 0°C while monitoring the process by TLC. Then aqueous _NH4Cl solution was added to the mixture and the mixture was extracted with ethyl acetate. _The organic layer was separated, dried over _Na2SO4 , concentrated in vacuo, and purified by column chromatography on silica gel (petroleum ether:ethyl acetate=8:1 to 5:1) to give mixture 5C (0.6 g, 73% over 2 steps) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 8.08-8.00 (m, 2H), 7.58-7.52 (m, 1H), 7.49-7.41 (m, 2H), 5.08-4.98 (m , 1H), 3.64 (t, J=8.6 Hz, 1H), 2.20-0.65 (m, 31H).

Step 2 : To a suspension of NaH (120 mg, 60%, 3 mmol) in THF (3 mL) was added a solution of 5D (0.6 g, 1.5 mmol) in THF (2 mL). The mixture was stirred at 0 °C for 30 min. Then, MeI (850 mg, 6 mmol) was added, and then the mixture was stirred at 40 °C for 5 h. The mixture was poured into aqueous NH ₄ Cl solution, extracted with ethyl acetate. The organic layer was separated, dried over Na ₂ SO ₄ , concentrated in vacuo, purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 40:1). Then, the mixture was treated with SFC to give 5D (350 mg) and 5E (100 mg, total yield: 72%) as a near solid.

¹ H NMR (5D):(400 MHz, CDCl₃) δ 8.20-8.08 (m, 2H), 7.63-7.55 (m, 1H), 7.52-7.44 (m, 2H), 5.08-5.00 (m , 1H), 3.37 (s, 3H), 3.24 (t, J=8.4 Hz, 1H), 2.20-1.40 (m, 13H), 1.37-0.70 ( m, 17H).

¹ H NMR (5E):(400 MHz, CDCl₃) δ 8.20-8.08 (m, 2H), 7.61-7.53 (m, 1H), 7.51-7.42 (m, 2H), 5.10-5.04 (m , 1H), 3.36 (s, 3H), 3.24 (t, J=8.4 Hz, 1H), 2.08-1.15 (m, 16H), 1.07-0.70 ( m, 14H).

Step 3a : To a solution of 5D (150 mg, 0.35 mmol) in THF (4 mL) were added MeOH (2 mL) and a solution of LiOH.H ₂ O (0.3 g, 7 mmol) in water (1 mL). The mixture was stirred at 30 °C for 2 days. The mixture was extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 124 (61 mg, 55%) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 3.80-3.75 (m, 1H), 3.34 (s, 3H), 3.21(t, J=8.4 Hz, 1H), 2.05-1.09 (m, 19H), 0.95-0.83 (m, 8H), 0.77-0.67 (m, 4H).

Step 3b : To a solution of 5E (300 mg, 0.7 mmol) in THF (4 mL) were added MeOH (2 mL) and a solution of LiOH.H ₂ O (0.3 g, 7 mmol) in water (1 mL). The mixture was stirred at 30 °C for 2 days. The mixture was extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 125 (189 mg, 86%) as a solid.

¹ H NMR (ST-400-135):(400 MHz, CDCl₃) δ 3.75-3.65 (m, 1H), 3.34 (s, 3H), 3.21 (t, J=8.4 Hz, 1H), 2.05-1.84 (m, 3H), 1.75-1.08 (m, 16H), 1.05-0.82 (m, 8H), 0.76-0.64 (m, 4H).

Example 107. Synthesis connections 126.

The synthesis of 6A is described in WO 2015/010054.

Step 1: To a solution of 6A (0.3 g, 0.9 mmol) in DMF (5 mL) were added imidazole (0.18 g, 2.7 mmol) and TBSCl (0.27 g, 1.8 mmol). The mixture was stirred at 25 °C for 16 h. Water was added to the mixture and the resulting mixture was extracted with petroleum ether/ethyl acetate (8:1). The organic layer was separated, dried over Na ₂ SO ₄ , and concentrated in vacuo to give 6B (0.4 g, quant.) as an oil.

¹ H NMR:(400 MHz, CDCl₃) δ 3.78-3.68 (m, 2H), 3.23 (s, 3H), 2.52-2.43 (m, 1H), 2.30-2.20 (m, 1H), 2.06-1.88 (m, 4H), 1.70-0.70 (m, 32H), 0.13 (s, 6H).

