CN118119389A

CN118119389A - Prodrugs and derivatives of des-phosphate nupharicin and uses thereof

Info

Publication number: CN118119389A
Application number: CN202280069600.6A
Authority: CN
Inventors: S·克拉克; M·A·J·邓克顿
Original assignee: Human Bioscience Co ltd
Current assignee: Human Bioscience Co ltd
Priority date: 2021-08-20
Filing date: 2022-08-19
Publication date: 2024-05-31

Abstract

Described herein are compounds that are derivatives (e.g., prodrugs) of des-phosphate nupharicin. Also described herein is the use of a compound provided herein for the treatment or prevention of a disease, disorder, or condition in which increased levels of dephosphorylated galectin are beneficial.

Description

Prodrugs and derivatives of des-phosphate nupharicin and uses thereof

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional patent application No. 63/235,543, filed 8/20 a 2021, and U.S. provisional patent application No. 63/289,025, filed 12/13 a 2021, the contents of each of which are incorporated herein by reference in their entirety.

Background

In the united states, nearly one fifth of adults suffer from mental disorders, and more than 50% of americans will be diagnosed with mental disorders at some point in their lifetime. Twenty-five of the americans have severe mental disorders such as major depressive disorder, schizophrenia, or bipolar disorder.

Disclosure of Invention

In one aspect, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof:

Wherein:

R ¹ is hydrogen, -OH, unsubstituted OR substituted alkyl, OR, OR C (O) OR; wherein R is unsubstituted alkyl;

R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷、-CH(R⁴)OC(O)NR⁶R⁷、-S(O)₂NR⁶R⁷、-S(O)₂OR⁵、-P(O)OR⁸(NR⁹R¹⁰)、-P(O)(OR¹¹)(OR¹²)、-CH(R⁴)OP(O)(OR¹¹)(OR¹²) or-Si (R ³)(R⁴)(R⁵);

Each of R ³、R⁴、R⁵ and R ⁸ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A;

Each of R ⁶ and R ⁷ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A; or R ⁶ and R ⁷ together with the atoms to which they are attached form a heterocyclylalkyl or heteroaryl ring that is unsubstituted or substituted with one or more R ^A;

each of R ⁹ and R ¹⁰ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A, or R ⁹ and R ¹⁰ together with the atom to which they are attached form a heterocyclylalkyl ring or heteroaryl ring that is unsubstituted or substituted with one or more R ^A;

Each of R ¹¹ and R ¹² is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A;

Each R ^A is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl is unsubstituted OR substituted with one OR more alkyl, aryl, halogen 、-S-R¹³、-OR¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

Each of R ¹³、R¹⁴、R¹⁵、R¹⁶ or R ¹⁷ is independently hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or substituted with one or more R ^B;

Each of R ¹⁸ and R ¹⁹ is independently hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^B; or R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form a heterocyclylalkyl ring or heteroaryl ring, each of which is unsubstituted or substituted with one or more R ^B;

Each R ^B is independently halogen, amino, cyano, hydroxy, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, -OC (O) R ¹⁸、-C(O)R¹⁸、-C(O)OR¹⁸、NHC(O)OR¹⁸, or heteroarylalkyl, wherein cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more halogen, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In certain embodiments, the compound of formula (I) has the structure of formula (Ia):

In certain embodiments, R ³ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In certain embodiments, R ³ is unsubstituted or substituted alkyl. In certain embodiments, R ³ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹. In certain embodiments, R ³ is unsubstituted alkyl. In certain embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In certain embodiments, R ³ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

In certain embodiments, R ³ is alkyl substituted with-C (O) OR ¹³. In certain embodiments, R ¹³ is hydrogen or alkyl. In certain embodiments, R ¹³ is hydrogen, methyl, ethyl, or tert-butyl.

In certain embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

In certain embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, benzoyl, phenyl, or NH-Boc.

In certain embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

In certain embodiments, R ³ is heterocyclylalkyl.

In certain embodiments, R ³ is

In certain embodiments, R ³ isWherein R ^C is the side chain of a natural amino acid and R' is hydrogen or-Boc.

In certain embodiments, R ³ is

In certain embodiments, R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ³ is

In certain embodiments, R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In certain embodiments, R ³ is heteroalkyl.

In certain embodiments, an unsubstituted or substituted aryl (e.g., phenyl).

In certain embodiments, substituted phenyl.

In certain embodiments, R ³ is phenyl substituted with-OC (O) R ¹⁸, wherein R ¹⁸ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl.

In certain embodiments, the compound of formula (I) has the structure of formula (Ib):

In certain embodiments, R ³ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In certain embodiments, R ³ is unsubstituted or substituted alkyl.

In certain embodiments, R ³ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In certain embodiments, R ³ is alkyl substituted with heterocyclylalkyl.

In certain embodiments, wherein R ³ is aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Substituted alkyl, wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ³ is unsubstituted alkyl.

In certain embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ³ is heteroalkyl.

In certain embodiments, R ³ is heterocyclylalkyl.

In certain embodiments, R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ³ is alkyl substituted with one or more-OC (O) R ¹⁵.

In certain embodiments, R ³ is isopropyl substituted with two-OC (O) R ¹⁵, wherein each R ¹⁵ is alkyl.

In certain embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

In certain embodiments, R ³ is oxetanyl.

In certain embodiments, the compound of formula (I) has the structure of formula (Ic):

In certain embodiments, each of R ⁶ and R ⁷ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A.

In certain embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form a heterocyclylalkyl or heteroaryl ring that is unsubstituted or substituted with one or more R ^A.

In certain embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form

In certain embodiments, R ⁶ is methyl.

In certain embodiments, R ⁷ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl.

In certain embodiments, R ⁷ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen, methyl, ethyl, OR tert-butyl.

In certain embodiments, the compound of formula (I) has the structure of formula (Id):

In certain embodiments, R ⁴ is hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In certain embodiments, R ⁴ is hydrogen or unsubstituted or substituted alkyl.

In certain embodiments, R ⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ⁴ is hydrogen.

In certain embodiments, R ⁵ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In certain embodiments, R ⁵ is unsubstituted or substituted alkyl.

In certain embodiments, R ⁵ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In certain embodiments, R ⁵ is unsubstituted alkyl.

In certain embodiments, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ⁵ is alkyl substituted with C (O) OR ¹³.

In certain embodiments, R ¹³ is hydrogen or alkyl.

In certain embodiments, R ¹³ is hydrogen, methyl, ethyl, or tert-butyl.

In certain embodiments, R ⁵ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

In certain embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

In certain embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In certain embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 36 to 39, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In certain embodiments, R ⁵ is heterocyclylalkyl.

In certain embodiments, R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ⁵ is optionally substituted piperidinyl.

In certain embodiments, R ⁵ is

In certain embodiments, R ⁵ is heteroalkyl.

In certain embodiments, R ⁵ is unsubstituted or substituted aryl (e.g., phenyl).

In certain embodiments, R ⁵ is tert-butyl 、-CH(NH₂)CH(CH₃)₂、-CH₂N(CH₃)₂、-CH₂CH₂OCH₃、-CH₂CH₂NH(CH₃)₂、-CH₂CH₂C(CH₃)₂OC(O)CH₃、-CH₂CH₂C(CH₃)₂NHC(O)CH₃ or-CH ₂CH₂C(CH₃)₂NHC(O)OCH₂ CH 3.

In certain embodiments, the compound of formula (I) has the structure of formula (Ie):

In certain embodiments, R ⁴ is unsubstituted or substituted alkyl.

In certain embodiments, R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ⁴ is hydrogen.

In certain embodiments, R ⁵ is unsubstituted or substituted alkyl.

In certain embodiments, R ⁵ is unsubstituted alkyl.

In certain embodiments, R ⁵ is heterocyclylalkyl.

In certain embodiments, R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ⁵ is morpholinyl, isopropyl, or ethyl.

In certain embodiments, R ⁵ is heteroalkyl.

In certain embodiments, R ⁵ is-CH ₂CH₂NHCH₃、-CH₂CH ₂NHCOCH₃ or-CH ₂CH₂NHCO(O)CH₂CH₃.

In certain embodiments, the compound of formula (I) has the structure of formula (If):

In certain embodiments, R ⁴ is unsubstituted or substituted alkyl.

In certain embodiments, R ⁴ is hydrogen.

In certain embodiments, each of R ⁶ and R ⁷ is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A.

In certain embodiments, R ⁶ is hydrogen or methyl, and R ⁷ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A.

In certain embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In certain embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form an optionally substituted piperidinyl group.

In certain embodiments, the compound of formula (I) has the structure of formula (Ig):

In certain embodiments, each of R ⁶ and R ⁷ is independently hydrogen or alkyl.

In certain embodiments, each of R ⁶ and R ⁷ is independently hydrogen or methyl.

In certain embodiments, R ⁶ and R ⁷ are each hydrogen.

In certain embodiments, the compound of formula (I) has the structure of formula (Ih):

In certain embodiments, each of R ¹¹ and R ¹² is hydrogen, independently unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In certain embodiments, each of R ¹¹ and R ¹² is independently hydrogen or unsubstituted or substituted alkyl.

In certain embodiments, each of R ¹¹ and R ¹² is independently alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In certain embodiments, each of R ¹¹ and R ¹² is independently unsubstituted alkyl.

In certain embodiments, each of R ¹¹ and R ¹² is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂.

In certain embodiments, each of R ¹¹ and R ¹² is independently alkyl substituted with-OC (O) R ^5A, wherein R ^5A is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In certain embodiments, each of R ¹¹ and R ¹² is independently alkyl substituted with-OC (O) OR ¹⁶, wherein R ¹⁶ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted OR further substituted with one OR more halo, amino, cyano, hydroxy, alkyl, acetyl, OR benzoyl.

In certain embodiments, R ¹⁶ is hydrogen or alkyl.

In certain embodiments, R ¹⁶ is hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

In certain embodiments, each of R ¹¹ and R ¹² is independently heteroalkyl.

In certain embodiments, each of R ¹¹ and R ¹² is independently unsubstituted or substituted aryl (e.g., phenyl).

In certain embodiments, the compound of formula (I) has the structure of formula (Ih'):

Wherein the method comprises the steps of

R ^4A and R ^4A 'are each independently hydrogen or alkyl, and R ^5A and R ^5A' are each independently hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In certain embodiments, R ^4A and R ^4A' are each hydrogen.

In certain embodiments, R ^5A and R ^5A' are each methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ^5A and R ^5A' are each isopropyl or tert-butyl.

In certain embodiments, the compound has the structure of formula (Ib'):

Wherein R ^6A and R ^6A' are each independently hydrogen or alkyl.

In certain embodiments, R ^6A and R ^6A' are each independently -CH₃、-C₂H₅、C₃H₇、C₄H₉、C₅H₁₁、C₆H₁₃、C₇H₁₅、C₈H₁₇、C₉H₁₉、C₁₀H₂₁、C₁₁H₂₃、C₁₂H₂₅、C₁₃H₂₇、C₁₄H₂₉、C₁₅H₃₁、C₁₆H₃₃ or C ₁₇H₃₅.

In certain embodiments, R ^6A and R ^6A' are the same.

In certain embodiments, the compound has the structure of formula (Ib "):

Wherein each of R ^6A、R^1B、R^2B and R ^3B is independently hydrogen or alkyl.

In certain embodiments, R ^6A is -CH₃、-C₂H₅、C₃H₇、C₄H₉、C₅H₁₁、C₆H₁₃、C₇H₁₅、C₈H₁₇、C₉H₁₉、C₁₀H₂₁、C₁₁H₂₃、C₁₂H₂₅、C₁₃H₂₇、C₁₄H₂₉、C₁₅H₃₁、C₁₆H₃₃ or C ₁₇H₃₅.

In certain embodiments, R ^1B、R^2B and R ^3B are each independently alkyl.

In certain embodiments, each of R ^1B、R^2B and R ^3B is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ^1B、R^2B and R ^3B are each methyl.

In certain embodiments, R ¹ is hydrogen.

In certain embodiments, the compound of formula (I) has the structure of formula (Ii):

in certain embodiments, each of R ³、R⁴ and R ⁵ is independently hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In certain embodiments, each of R ³、R⁴ and R ⁵ is unsubstituted or substituted alkyl.

In certain embodiments, each of R ³、R⁴ and R ⁵ is independently alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In certain embodiments, each of R ³、R⁴ and R ⁵ is independently unsubstituted alkyl.

In certain embodiments, each of R ³、R⁴ and R ⁵ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In certain embodiments, R ³、R⁴ and R ⁵ are the same unsubstituted alkyl.

In certain embodiments, R ³ and R ⁴ are methyl, ethyl, or isopropyl.

In certain embodiments, R ⁵ is ethyl, isopropyl, or tert-butyl.

In certain embodiments, (i) R ³ and R ⁴ are methyl, and R ⁵ is ethyl; (ii) R ³、R⁴ and R ⁵ are isopropyl; or (iii) R ³、R⁴ and R ⁵ are ethyl.

In certain embodiments, each of R ³、R⁴ and R ⁵ is independently heteroalkyl.

In certain embodiments, each of R ³、R⁴ and R ⁵ is independently unsubstituted or substituted aryl (e.g., phenyl).

In certain embodiments, the compound of formula (I) has the structure of formula (Ij):

In certain embodiments, R ⁵ is unsubstituted or substituted alkyl.

In certain embodiments, R ⁵ is unsubstituted alkyl.

In certain embodiments, R ⁵ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl.

In certain embodiments, R ⁵ is hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

In certain embodiments, R ⁵ is heterocyclylalkyl.

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

/>

In another aspect, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof:

Wherein:

r ²¹ is CH ₃、CH₂D、CHD₂ or CD ₃;

Each of R ²² and R ²³ is independently hydrogen or alkyl, wherein one or more hydrogens in the alkyl are optionally substituted with deuterium;

Each of Y ¹、Y²、Y³、Y⁴、Y⁵、Y⁶、Y⁷、Y⁸ and Y ⁹ is independently hydrogen or deuterium; and

Wherein when R ²¹ is CH ₃ and R ²² and R ²³ do not include deuterium, at least one of Y ¹、Y²、Y³、Y⁴、Y⁵、Y⁶、Y⁷、Y⁸ and Y ⁹ is deuterium.

In certain embodiments, R ²¹ is-CH ₃.

In certain embodiments, R ²¹ is-CD ₃.

In certain embodiments, R ²² and R ²³ are each independently-CH ₃、-CH₂D、-CH D₂ or-CD ₃.

In certain embodiments, at least one of R ²² and R ²³ comprises deuterium.

In certain embodiments, one of R ²² and R ²³ is-CD ₃.

In certain embodiments, both R ²² and R ²³ are-CD ₃.

In certain embodiments, Y ¹ is D.

In certain embodiments, Y ³ is D.

In certain embodiments, Y ¹ and Y ² are each D.

In certain embodiments, Y ³ and Y ⁴ are each D.

In certain embodiments, Y ¹、Y²、Y³ and Y ⁴ are each D.

In certain embodiments, Y ⁶ is H.

In certain embodiments, the compound of formula (II) is selected from the group consisting of:

In certain embodiments, the compound of formula (I) is a compound described in table 1.

In yet another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In yet another aspect, provided herein is a method of treating or preventing a disease, disorder, or condition in which increased levels of dephosphorylated nupharmorin are beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt, solvate, or isotopologue described herein or a pharmaceutical composition described herein.

In certain embodiments, the disease, disorder or condition is selected from post-traumatic stress disorder, major depressive disorder, schizophrenia, alzheimer's disease, frontotemporal dementia, parkinson's disease, parkinson's dementia, dementia with lewy bodies, multiple system atrophy and drug abuse.

Drawings

FIG. 1 shows the average concentration-time profile of dephosphorylated ouabain after Intravenous (IV) administration of dephosphorylated ouabain (1 mg/kg) to male Sprague Dawley (SD) rats.

FIG. 2 shows the average concentration-time profile of dephosphorylated ouabain after oral (PO) administration of dephosphorylated ouabain (2 mg/kg) to male Sprague Dawley (SD) rats.

FIG. 3 shows the average concentration-time profile of metabolite dephosphorylated ouabain after oral administration of ouabain (2 mg/kg) to male Sprague Dawley (SD) rats.

FIG. 4 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-TBDMS ether prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 5 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-TIPS ether prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 6 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-adipate hydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 7 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of tetrahydrofuran-3-ester hydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 8 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of the trimethyl locked formate prodrug (2 mg/Kg) of dephosphorylated ouabain to male Sprague Dawley (SD) rats.

FIG. 9 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of 2-oxa-6-azaspiro [3.3] heptanecarboxylate formate prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 10 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-TES ether prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 11 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of lysine tri-hydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 12 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of an oxazolidine hydrochloride prodrug (2 mg/Kg) of dephosphorylated ouabain to male Sprague Dawley (SD) rats.

FIG. 13 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of morpholinocarbamate hydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 14 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-methylethyl carbonate prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 15 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of di-t-butyl phosphonate hydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 16 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of Boc-valine formate prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 17 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of Boc-proline formate prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 18 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of phenylalanine dihydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 19 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of Boc-phenylalanine formate prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 20 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of Pivaloyloxymethyl (POM) prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 21 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-proline ester dihydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 22 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of N-POM ether prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 23 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of N-POM ether O-pivaloyl prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 24 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-methylglutarate ether tert-butyl ester prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 25 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-methylsuccinate ether tert-butyl ester prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 26 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of O-methyl adipate ether tert-butyl ester prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 27 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of valine dihydrochloride prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 28 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of N-Boc-L-phenylalanine-sarcosinate prodrug of dephosphorylated ouabain (2 mg/Kg) to male Sprague Dawley (SD) rats.

FIG. 29 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dimethylglycinate diformate prodrug (2 mg/Kg) of dephosphorylated ouabain to male Sprague Dawley (SD) rats.

Detailed Description

Described herein are compound analogs, including prodrugs and deuterated analogs of desphosphoric acid galectin. The prodrug analog of the des-phosphate nupharicin can be metabolically converted to the des-phosphate nupharicin or a derivative thereof upon administration to a subject. The compounds disclosed herein may be useful in the treatment of neurological disorders such as psychotic disorders, substance abuse disorders, or conditions in which increasing neuronal plasticity would be beneficial.

And (5) defining.

The compounds herein may include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers and tautomers thereof.

Any of the compounds disclosed herein may be substituted unless otherwise specified. Non-limiting examples of optional substituents include hydroxy, mercapto, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, formaldehyde, imine, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, heterocyclylalkyl, heteroaryl, cycloalkyl, acyl, acyloxy, carbamate, amide, urea, epoxy, and ester groups.