Step 2: To a solution of 6B (0.4 g, 0.9 mmol) in tetrahydrofuran (2 mL) and MeOH (4 mL) was added NaBH ₄ (0.08 g, 2 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 min. Then NH ₄ Cl (aq) was added. The mixture was extracted with ethyl acetate. The combined organic layer was separated, dried over Na ₂ SO ₄ , concentrated in vacuo to give 6C (0.5 g, crude product) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 3.75-3.55 (m, 2H), 3.22 (s, 3H), 2.30-2.25 (m, 1H), 2.08-2.00 (m, 1H), 1.70-1.55 (m, 6H), 1.50-1.08 (m, 9H), 0.98-0.85 (m, 22H), 0.11 (s, 6H).

Step 3: To a solution of 6C (0.5 g, 1.1 mmol) in tetrahydrofuran (5 mL) was added NaH (0.2 g, 60%, 5 mmol) at 15 °C. The mixture was stirred at 25 °C for 30 min. Then MeI (1.4 g, 10 mmol) was added to the mixture. The mixture was stirred at 25 °C for 16 h. Then NH ₄ Cl (aq) was added to the mixture, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo to give 6D (0.5 g, crude) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 3.75-3.62 (m, 2H), 3.35 (s, 3H), 3.25-3.15 (m, 4H), 2.40-2.30 (m, 1H), 2.03-1.92 (m, 1H), 1.70-1.60 (m, 3H), 1.50-0.75 (m, 32H), 0.14 (s, 6H).

Step 4: To a solution of 6D (0.5 g, 1.1 mmol) in _CH2Cl2 (5 mL) was added _CF3COOH (0.5 mL). The mixture was stirred at 25°C for ₃ h. Then _NaHCO3 (aq) was added to the mixture. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 125 (119 mg, 37% over 3 steps) as a near solid.

¹ H NMR:(400 MHz, CDCl₃) δ 3.83-3.75 (m, 1H), 3.70-3.63 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H), 3.20 ( T, J=8 Hz, 1H), 2.42-2.30 (m, 1H), 2.05-1.95 (m, 1H), 1.85-1.72 (m, 3H), 1.65- 1.10 (m, 12H), 1.05-0.90 (m, 11H), 0.83-0.75 (m, 1H).

Example 108. Synthesis connections 127.

Step 1: To a solution of 7A (50 g, 146 mmol) and Pd/C (2.5 g, 10% palladium on carbon, 50% water, wet) in THF (500 mL) was added concentrated hydrobromic acid (1.0 mL, 48% in water). The reaction mixture was hydrogenated under 15 psi (103.4 kPa) of hydrogen at 25 °C for 16 h. The reaction was performed four times in parallel. The reaction mixture was filtered through a pad of celite and washed with THF (1 L x 3) and DCM (1 L x 3). The filtrate was concentrated in vacuo to give 7B (196 g, crude).

¹ H NMR(400MHz, CDCl₃) δ 2.64-2.53 (m, 1H), 2.52-2.41 (m, 1H), 2.30-2.03 (m, 6H), 2.01-1.91 (m , 1H), 1.90-1.69 (m, 3H), 1.68-1.48 (m, 5H), 1.47-1.29 (m, 4H), 1.28-1.13 (m, 2H), 0.68 (s, 3H).

Step 2: To a solution of 2,6-di-tert-butyl-4-methylphenol (240 g, 1.08 mol) in toluene (150 mL) was added dropwise AlMe ₃ (270 mL, 540 mmol, 2 M in toluene) at 0 °C. The mixture was stirred at 25 °C for 1 h. 7B (50 g, 182 mmol) in toluene (200 mL) was added dropwise to the solution at -70 °C. After stirring at -70 °C for 1 h, MeMgBr (63.6 mL, 190 mmol, 3 M in ethyl ether) was added dropwise at -70 °C. The resulting solution was stirred at -70 °C for 1 h. The reaction was quenched with saturated aqueous _NH4Cl (200 mL) at -70 °C. After stirring at 25 °C for 0.5 h, the resulting mixture was filtered through a pad of celite and the filtrate was washed with EtOAc (500 mL). The combined organic layer was separated, washed with brine (500 mL x 2) and concentrated in vacuo. The crude product was purified on a silica gel column eluted with PE/EtOAc=50/1 to 3/1 to give 7C (25 g, 47%) as a near solid.