Non-limiting examples of alkyl groups include straight, branched, and cyclic alkyl groups and alkylene groups. Alkyl groups may be, for example, substituted or unsubstituted C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、C₁₂、C₁₃、C₁₄、C₁₅、C₁₆、C₁₇、C₁₈、C₁₉、C₂₀、C₂₁、C₂₂、C₂₃、C₂₄、C₂₅、C₂₆、C₂₇、C₂₈、C₂₉、C₃₀、C₃₁、C₃₂、C₃₃、C₃₄、C₃₅、C₃₆、C₃₇、C₃₈、C₃₉、C₄₀、C₄₁、C₄₂、C₄₃、C₄₄、C₄₅、C₄₆、C₄₇、C₄₈、C₄₉ or C ₅₀ groups.

Alkyl groups may include branched and unbranched alkyl groups. Non-limiting examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

Branched alkyl includes any linear alkyl substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and tert-butyl.

Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1, 2-difluoroethyl and 3-carboxypropyl.

Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl also includes fused, bridged and spiro-bicyclic and higher fused, bridged and spiro-systems. Cycloalkyl groups may be substituted with any number of straight, branched or cyclic alkyl groups. Non-limiting examples of cycloalkyl include cyclopropyl, 2-methyl-cyclopropyl-1-yl, cyclopropyl-2-en-1-yl, cyclobutyl, 2, 3-dihydroxycyclobut-1-yl, cyclobut-2-en-1-yl, cyclopentyl, cyclopent-2-en-1-yl, cyclopent-2, 4-dien-1-yl, cyclohexyl, cyclohex-2-en-1-yl, cycloheptyl, cyclooctyl, 2, 5-dimethylcyclopent-1-yl, 3, 5-dichlorocyclohex-1-yl, 4-hydroxycyclohex-1-yl, 3, 5-trimethylcyclohex-1-yl, octahydropentenyl, octahydro-1H-indenyl, 3a,4,5,6,7 a-hexahydro-3H-inden-4-yl, decahydro azulenyl, bicyclo- [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, 4-hydroxy-1, 3, 2.2.1-bicyclooctyl ] 2.2.2-undecyl and bicyclo [ 2.3.2.3 ] bicyclo-1-yl.

Non-limiting examples of alkenyl groups include straight chain, branched, and cyclic alkenyl groups. The one or more olefins of the alkenyl group may be, for example, E, Z, cis, trans, terminal or exomethylene. Alkenyl groups may be, for example, substituted or unsubstituted C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、C₁₂、C₁₃、C₁₄、C₁₅、C₁₆、C₁₇、C₁₈、C₁₉、C₂₀、C₂₁、C₂₂、C₂₃、C₂₄、C₂₅、C₂₆、C₂₇、C₂₈、C₂₉、C₃₀、C₃₁、C₃₂、C₃₃、C₃₄、C₃₅、C₃₆、C₃₇、C₃₈、C₃₉、C₄₀、C₄₁、C₄₂、C₄₃、C₄₄、C₄₅、C₄₆、C₄₇、C₄₈、C₄₉ or C ₅₀ groups. Non-limiting examples of alkenyl and alkenylene groups include vinyl, prop-1-en-1-yl, isopropenyl, but-1-en-4-yl; 2-chlorovinyl, 4-hydroxybuten-1-yl, 7-hydroxy-7-methylooct-4-en-2-yl and 7-hydroxy-7-methylooct-3, 5-dien-2-yl.

Non-limiting examples of alkynyl groups include straight, branched, and cyclic alkynyl groups. The triple bond of the alkynyl group may be internal or terminal. Alkynyl or alkynylene groups may be, for example, substituted or unsubstituted C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、C₁₂、C₁₃、C₁₄、C₁₅、C₁₆、C₁₇、C₁₈、C₁₉、C₂₀、C₂₁、C₂₂、C₂₃、C₂₄、C₂₅、C₂₆、C₂₇、C₂₈、C₂₉、C₃₀、C₃₁、C₃₂、C₃₃、C₃₄、C₃₅、C₃₆、C₃₇、C₃₈、C₃₉、C₄₀、C₄₁、C₄₂、C₄₃、C₄₄、C₄₅、C₄₆、C₄₇、C₄₈、C₄₉ or C ₅₀ groups. Non-limiting examples of alkynyl groups include ethynyl, prop-2-yn-1-yl, prop-1-yn-1-yl, and 2-methyl-hex-4-yn-1-yl; 5-hydroxy-5-methylhex-3-yn-1-yl, 6-hydroxy-6-methylhept-3-yn-2-yl and 5-hydroxy-5-ethylhept-3-yn-1-yl.

Haloalkyl can be any alkyl substituted with any number of halogen atoms (e.g., fluorine, chlorine, bromine, and iodine atoms). The haloalkenyl group may be any alkenyl group substituted with any number of halogen atoms. A haloalkynyl group may be any alkynyl group substituted with any number of halogen atoms.

Alkoxy groups may be, for example, oxygen atoms substituted with any alkyl, alkenyl or alkynyl groups. The ether or ether group comprises an alkoxy group. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

A heterocycle may be any ring containing a ring atom other than carbon (e.g., N, O, S, P, si, B, or any other heteroatom). The heterocycle may be substituted with any number of substituents (e.g., alkyl groups and halogen atoms). The heterocycle may be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

Non-limiting examples of heterocycles include: non-limiting examples of heterocyclic units having a single ring containing one or more heteroatoms include diazacyclopropenyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoin, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4, 5-tetrahydro-1H-azetidinyl, 2, 3-dihydro-1H-indole, and 1,2,3, 4-tetrahydroquinoline; and ii) a heterocyclic unit having 2 or more rings, one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7 a-hexahydro-1H-benzo [ d ] imidazolyl, 3a,4,5,6,7 a-hexahydro-1H-indolyl, 1,2,3, 4-tetrahydroquinolinyl and decahydro-1H-cycloocta [ b ] pyrrolyl.

Non-limiting examples of heteroaryl groups include: i) Heteroaryl rings containing a single ring, non-limiting examples of which include 1,2,3, 4-tetrazolyl, [1,2,3] triazolyl, [1,2,4] triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl; and ii) a heteroaryl ring containing 2 or more fused rings, one of which is a heteroaryl ring, non-limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo [3,2-d ] pyrimidinyl, 7H-pyrrolo [2,3-d ] pyrimidinyl, pyrido [2,3-d ] pyrimidinyl, 4,5,6, 7-tetrahydro-1-H-indolyl, quinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl and isoquinolinyl.

"Alkyl" refers to an optionally substituted straight or optionally substituted branched saturated hydrocarbon having from one to about ten carbon atoms, or from one to six carbon atoms, wherein the sp ³ hybridized carbon of the alkyl residue is attached to the remainder of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isopentyl, neopentyl, tertiary pentyl and hexyl, and longer alkyl groups such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as "C ₁-C₆ alkyl" means that the alkyl consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, however the present definition also covers the appearance of the term "alkyl" without specifying a numerical range. In some embodiments, alkyl is C ₁-C₁₀ alkyl, C ₁-C₉ alkyl, C ₁-C₈ alkyl, C ₁-C₇ alkyl, C ₁-C₆ alkyl, C ₁-C₅ alkyl, C ₁-C₄ alkyl, C ₁-C₃ alkyl, C ₁-C₂ alkyl, or C ₁ alkyl. Unless otherwise specifically indicated in the specification, alkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or-OMe. In some embodiments, the alkyl group is optionally substituted with halo.

"Alkenyl" refers to an optionally substituted straight or optionally substituted branched hydrocarbon having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein the sp ² hybridized carbon of the alkenyl residue is attached to the remainder of the molecule by a single bond. The group may be in cis or trans configuration with respect to the double bond and is understood to include both isomers. Examples include, but are not limited to, vinyl (-ch=ch ₂), 1-propenyl (-CH ₂CH＝CH₂), isopropenyl [ -C (CH ₃)＝CH₂), butenyl, 1, 3-butadienyl, and the like. Whenever it appears herein, a numerical range such as "C ₂-C₆ alkenyl" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, however the present definition also covers the occurrence of the term "alkenyl" for which a numerical range is not specified. In some embodiments, the alkenyl is C ₂-C₁₀ alkenyl, C ₂-C₉ alkenyl, C ₂-C₈ alkenyl, C ₂-C₇ alkenyl, C ₂-C₆ alkenyl, C ₂-C₅ alkenyl, C ₂-C₄ alkenyl, C ₂-C₃ alkenyl, or C ₂ alkenyl. Unless otherwise specifically indicated in the specification, alkenyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or-OMe. In some embodiments, alkenyl is optionally substituted with halo.

"Alkynyl" refers to an optionally substituted straight or optionally substituted branched hydrocarbon having one or more carbon-carbon triple bonds and from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Whenever it appears herein, a numerical range such as "C ₂-C₆ alkynyl" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, however the present definition also covers the occurrence of the term "alkynyl" where a numerical range is not specified. In some embodiments, the alkynyl is C ₂-C₁₀ alkynyl, C ₂-C₉ alkynyl, C ₂-C₈ alkynyl, C ₂-C₇ alkynyl, C ₂-C₆ alkynyl, C ₂-C₅ alkynyl, C ₂-C₄ alkynyl, C ₂-C₃ alkynyl, or C ₂ alkynyl. Unless explicitly stated otherwise in the specification, alkynyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or-OMe. In some embodiments, alkynyl is optionally substituted with halo.

"Alkoxy" refers to a group of formula-OR _a, wherein R _a is alkyl as defined. Unless otherwise specifically indicated in the present specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, the alkoxy group is optionally substituted with oxo, halogen, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, the alkoxy group is optionally substituted with oxo, halogen, -CN, -CF ₃, -OH, or-OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

"Aminoalkyl" refers to an alkyl group as defined above substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the hydroxyalkyl group is an aminomethyl group.

"Aryl" refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. Aryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused rings (when fused to a cycloalkyl or heterocyclylalkyl ring, the aryl groups are bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a6 to 10 membered aryl. In some embodiments, the aryl is a6 membered aryl. Aryl groups include, but are not limited to, those derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene,Aryl groups of hydrocarbon ring systems of fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, obsidian, pyrene, and triphenylene. In some embodiments, the aryl group is phenyl. Unless otherwise specifically indicated in the present specification, aryl groups may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, aryl is optionally substituted with halo.

"Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocycle, which may include fused rings (which cycloalkyl is bonded through a non-aromatic ring atom when fused to an aryl or heteroaryl ring), bridged rings, or spiro ring systems. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (C ₃-C₁₅ cycloalkyl), three to ten carbon atoms (C ₃-C₁₀ cycloalkyl), three to eight carbon atoms (C ₃-C₈ cycloalkyl), three to six carbon atoms (C ₃-C₆ cycloalkyl), three to five carbon atoms (C ₃-C₅ cycloalkyl), or three to four carbon atoms (C ₃-C₄ cycloalkyl). In some embodiments, cycloalkyl is 3 to 6 membered cycloalkyl. In some embodiments, cycloalkyl is 5-to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis decalin, trans decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless explicitly stated otherwise in the specification, cycloalkyl is optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, cycloalkyl is optionally substituted with halo.

"Deuterated alkyl" refers to an alkyl group as defined above substituted with one or more deuterium. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuterium. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium. Deuterated alkyl includes (e.g., )CD₃、CH₂D、CHD₂、CH₂CD₃、CD₂CD₃、CHDCD₃、CH₂CH₂D or CH ₂CHD₂. In some embodiments, deuterated alkyl is CD ₃.

"Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens. In some embodiments, the alkyl is substituted with one, two, or three halogens. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl and the like. In some embodiments, the haloalkyl is trifluoromethyl.

"Halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

"Heteroalkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, or a combination thereof). The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl is a C ₁-C₆ heteroalkyl, wherein the heteroalkyl contains 1 to 6 carbon atoms and one or more atoms other than carbon, for example, oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, or a combination thereof, wherein the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl groups are (e.g., )-CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₂OCH₃ or-CH (CH ₃)OCH₃. Unless specifically indicated otherwise in this specification, heteroalkyl groups are optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, etc.. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe.

"Hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxy groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

"Heterocyclylalkyl" refers to a stable 3-to 24-membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. Unless explicitly stated otherwise in the specification, the heterocyclylalkyl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused rings (when fused to an aryl or heteroaryl ring, the heterocyclylalkyl groups are bonded through non-aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon or sulfur atom in the heterocyclylalkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized.

Representative heterocyclylalkyl groups include, but are not limited to, heterocyclylalkyl groups having from two to fifteen carbon atoms (C ₂-C₁₅ heterocyclylalkyl), from two to ten carbon atoms (C ₂-C₁₀ heterocyclylalkyl), from two to eight carbon atoms (C ₂-C₈ heterocyclylalkyl), from two to six carbon atoms (C ₂-C₆ heterocyclylalkyl), from two to five carbon atoms (C ₂-C₅ heterocyclylalkyl), or from two to four carbon atoms (C ₂-C₄ heterocyclylalkyl). In some embodiments, the heterocyclylalkyl is a 3-to 6-membered heterocyclylalkyl. In some embodiments, cycloalkyl is 5-to 6-membered heterocyclylalkyl. Examples of such heterocyclylalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl (thiomorpholinyl), thiomorpholinyl (thiamorpholinyl), 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl and 2-oxo-1, 3-dioxol-4-yl. The term heterocyclylalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. It will be appreciated that when referring to the number of carbon atoms in a heterocyclylalkyl group, the number of carbon atoms in the heterocyclylalkyl group is different from the total number of atoms (including heteroatoms) that make up the heterocyclylalkyl group (i.e., the backbone atoms of the heterocyclylalkyl ring). Unless otherwise specifically indicated in the specification, heterocyclylalkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, the heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, the heterocyclylalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, the heterocyclylalkyl is optionally substituted with halo. In one embodiment, the heterocyclylalkyl is

"Heteroaryl" means a 5-to 14-membered ring system group comprising a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. Heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused rings (when fused to a cycloalkyl or heterocyclylalkyl ring, heteroaryl groups are bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ] [1,4] dioxazolyl, 1, 4-benzodioxanyl, benzonaphtalenofuranyl, benzoxazolyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, isothiazolyl imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxopyridinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically indicated in the specification, heteroaryl groups are optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃、-OH、-OMe、-NH₂, or-NO ₂. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF ₃, -OH, or-OMe. In some embodiments, heteroaryl is optionally substituted with halo.

Any of the compounds herein may be purified. The compounds herein may be at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 36%, at least at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

Pharmaceutically acceptable salts.

The present disclosure provides for the use of pharmaceutically acceptable salts of any of the compounds described herein. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid that may be added to the compound to form the acid addition salt may be an organic acid or an inorganic acid. The base that may be added to the compound to form the base addition salt may be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt. In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

The metal salt may result from the addition of an inorganic base to the compounds of the present disclosure. Inorganic bases consist of metal cations paired with basic counter ions such as, for example, hydroxides, carbonates, bicarbonates or phosphates. The metal may be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

In some embodiments, the metal salt is a lithium salt, sodium salt, potassium salt, cesium salt, cerium salt, magnesium salt, manganese salt, iron salt, calcium salt, strontium salt, cobalt salt, titanium salt, aluminum salt, copper salt, cadmium salt, or zinc salt.

Ammonium salts may be produced by adding ammonia or an organic amine to the compounds of the present disclosure. In some embodiments, the organic amine is trimethylamine, triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, benzhydrylamine, piperazine, pyridine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine, imidazole, or pyrazine.

In some embodiments, the ammonium salt is a triethylamine salt, trimethylamine salt, diisopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, morpholine salt, N-methylmorpholine salt, piperidine salt, N-methylpiperidine salt, N-ethylpiperidine salt, benzhydryl amine salt, piperazine salt, pyridine salt, pyrazole salt, pyridazine salt, pyrimidine salt, imidazole salt, or pyrazine salt.

Acid addition salts may result from the addition of an acid to the compounds of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, glucaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

In some embodiments, the salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

Pharmaceutical compositions.

According to another embodiment, the present disclosure provides a composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition is an amount effective to treat the relevant disease, disorder or condition in a patient in need thereof ("effective amount"). In some embodiments, the compositions of the present disclosure are formulated for oral administration to a patient.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the formulation with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the disclosed compositions include, but are not limited to, ion exchangers, alumina, stearates such as aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

The compositions of the present disclosure may be administered orally, parenterally, enterally, intracisternally, intraperitoneally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. In some embodiments, the composition is a transmucosal formulation. The sterile injectable form of the compositions of the present disclosure may be an aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in l, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium.

To aid in the delivery of the composition, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms (such as Tweens, spans, and other emulsifying agents or bioavailability enhancers) may also be used for formulation purposes.

The pharmaceutically acceptable composition may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. A lubricant (such as magnesium stearate) may also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavoring agents or coloring agents may also be added.

Or the pharmaceutically acceptable composition may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

In some embodiments, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without feeding. In some embodiments, the pharmaceutically acceptable composition is administered without feeding. In other embodiments, the pharmaceutically acceptable composition is administered in the presence of food.

It will also be appreciated that the particular dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the particular compound employed, the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water, or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable formulations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in l, 3-butanediol. Acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. And isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids (such as oleic acid) are useful in the preparation of injectables.

The injectable formulation may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the effect of the compounds of the present disclosure, it may be desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of a compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Or delayed absorption of the parenterally administered compound form is performed by dissolving or suspending the compound in an oil vehicle. The injectable depot form (depot form) is made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycidylester. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) Binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) Humectants, such as glycerin; d) Disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) Dissolution retarders such as paraffin; f) Absorption enhancers such as quaternary ammonium compounds; g) Wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) Absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose (lactos e or milk sugar) and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. It may optionally contain an opacifying agent and may also have a composition which releases the active ingredient only, or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like.

The therapeutic agent may also be in microencapsulated form together with one or more excipients as noted above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, in accordance with conventional practice, additional substances other than inert diluents, for example, tabletting lubricants and other tabletting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. It may optionally contain an opacifying agent and may also have a composition which releases the active ingredient only, or preferentially in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, emulsions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient may be admixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as falling within the scope of the present disclosure. In addition, the present disclosure contemplates the use of transdermal patches that have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of a compound across the skin. The rate may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Compounds of formula (I)

In one aspect, disclosed herein are dephosphorylated galectin analogs.

Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or isotopologue thereof:

Wherein:

r ¹ is hydrogen, -OH, unsubstituted OR substituted alkyl, -OR, OR C (O) OR; wherein R is unsubstituted alkyl;

In some embodiments, R ¹ is hydrogen, -OH, unsubstituted OR substituted alkyl, OR C (O) OR; wherein R is unsubstituted alkyl. In some embodiments, R ¹ is hydrogen or unsubstituted or substituted alkyl. In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is unsubstituted or substituted alkyl. In some embodiments, R ¹ is unsubstituted alkyl. In some embodiments, R ¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R ¹ is methyl.

In some embodiments, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R is methyl.