¹ H NMR(400 MHz, CDCl₃) δ 2.47-2.40 (m, 1H), 2.12-2.03 (m, 1H), 1.96-1.75 (m, 6H), 1.71-1.61 (m , 1H), 1.54-1.32 (m, 7H), 1.30-1.02 (m, 11H), 0.86 (s, 3H).

Step 3: To a solution of 7C (0.1 g, 0.34 mmol) in THF (5 mL) was added MeLi (4.29 mL, 1.6 M) at 15 °C. The mixture was stirred at 15 °C for 16 h and for 1 h at 50 °C and blocked with NH ₄ Cl (5 mL, sat.). The mixture was extracted with EtOAc (20 mL). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude material, which was purified on silica gel column (PE/EtOAc=4/1 to 3/1) to give crude compound 126 (80 mg) as a near solid. The crude product was dissolved in MeCN (10 mL) at 50 °C. Water (3 mL) was added. The mixture was concentrated under vacuum at 15°C to 5 mL, and a near-solid was formed. The mixture was filtered. The solid was washed with MeCN/water (5 mL, 1:1), dried under vacuum to give compound 126 (49 mg, yield: 47%) as a near-solid.

¹ H NMR(400 MHz, CDCl₃) δ 1.90-1.60 (m, 7H), 1.57-1.38 (m, 8H), 1.37-1.18 (m, 13H), 1.17-0.99 (m , 3H), 0.85 (s, 3H).

LC/MS _Rt =0.818 min in 2.0 min chromatography, 30-90 AB, purity 100%, ESI MS calcd for _C20H31 [M+H- _2H2O ] ⁺ 271, found 271.

Connection structure Connection number TBPS IC ₅₀ (nM) 1 C 2 D 3 A 4 B 5 C 6 E 7 E 8 C 9 D 10 D 11 E 12 E 13 D 14 E 15 D 16 D 17 D 18 C 19 D 20 D 21 B 22 E 23 D 24 E 25 D 26 D 27 D 28 D 29 E 30 D 31 C 32 B 33 D 34 D 35 D 36 - 37 B 38 A 39 C 40 A 41 A 42 B 43 B 44 C 48 D 49 C 50 D 55 E 56 D 57 D 58 E 60 E 61 D 63 D 64 C 65 D 66 C 69 D 70 D 73 C 74 E 75 B 76 A 77 B 78 C 79 D 80 E 83 D 84 B 85 E 86 D 87 D 88 E 89 D 90 D 91 E 92 E 93 E 94 E 95 E 96 E 97 E 98 E 99 E 100 E 101 D 102 D 103 B 104 C 105 B 106 B 107 E 108 D 109 E 110 B 111 C 112 E 118 B 119 B 120 D 121 D 122 D 123 C 125 B 125 D 126 E

For Table 2: TBPS: “A” means IC ₅₀ < 10 nM, “B” means IC ₅₀ from 10 to < 50 nM, “C” means IC ₅₀ from 50 nM to < 100 nM, “D” means IC ₅₀ from 100 nM to < 500 nM, and “E” means IC ₅₀ greater than or equal to 500 nM.

Equivalents and scope of application

In the claims, the singular may mean one or more than one, unless otherwise stated or otherwise clearly evident from the context. Claims or descriptions that include the conjunction "or" between one or more members of a group are considered satisfied if one, more than one, or all of the members of the group are present, used, or otherwise related to the given product or process, unless otherwise stated or otherwise clearly evident from the context. The invention includes embodiments in which only one member of the group is present, used, or otherwise related to the given product or process. The invention includes embodiments in which more than one or all of the members of the group are present, used, or otherwise related to the given product or process.

Furthermore, the invention encompasses all variations, combinations and permutations in which one or more limitations, elements, provisions and descriptive terms from one or more of the listed claims are included in another claim. For example, any claim that depends on another claim may be amended to include one or more limitations stated in any other claim that depends on the same base claim. When elements are presented in list form, such as in a Markush group, each subgroup of elements is also disclosed and any element(s) may be deleted from the group. It should be understood that, in general, when the invention or aspects of the invention are referred to as including specific elements and/or features, certain embodiments of the invention or aspects of the invention consist of or essentially consist of such elements and/or features. For simplicity, these embodiments have not been specifically set forth herein. It should also be noted that the terms "comprising" and "consisting of" are open-ended and allow for the inclusion of additional elements or steps. Where ranges are stated, the endpoints are included. Furthermore, unless otherwise stated or clearly evident from the context and obvious to a person skilled in the art, values that are expressed as ranges can take any specific value or subrange within the stated ranges in various embodiments of the invention, up to a decimal place of the lower limit of the range, unless the context clearly indicates otherwise.