In some embodiments, R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷、-CH(R⁴)OC(O)NR⁶R⁷、-S(O)₂NR⁶R⁷、-P(O)OR⁸(NR⁹R¹⁰) OR-P (O) (OR ¹¹)(OR¹²).

In some embodiments, R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷、-CH(R⁴)OC(O)NR⁶R⁷、-P(O)OR⁸(NR⁹R¹⁰) OR-P (O) (OR ¹¹)(OR¹²).

In some embodiments, R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷、-CH(R⁴)OC(O)NR⁶R⁷ or-S (O) ₂NR⁶R⁷.

In some embodiments, R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷、-CH(R⁴)OC(O)NR⁶R⁷、-S(O)₂NR⁶R⁷ OR-P (O) (OR ¹¹)(OR¹²).

In some embodiments, R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷、-CH(R⁴)OC(O)NR⁶R⁷、-S(O)₂NR⁶R⁷ OR-P (O) OR ⁸(NR⁹R¹⁰.

In some embodiments, R ² is -C(O)R³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is -C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is -C(O)R³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is-C (O) R ³、-C(O)OR³、-CH(R⁴)OC(O)OR⁵、-C(O)NR⁶R⁷ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is-C (O) R ³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-C(O)NR⁶R⁷ or-CH (R ⁴)OC(O)NR⁶R⁷). In some embodiments, R ² is-C (O) R ³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is-C (O) R ³、-C(O)OR³、-CH(R⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵ or-C (O) NR ⁶R⁷.

In some embodiments, R ² is-C (O) R ³、-C(O)OR³ or-C (O) NR ⁶R⁷. In some embodiments, R ² is-C (O) OR ³ OR-C (O) NR ⁶R⁷. In some embodiments, R ² is-C (O) R ³ or-C (O) NR ⁶R⁷. In some embodiments, R ² is-C (O) R ³ OR-C (O) OR ³. In some embodiments, R ² is-CH (R ⁴)OC(O)R⁵、-CH(R⁴)OC(O)OR⁵ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is-CH (R ⁴)OC(O)OR⁵ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is-CH (R ⁴)OC(O)R⁵ or-CH (R ⁴)OC(O)NR⁶R⁷. In some embodiments, R ² is-CH (R ⁴)OC(O)R⁵ or-CH (R ⁴)OC(O)OR⁵).

In some embodiments, R ² is-C (O) R ³. In some embodiments, R ² is-C (O) OR ³. In some embodiments, R ² is-CH (R ⁴)OC(O)R⁵. In some embodiments, R ² is-CH (R ⁴)OC(O)OR⁵. In some embodiments, R ² is-C (O) NR ⁶R⁷. In some embodiments, R ² is-CH (R ⁴)OC(O)NR⁶R⁷).

In some embodiments, R ² is-S (O) ₂NR⁶R⁷、-P(O)OR⁸(NR⁹R¹⁰) OR-P (O) (OR ¹¹)(OR¹²).

In some embodiments, R ² is-S (O) ₂NR⁶R⁷.

In some embodiments, R ² is-P (O) OR ⁸(NR⁹R¹⁰) OR-P (O) (OR ¹¹)(OR¹²).

In some embodiments, R ² is-P (O) OR ⁸(NR⁹R¹⁰.

In some embodiments, R ² is OR-P (O) (OR ¹¹)(OR¹²).

Ester prodrugs

In some embodiments of the compounds of formula (I), the compounds have the structure of formula (Ia):

In some embodiments, R ³ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In some embodiments, R ³ is unsubstituted or substituted alkyl. In some embodiments, R ³ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In some embodiments, R ³ is unsubstituted alkyl. In some embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In some embodiments, R ³ is alkyl substituted with-C (O) OR ¹³. In some embodiments, R ¹³ is hydrogen or alkyl. In some embodiments, R ¹³ is hydrogen, methyl, ethyl, or tert-butyl.

In some embodiments, R ³ is

In some embodiments, R ³ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

In some embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

In some embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, benzoyl, phenyl, or NH-Boc.

In some embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments, R ³ is heterocyclylalkyl.

In some embodiments, R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe-.

In some embodiments, R ³ is heterocyclylalkyl. In some embodiments, R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe. In some embodiments, R ³ is/>In some embodiments, R ³ is oxetanyl.

In some embodiments, R ³ is heteroalkyl.

In some embodiments, R ³ is unsubstituted or substituted aryl (e.g., phenyl). In some embodiments, R ³ is substituted phenyl. In some embodiments, R ³ is phenyl substituted with-OC (O) R ¹⁸, wherein R ¹⁸ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^B.

In some embodiments, R ³ isWherein R ^C is the side chain of a natural amino acid and R' is hydrogen or-Boc. In some embodiments, R ³ is/>

In some embodiments, R ³ is selected from the group consisting of alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, vinyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl. In some embodiments, R ³ is selected from the group consisting of hydrogen, -CD ₃, et, n-Pr, iPr, tBu, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH ₂CF₃、-CH₂ -cyclopropyl, ph, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, and 6-pyrimidinyl.

In some embodiments, R ³ is alkyl or heteroalkyl. In some embodiments, R ³ is unsubstituted alkyl or unsubstituted heteroalkyl. In some embodiments, R ³ is alkyl. In some embodiments, R ³ is unsubstituted alkyl. In some embodiments, R ¹ is methoxy and R ³ is alkyl. In some embodiments, R ¹ is methoxy and R ³ is unsubstituted alkyl. In some embodiments, R ¹ is hydrogen and R ³ is alkyl. In some embodiments, R ¹ is hydrogen and R ³ is unsubstituted alkyl.

In some embodiments, R ³ is heteroalkyl. In some embodiments, R ³ is unsubstituted heteroalkyl. In some embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments, R ³ is aryl. In some embodiments, R ³ is phenyl. In some embodiments, R ³ is heterocyclylalkyl. In some embodiments, R ³ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, R ³ is ethyl. In some embodiments, R ¹ is hydrogen and R ³ is ethyl. In some embodiments, R ¹ is methoxy and R ³ is ethyl. In some embodiments, R ³ is alkyl substituted with heteroaryl. In some embodiments, R ³ isIn some embodiments, R ¹ is methoxy and R ³ isIn some embodiments, R ¹ is hydrogen and R ³ is/>

In some embodiments, the compound of formula (Ia) has a formula selected from the group consisting of:

Wherein each occurrence of R' is independently hydrogen or methyl; each occurrence of X is-CH ₂-、-O-、-S-、-SO₂ -, -NH-or-NMe-; r ^C1 is H, me, CH ₂Ph、CH₂CH(CH ₃)₂、CH(CH₃)CH₂CH₃ or CH ₂CH₂SCH₃;R^C2 and R ^C3 are each H, CH ₃ or CH ₂CH₃; and each occurrence of R ^C4 is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, benzoyl, phenyl, or NH-Boc. In certain embodiments of formula (Iaa), R ^C1 is H, me, CH ₂Ph、CH₂CH(Me)₂、CH(CH₃)CH₂CH₃, or CH ₂CH₂SCH₃. In certain embodiments of formula (Iac), R ^C2 and R ^C3 are each H, CH ₃ or CH ₂CH₃. In certain embodiments of formula (Iac), R ^C2 and R ^C3 are each CH ₃. In certain embodiments, R ^C4 is selected from the group consisting of hydrogen, -CD3, et, n-Pr, iPr, tBu, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH ₂CF₃、-CH₂ -cyclopropyl, ph, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, and 6-pyrimidinyl.

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

Trimethyl lock prodrug

In some embodiments, the compound of formula (Ia) has the structure of formula (Ial):

Wherein R ^C5 is selected from the group consisting of hydrogen, -CD ₃, et, n-Pr, iPr, tBu, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH ₂CF₃、-CH₂ -cyclopropyl, ph, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 6-pyrimidinyl.

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

Carbamate prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ic):

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form a heterocyclylalkyl or heteroaryl ring that is unsubstituted or substituted with one or more R ^A.

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form unsubstituted heterocyclylalkyl. In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe. In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached formIn some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form an unsubstituted or substituted piperidinyl group. In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form an unsubstituted or substituted 1-piperidinyl group.

In some embodiments, the compound of formula (Ic) has a formula selected from the group consisting of:

Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe, and each R ^C6 is independently hydrogen, -CH ₃、-CD₃, or-CH ₂CH₃.

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

In some embodiments, R ⁷ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl. In some embodiments, R ⁷ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen, methyl, ethyl, OR tert-butyl.

In some embodiments, each of R ⁶ and R ⁷ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A.

In some embodiments, R ⁶ is hydrogen and R ⁷ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A. In some embodiments, R ⁶ is hydrogen and R ⁷ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In some embodiments, R ⁶ is hydrogen and R ⁷ is unsubstituted or substituted alkyl. In some embodiments, R ⁶ is hydrogen and R ⁷ is unsubstituted alkyl. In some embodiments, R ⁶ is hydrogen and R ⁷ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R ⁶ is hydrogen and R ⁷ is alkyl substituted with heterocyclylalkyl. In some embodiments, R ⁶ is hydrogen and R ⁷ is aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazaidinyl, Substituted alkyl, wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or NMe.

In some embodiments, R ⁶ is methyl.

In some embodiments, the compound of formula (Ic) has the structure of formula (Icc):

Carbonate prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ib):

in some embodiments, R ³ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R ^A.

In some embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments, R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

In some embodiments, R ³ is alkyl substituted with one or more-OC (O) R ¹⁵. In some embodiments, R ³ is isopropyl substituted with two-OC (O) R ¹⁵, wherein each R ¹⁵ is alkyl. In some embodiments, R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments, R ³ is heterocyclylalkyl.