This application references various issued patents, published patent applications, journal articles and other publications, each of which is incorporated herein by reference. If there is a conflict between any of the incorporated references and this specification, the specification controls. In addition, any specific embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more claims. Because such embodiments are believed to be known to those skilled in the art, they may be excluded even if the exclusion is not expressly stated in this application. Any specific embodiment of the invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of prior art.

Those skilled in the art will be able to identify or ascertain by routine experimentation many equivalents to the specific embodiments described in this application. The scope of the present embodiments described in this application is not limited by the above description, but only by the appended claims. Those skilled in the art will understand that various changes and modifications of this description can be made without departing from the spirit or scope of the present invention, as defined by the following claims.

Claims (39)

1. Compound of formula ( 1-A ) ( 1-A ) or a pharmaceutically acceptable salt thereof, wherein: a) the compound of formula (1-A) is a compound of formula ( 1-A-1 ) ( 1-A-1 ) where each R ^Y4 is independently C ₁ -C ₂₀ alkyl, cyano or halogen; and e is 0 or 2; or b) the compound of formula (1-A) is a compound of formula ( 1-A-3 ) ( 1-A-3 ), wherein each R ^Y1 is hydrogen, C ₁ -C ₆ alkyl or C ₆ cycloalkyl; and each R ^Y2 is independently C ₁ -C ₆ alkyl, C ₆ cycloalkyl, C ₆ heterocyclyl having 1-4 heteroatoms, wherein each heteroatom is selected from N, O or S, C ₆ aryl or C ₆ heteroaryl having 1-4 heteroatoms, wherein each heteroatom is selected from N, O or S; and b= 0 or 1; or c) the compound of formula (1-A) is a compound of formula ( 1-A-5 ) ( 1-A-5 ), wherein each R ^Y3 is C ₆ aryl or C ₅ -C ₆ heteroaryl having 1-4 heteroatoms, wherein each heteroatom is selected from N, O or S; or two R ^Y3 groups are joined together to form a 6-membered ring; c is 1, 2, or 3; and d is 0, 1, or 2; and where R ³ is C ₁ -C ₆ alkyl; R ^X is independently hydrogen or C ₁ -C ₆ alkyl, R ^Y is independently C ₆ aryl, C ₆ cycloalkyl or C ₆ heterocyclyl containing 1-4 heteroatoms, wherein each heteroatom is selected from N, O or S; or R ^X and R ^Y are joined together to form a 6-membered heterocyclic ring; R ¹⁹ represents hydrogen or C ₁ -C ₆ alkyl; R ⁵ is hydrogen; and represents a single bond. 2. The compound or salt thereof according to claim 1, which is a compound of formula ( 1-A-2 ) ( 1-A-2 ). 3. The compound or salt thereof according to claim 2, wherein each R ^Y4 independently represents hydrogen, -CH ₃ , -CN or -F. 4. The compound or salt thereof according to claim 2, wherein R ^X is hydrogen. 5. The compound or salt thereof according to claim 1, which is a compound of formula ( 1-A-4 ) ( 1-A-4 ). 6. The compound or salt thereof according to claim 5, wherein R ^Y1 is hydrogen, -CH ₃ or -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , or C ₆ cycloalkyl. 7. The compound or salt thereof according to claim 5, wherein R ^Y2 is C ₆ heterocyclyl having 1-4 heteroatoms, wherein each heteroatom is selected from N or O, C ₆ aryl or C ₆ heteroaryl having 1-4 heteroatoms, wherein each heteroatom is selected from N, O or S. 8. A compound selected from the group consisting of: And or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition having the ability to inhibit the function of a GABA receptor, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims and a pharmaceutically acceptable carrier. 10. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound or salt thereof according to claim 1 or 8 or a pharmaceutical composition according to claim 9, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory disorder and/or a cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a chemical dependency disorder and/or an abstinence syndrome, and tinnitus. 12. The method of claim 10, wherein the CNS-related disorder is a seizure. 13. The method of claim 10, wherein the CNS-related disorder is epilepsy or status epilepticus. 14. The method of claim 10, wherein the CNS-related disorder is tremor. 15. The method of claim 10, wherein the CNS-related disorder is bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder, depression, postpartum depression, or major depressive disorder.