In some embodiments, R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In some embodiments, R ³ is alkyl substituted with heterocyclylalkyl. In some embodiments, R ³ is aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Substituted alkyl, wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In some embodiments, R ³ is heteroalkyl.

In some embodiments, R ³ is heteroalkyl. In some embodiments, R ³ is unsubstituted heteroalkyl. In some embodiments, R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments, R ³ is aryl. In some embodiments, R ³ is phenyl. In some embodiments, R ³ is heterocyclylalkyl. In some embodiments, R ³ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, R ³ is ethyl. In some embodiments, R ¹ is hydrogen and R ³ is ethyl. In some embodiments, R ¹ is methoxy and R ³ is ethyl. In some embodiments, R ³ is alkyl substituted with heteroaryl. In some embodiments, R ³ isIn some embodiments, R ¹ is methoxy and R ³ is/>In some embodiments, R ¹ is hydrogen and R ³ is/>

In some embodiments, the compound of formula (Ib) has a structure selected from the following formulae:

Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe, each R' is independently hydrogen or-CH ₃; and R ¹⁵ is defined herein above.

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

Acyloxymethyl prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Id):

In some embodiments, R ⁴ is hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In some embodiments, R ⁴ is unsubstituted or substituted alkyl. In some embodiments, R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R ⁴ is hydrogen, methyl, or isopropyl. In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is isopropyl.

In some embodiments, R ⁵ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In some embodiments, R ⁵ is unsubstituted or substituted alkyl. In some embodiments, R ⁵ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In some embodiments, R ⁵ is unsubstituted alkyl. In some embodiments, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In some embodiments, R ⁵ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

In some embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

In some embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

In some embodiments, R ⁵ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments, R ⁵ is alkyl substituted with-C (O) OR ¹⁵. In some embodiments, R ⁵ is alkyl substituted with-C (O) OR ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted OR further substituted with one OR more halo, amino, cyano, hydroxy, alkyl, acetyl, OR benzoyl. In some embodiments, R ¹³ is hydrogen or alkyl. In some embodiments, R ¹³ is hydrogen, methyl, ethyl, or tert-butyl.

In some embodiments, R ⁵ is heterocyclylalkyl.

In some embodiments, R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In some embodiments, R ⁵ is optionally substituted piperidinyl. In some embodiments, R ⁵ is

In some embodiments, R ⁵ is heterocyclylalkyl. In some embodiments, R ⁵ is aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Substituted alkyl, wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In some embodiments, R ⁵ is heteroalkyl.

In some embodiments, R ⁵ is unsubstituted or substituted aryl (e.g., phenyl). In some embodiments, R ⁵ is substituted phenyl. In some embodiments, R ⁵ is phenyl substituted with-OC (O) R ¹⁸, wherein R ¹⁸ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^B.

In some embodiments, R ⁵ is selected from the group consisting of alkyl, cycloalkyl, substituted alkyl, substituted cycloalkyl, vinyl, aryl, heteroaryl, substituted aryl, and substituted heteroaryl. In some embodiments, R ⁵ is selected from the group consisting of hydrogen, -CD ₃, et, n-Pr, iPr, tBu, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, CH ₂CF₃、-CH₂ -cyclopropyl, ph, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, and 6-pyrimidinyl.

In some embodiments, R ⁵ is alkyl or heteroalkyl. In some embodiments, R ⁵ is unsubstituted alkyl or unsubstituted heteroalkyl. In some embodiments, R ⁵ is alkyl. In some embodiments, R ⁵ is unsubstituted alkyl. In some embodiments, R ¹ is methoxy and R ⁵ is alkyl. In some embodiments, R ¹ is methoxy and R ⁵ is unsubstituted alkyl. In some embodiments, R ¹ is hydrogen and R ⁵ is alkyl. In some embodiments, R ¹ is hydrogen and R ⁵ is unsubstituted alkyl.

In some embodiments, R ⁵ is heteroalkyl. In some embodiments, R ⁵ is unsubstituted heteroalkyl. In some embodiments, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments, R ⁵ is aryl. In some embodiments, R ⁵ is phenyl. In some embodiments, R ⁵ is heterocyclylalkyl. In some embodiments, R ⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, R ⁵ is ethyl. In some embodiments, R ¹ is hydrogen and R ⁵ is ethyl. In some embodiments, R ¹ is methoxy and R ⁵ is ethyl. In some embodiments, R ⁵ is alkyl substituted with heteroaryl. In some embodiments, R ⁵ isIn some embodiments, R ¹ is methoxy and R ⁵ is/>In some embodiments, R ¹ is hydrogen and R ⁵ is/>

In some embodiments, the compound of formula (Id) has a structure of formula selected from:

Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe, each R' is independently hydrogen or-CH ₃; RC7 is H, me, CH ₂Ph、CH₂CH(Me)₂、CH(CH₃)CH₂CH₃ or CH ₂CH₂SCH₃,R^C8 and R ^C9 are each H, CH ₃ or CH ₂CH₃, and R ¹⁴ and R ¹⁵ are defined herein above.

In some embodiments, the compound of formula (Id) has the structure of formula (Ida). In some embodiments, the compound of formula (Id) has the structure of formula (Idb). In some embodiments, the compound of formula (Id) has the structure of formula (Idc). In some embodiments, the compound of formula (Id) has the structure of formula (Id). In some embodiments, the compound of formula (Id) has the structure of formula (Ide). In some embodiments, the compound of formula (Id) has the structure of formula (Idf). In some embodiments, the compound of formula (Id) has the structure of formula (Idg). In some embodiments, the compound of formula (Id) has the structure of formula (Idh). In some embodiments, the compound of formula (Id) has the structure of formula (Idi). In some embodiments, the compound of formula (Id) has the structure of formula (Idj).

In some embodiments, the compound of formula (Id) has the structure of formula (Idk):

in some embodiments, the compound of formula (Id) has the structure of formula (Idl):

in some embodiments, the compound of formula (Id) has the structure of formula (Idm):

in some embodiments, the compound of formula (Id) is selected from the group consisting of:

alkoxycarbonyloxymethyl prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ie):

In some embodiments, R ⁴ is hydrogen, unsubstituted or substituted hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In some embodiments, R ⁴ is unsubstituted or substituted alkyl. In some embodiments, R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R ⁴ is hydrogen, methyl, or isopropyl. In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is isopropyl.

In some embodiments, R ⁵ is heterocyclylalkyl.

In some embodiments, R ⁵ is heterocyclylalkyl. In some embodiments, R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In some embodiments, R ⁵ is heteroalkyl.

In some embodiments, R ⁵ is heteroalkyl. In some embodiments, R ⁵ is unsubstituted heteroalkyl. In some embodiments, R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments, R ⁵ is aryl. In some embodiments, R ⁵ is phenyl. In some embodiments, R ⁵ is heterocyclylalkyl. In some embodiments, R ⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, R ⁵ is ethyl. In some embodiments, R ¹ is hydrogen and R ⁵ is ethyl. In some embodiments, R ¹ is methoxy and R ⁵ is ethyl. In some embodiments, R ⁵ is alkyl substituted with heteroaryl. In some embodiments, R ⁵ isIn some embodiments, R ¹ is methoxy and R ⁵ isIn some embodiments, R ¹ is hydrogen and R ⁵ is/>

In some embodiments, R ⁵ is morpholinyl, isopropyl, or ethyl.

In some embodiments, the compound of formula (Ie) has a structure of formula selected from:

/>

Wherein R ^C10 and R ^C11 are each H, CH ₃ or CH ₂CH₃; and R ⁴ and R ¹⁴ are defined herein above.

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

aminocarbonyloxymethyl prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (If):

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form unsubstituted heterocyclylalkyl. In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form/>

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form an unsubstituted or substituted piperidinyl group. In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form an unsubstituted or substituted 1-piperidinyl group. In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form

In some embodiments, the compound of formula (If) has the structure of formula (Ifa) or formula (Ifb):

wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe; r ^C12 and R ^C13 are each H, CH ₃、CD₃ or CH ₂CH₃; and R ⁴ is defined herein above.

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

In some embodiments, the compound of formula (If) is a compound of formula (If'):

Phosphonate prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ih):

In some embodiments, R ¹¹ and R ¹² are independently unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In some embodiments, R ¹¹ and R ¹² are independently hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl. In some embodiments, each of R ¹¹ and R ¹² is independently hydrogen or unsubstituted or substituted alkyl. In some embodiments, each of R ¹¹ and R ¹² is independently unsubstituted or substituted alkyl.

In some embodiments, each of R ¹¹ and R ¹² is independently alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In some embodiments, each of R ¹¹ and R ¹² is independently unsubstituted alkyl.

In some embodiments, each of R ¹¹ and R ¹² is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂.

In some embodiments, each of R ¹¹ and R ¹² is independently alkyl substituted with-OC (O) R ^5A, wherein R ^5A is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments, R ¹¹ and R ¹² are independently alkyl substituted with-OC (O) OR ¹⁶, wherein R ¹⁶ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted OR further substituted with one OR more halo, amino, cyano, hydroxy, alkyl, acetyl, OR benzoyl. In some embodiments, R ¹⁶ is hydrogen or alkyl. In some embodiments, R ¹⁶ is hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, each of R ¹¹ and R ¹² is independently heteroalkyl.

In some embodiments, each of R ¹¹ and R ¹² is independently unsubstituted or substituted aryl (e.g., phenyl).

In some embodiments, the compound of formula (Ih) has the structure of formula (Ih'):

Wherein R ^4A and R ^4A' are each independently hydrogen or alkyl, and R ^5A and R ^5A' are each independently hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

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

sulfamate prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ig):

In some embodiments, R ⁶ and R ⁷ are each independently hydrogen or alkyl. In some embodiments, R ⁶ and R ⁷ are each independently hydrogen or methyl.

In some embodiments, R ⁶ and R ⁷ are each hydrogen.

In some embodiments, R ⁶ and R ⁷ together with the atoms to which they are attached form aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-O-, -S-, a-SO ₂, -NH-or-NMe.

In some embodiments, the compound of formula (Ig) is:

Glyceride prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ib'):

Wherein R ^6A and R ^6A' are each independently hydrogen or alkyl.

In some embodiments, R ^6A and R ^6A' are each independently -CH₃、-C₂H₅、C₃H₇、C₄H₉、C₅H₁₁、C₆H₁₃、C₇H₁₅、C₈H₁₇、C₉H₁₉、C₁₀H₂₁、C₁₁H₂₃、C₁₂H₂₅、C₁₃H₂₇、C₁₄H₂₉、C₁₅H₃₁、C₁₆H₃₃ or C ₁₇H₃₅. In some embodiments, R ^6A and R ^6A' are the same. In some embodiments, R ^6A and R ^6A' are each C ₁₅H₃₁ or C ₁₇H₃₅. In some embodiments, R ^6A and R ^6A' are each C ₁₅H₃₁. In some embodiments, R ^6A and R ^6A' are each C ₁₇H₃₅.

In some embodiments, the compound of formula (Ib') is:

in some embodiments, the compound of formula (I) has the structure of formula (Ib "):

In some embodiments, R ^6A is -CH₃、-C₂H₅、C₃H₇、C₄H₉、C₅H₁₁、C₆H₁₃、C₇H₁₅、C₈H₁₇、C₉H₁₉、C₁₀H₂₁、C₁₁H₂₃、C₁₂H₂₅、C₁₃H₂₇、C₁₄H₂₉、C₁₅H₃₁、C₁₆H₃₃ or C ₁₇H₃₅. In some embodiments, R ^6A is C ₁₅H₃₁ or C ₁₇H₃₅. In some embodiments, R ^6A is C ₁₅H₃₁. In some embodiments, R ^6A is C ₁₇H₃₅.

In some embodiments, R ^1B、R^2B and R ^3B are each independently alkyl. In some embodiments, each of R ^1B、R^2B and R ^3B is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R ^1B、R^2B and R ^3B are each methyl.

In some embodiments, the compound of formula (Ib') is:

In some embodiments, the compound of formula (I) has the structure of formula (Ia'):

Wherein R ^C14 is hydrogen or alkyl.

In some embodiments, R ^C14 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In some embodiments, the compound of formula (Ia) has the structure of formula (Ia-1):

Wherein R ^D1 and R ^D2 together with the atoms to which they are attached form a cycloalkyl or heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A; r ^D3 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, -OC (O) R ¹⁵, OR-C (O) OR ¹³, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl are unsubstituted OR substituted with one OR more alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹); m is 0 to 10.

In some embodiments, R ^D1 and R ^D2 together with the atoms to which they are attached form an unsubstituted or substituted cycloalkyl ring. In some embodiments, R ^D1 and R ^D2 together with the atoms to which they are attached form an unsubstituted cycloalkyl ring. In some embodiments, R ^D1 and R ^D2 together with the atoms to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl ring. In one embodiment, R ^D1 and R ^D2 together with the atoms to which they are attached form a cyclohexyl group.

In some embodiments, m is 0 to 8. In some embodiments, m is 0 to 6. In some embodiments, m is 0 to 4. In some embodiments, m is 1 to 4. In some embodiments, m is 1 to 3. In some embodiments, m is 1 to 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, R ^D3 is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹. In some embodiments, R ^D3 is alkyl substituted with-C (O) OR ¹³. In some embodiments, R ^D3 is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, OR-C ₁₀H₂₁. In some embodiments, R ¹³ is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R ^D3 is-CH ₂OC(O)R¹³, wherein R ¹³ is methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, the compound of formula (Ib) has the structure of formula (Ib-1):

In some embodiments, R ^D3 is-C (O) OR ¹³. In some embodiments, R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁. In some embodiments, R ¹³ is methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, the compound of formula (Ic) has the structure of formula (Ic-1):

Wherein R ⁶ is defined herein above; r ^D1 and R ^D2 together with the atoms to which they are attached form a cycloalkyl or heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A; r ^D3 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, -OC (O) R ¹⁵, OR-C (O) OR ¹³, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl are unsubstituted OR substituted with one OR more alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹); m is 0 to 10.

In some embodiments, R ⁶ is hydrogen or alkyl. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is alkyl. In some embodiments, R ⁶ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

Silyl prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ii):

In some embodiments, each of R ³、R⁴ and R ⁵ is independently hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

In some embodiments, each of R ³、R⁴ and R ⁵ is unsubstituted or substituted alkyl. In some embodiments, each of R ³、R⁴ and R ⁵ is independently alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

In some embodiments, each of R ³、R⁴ and R ⁵ is independently unsubstituted alkyl. In some embodiments, each of R ³、R⁴ and R ⁵ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

In some embodiments, R ³、R⁴ and R ⁵ are the same unsubstituted alkyl. In some embodiments, R ³ and R ⁴ are methyl, ethyl, or isopropyl.

In some embodiments, R ⁵ is ethyl, isopropyl, or tert-butyl.

In some embodiments, (i) R ³ and R ⁴ are methyl, and R ⁵ is ethyl; (ii) R ³、R⁴ and R ⁵ are isopropyl; or (iii) R ³、R⁴ and R ⁵ are ethyl.

In some embodiments, each of R ³、R⁴ and R ⁵ is independently heteroalkyl.

In some embodiments, each of R ³、R⁴ and R ⁵ is independently unsubstituted or substituted aryl (e.g., phenyl).

Sulfate prodrugs

In some embodiments, the compound of formula (I) has the structure of formula (Ij):

In some embodiments, R ⁵ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl.

In some embodiments, R ⁵ is hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

In some embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl, in some embodiments, R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl groups.

Selected compounds of the present disclosure

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

/>

In some embodiments, one or more hydrogens in the compound of formula (I) are replaced with deuterium.

Selected compounds of the present disclosure having corresponding simplified molecular input column input system (SIMPLIFIED MOL ECULAR-input line-ENTRY SYSTEM, SMILES) strings are provided in table 1.

TABLE 1

/>

In certain embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

/>

Deuterated analogs of O-acetyl dephosphorylated nupharmorin in another aspect, provided herein are compounds of formula (II):

Wherein:

R ²¹ is-CH ₃、-CH₂D、-CHD₂ or-CD ₃;

In certain embodiments, R ²¹ is-CH ₃、-CH₂D、-CHD₂ or-CD ₃. In certain embodiments, R ²¹ is-CH ₂D、-CHD₂ or-CD ₃. In certain embodiments, R ²¹ is-CH ₃、-CHD₂ or-CD ₃. In certain embodiments, R ²¹ is-CH ₃、-CH₂ D or-CD ₃. In certain embodiments, R ²¹ is-CH ₃、-CH₂ D or-CHD ₂.

In certain embodiments, R ²¹ is-CH ₃. In certain embodiments, R ²¹ is-CD ₃. In certain embodiments, R ²¹ is-CH ₂ D. In certain embodiments, R ²¹ is-CH D ₂.

In certain embodiments, R ²² and R ²³ are each independently-CH ₃、-CH₂D、-CH D₂ or-CD ₃. In certain embodiments, at least one of R ²² and R ²³ comprises deuterium. In certain embodiments, one of R ²² and R ²³ is-CD ₃. In certain embodiments, both R ²² and R ²³ are-CD ₃.

In certain embodiments, Y ¹ is D. In certain embodiments, Y ³ is D. In certain embodiments, Y ¹ and Y ² are each D. In certain embodiments, Y ³ and Y ⁴ are each D. In certain embodiments, Y ¹、Y²、Y³ and Y ⁴ are each D.

In certain embodiments, Y ⁶ is H.

In some embodiments, disclosed herein are deuterated analogs of O-acetyl dephosphorylated nupharin.

In some embodiments, the compound of formula (II) is a compound of formula (IIa) or formula (IIb):

Wherein the method comprises the steps of

R ²¹ is CH ₃、CH₂D、CHD₂ or CD ₃;

Each of R ²² and R ²³ is independently hydrogen or alkyl, wherein one or more hydrogens in the alkyl are optionally substituted with deuterium; and

At least one of R ²¹、R²² and R ²³ comprises one or more deuterium.

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

In another aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a compound according to any one of formulas (I), (Ia '), (Ib '), (Ic), (Id), (Ie), (If), (Ig), (Ih '), (Ia-1), (Ib-1), (Ic-1) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In another aspect, the present disclosure provides a pharmaceutically acceptable composition comprising a compound as any one of formulas (Ii) or (Ii), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

The pharmaceutical compositions of the present disclosure may comprise a racemic, non-racemic (scalemic) or diastereomerically enriched mixture of any compound described herein, including a stereogenic center.

Therapeutic method

In another aspect, the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which increased levels of a phenethylamine hallucinogen, such as MDMA, are beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (Ia '), (Ib '), (Ic), (Id), (Ie), (If), (Ig), (Ih '), (Ia-1), (Ib-1), (Ic-1), or (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the condition comprises post-traumatic stress disorder, major depressive disorder, schizophrenia, alzheimer's disease, frontotemporal dementia, parkinson's disease, parkinson's dementia, dementia with lewy bodies, multiple system atrophy, or drug abuse. In some embodiments, the condition comprises a musculoskeletal pain disorder, including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle spasms. In some embodiments, the present disclosure provides a method of treating reproductive health disorders in women, including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), postnatal depression, and menopause. The compounds of the invention may also be used to treat any brain disease.

In one embodiment, the present disclosure provides a method of treating or preventing a disease, disorder, or condition in which increased levels of a phenethylamine hallucinogen, such as MDMA, are beneficial, comprising administering to a subject in need thereof an effective amount of a compound of formula (Ii) or (Ij), or a pharmaceutically acceptable salt thereof. In some embodiments, the condition comprises post-traumatic stress disorder, major depressive disorder, schizophrenia, alzheimer's disease, frontotemporal dementia, parkinson's disease, parkinson's dementia, dementia with lewy bodies, multiple system atrophy, or drug abuse. In some embodiments, the condition comprises a musculoskeletal pain disorder, including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle spasms. In some embodiments, the invention provides a method of treating female reproductive health disorders, the method comprising premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), postnatal depression, and menopause. The compounds of the invention are also useful in the treatment of any brain disease.

In some embodiments, the compounds disclosed herein have activity as 5-HT _2A modulators. In some embodiments, the compounds disclosed herein elicit a biological response by activating the 5-HT _2A receptor (e.g., allosteric modulation or modulation of a biological target that activates the 5-HT _2A receptor). 5-HT _2A agonism has been associated with promotion of neuroplasticity. 5-HT _2A antagonists abrogate the neurite-generating and dendritic spinogenic effects of fanciful compounds (e.g., DMT, LSD and DOI) with 5-HT _2A agonistic activity. In some embodiments, the compounds disclosed herein are 5-HT _2A modulators and promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, the compounds disclosed herein are selective 5-HT _2A modulators and promote neuroplasticity (e.g., cortical structural plasticity). Promoting neuroplasticity may include, for example, increasing dendritic spine growth, increasing synthesis of synaptoproteins, enhancing synaptic responses, increasing dendritic axis (DENDRITIC ARBOR) complexity, increasing dendritic branch content, increasing dendritic spine production, increasing neurite production, or any combination thereof. In some embodiments, increasing neuroplasticity comprises increasing cortical structural plasticity in the anterior portion of the brain.

In some embodiments, the 5-HT _2A modulator (e.g., 5-HT _2A agonist) is non-fanciful. In some embodiments, a non-fanciful 5-HT _2A modulator (e.g., a 5-HT _2A agonist) is used to treat a neurological disease, the modulator not eliciting dissociative side effects. In some embodiments, the fanciful potential of the compounds described herein is assessed in vitro. In some embodiments, the fanciful potential of a compound described herein evaluated in vitro is compared to the fanciful potential of a fanciful homolog evaluated in vitro. In some embodiments, the compounds described herein cause less in vitro camouflage potential than the camouflage homolog.

In some embodiments, a serotonin receptor modulator, such as a modulator of serotonin receptor 2A (5-HT _2A modulator, e.g. 5-HT _2A agonist), is used to treat a brain disorder. In some embodiments, the compounds of the present disclosure are used as 5-HT _2A agonists alone or in combination with a second therapeutic agent, which is also a 5-HT _2A modulator. In such cases, the second therapeutic agent may be an agonist or an antagonist. In some cases, it may be helpful to administer a 5-HT _2A antagonist in combination with a compound of the disclosure to mitigate undesirable effects of 5-HT _2A agonism, such as potential illusive effects. Serotonin receptor modulators suitable as a second therapeutic agent for combination therapy as described herein are known to those of skill in the art and include, but are not limited to, ketanserin (KETA NSERIN), flurbiprofen (volinanserin) (MDL-100907), irinotelin (EPLIVANSERI N) (SR-46349), pinacolin (PIMAVANSERIN) (ACP-103), gliochrin (GLE MANSERIN) (MDL-11939), ritanserin (ritanserin), letan (EPLIVANSERI N), Flibanserin (flibanserin), neban Luo Selin (nelotanserin), blonanserin (blonanserin), mianserin (mianserin), mirtazapine (mirtazapine), luo Lupai ketone (roluperiodone) (CYR-101, MIN-101), quetiapine (quetiapine), olanzapine (olanzapine), atain (altanserin), levulinic acid (acepromazine), nefazodone (nefazodone), Risperidone (risperidone), pu Mo Selin (pruvanserin), AC-90179, AC-279, adapalene (adatanserin), farneserin (fananserin), HY10275, benjamin (benanserin), blonanserin (butanserin), mansalin (manserin), ifer serin (iferanserin), lidanserin (LIDAN SERIN), perlanin (pelanserin), seganserin (seganserin), blonanserin (butanserin), Tropane-color-line (tropan serin), chlorocarbaerin (lorcaserin), ICI-169369, methipine (methiothepin), dimethylergoline (METHYSERGIDE), trazodone (trazodone), cilazapril (cinitapride), cyproheptadine (cyproheptadine), bripiprazole (brexpiprazole), calicheazine (cariprazi ne), agomelatine (agomelatine), setopine (setoperone), and, 1- (1-naphthyl) piperazine, LY-367265, pirenperone (pirenperone), methylergoline (metergoline), deramciclane (DERAMCICLANE), bupivaloine (amperozide), AMDA, cinaloline (CINANSE RIN), LY-86057, GSK-215083, cyanocarbamazine (cyamemazine), messaging ergot (mesulergine), BF-1, LY-215840, ergoline (sergolexole), Spiromide (SPI RAMIDE), LY-53857, an Maijiao (amesergide), LY-108742, piparone (pipa mperone), LY-314228, 5-I-R91150, 5-MeO-NBpBrT, 9-aminomethyl-9, 10-dihydroanthracene, nipradizine (niaprazine), SB-215505, SB-204741, SB-206553, SB-242084, LY-272015, SB-243213, SB-200646, RS-102221, zotepine (zotepine), clozapine (clozapine), chlorpromazine (chlorpromazine), sertindole (sertindone), iloperidone (iloperidone), risperidone, paliperidone (PALIPERID ONE), asenapine (asenapine), amisulpride (amisulpride), aripiprazole (arip iprazole), bripiprazole, lurasidone (lurasidone), ji Pai cilidone (ziprasidone) or lumeperide (lumateperone), or a pharmaceutically acceptable salt, solvate, metabolite, deuterated analog, derivative, prodrug, or combination thereof. In some embodiments, the serotonin receptor modulator used as the second therapeutic agent is pimavanserin or a pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug thereof. In some embodiments, the serotonin receptor modulator is administered prior to administration of the compound disclosed herein, such as about three hours or several hours prior to administration of the compound. In some embodiments, the serotonin receptor modulator is administered up to about one hour prior to the compound. In some embodiments, the second therapeutic agent is a serotonin receptor modulator. In some embodiments, the serotonin receptor modulator is provided in a dose of from about 10mg to about 350 mg. In some embodiments, the serotonin receptor modulator is provided in a dosage of from about 20mg to about 200 mg. In some embodiments, the serotonin receptor modulator is provided in a dosage of from about 10mg to about 100 mg. In certain such embodiments, the compounds of the invention are provided in a dose of about 10mg to about 100mg, or about 20 to about 200mg, or about 15 to about 300mg, and the serotonin receptor modulator is provided in a dose of about 10mg to about 100 mg.

In some embodiments, a non-fanciful 5-HT2 _A modulator (e.g., a 5-HT2 _A agonist) is used to treat a neurological disease. In some embodiments, the neurological disorder comprises reduced neuroplasticity, reduced cortical structure plasticity, reduced 5-HT _2A receptor content, reduced dendritic shaft complexity, loss of dendritic spines, reduced dendritic branch content, reduced dendritic spinogenesis, reduced neurite formation, axonal contractions, or any combination thereof.

In some embodiments, a non-fanciful 5-HT _2A modulator (e.g., a 5-HT _2A agonist) is used to increase neuronal plasticity. In some embodiments, a non-fanciful 5-HT _2A modulator (e.g., a 5-HT _2A agonist) is used to treat a brain disorder. In some embodiments, a non-fanciful 5-HT _2A modulator (e.g., a 5-HT _2A agonist) is used to increase at least one of translation, transcription, or secretion of a neurotrophic factor.

The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. In general, the appropriate dosage and treatment regimen provides sufficient therapeutic and/or prophylactic benefit (e.g., improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and/or overall survival, or reduction in symptom severity).

Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose or another suitable material which is readily soluble in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (see, e.g., remington: THE SCIENCE AND PRACTICE of Pharmacy (Gen naro, 21 ^{Plate for printing} Mack pub. Co., easton, PA (2005)).

In some embodiments, the compounds described herein are administered to a patient at a low dose that is below that which would produce a pronounced illusive effect but high enough to provide a therapeutic benefit. This dose range is expected to be between 200 μg (micrograms) and 2 mg.

In some embodiments, the oral dosage is typically in the range of about 1.0mg to about 350mg, one to four or more times per day. In certain embodiments, the compound is administered to the subject in a daily dose of between 0.01mg/kg to about 50mg/kg body weight. In other embodiments, the dose is 1 to 350 mg/day. In certain embodiments, the daily dose is from 1 to 750 mg/day; or 10 to 350 mg/day. In certain embodiments, the compounds disclosed herein, including those described in table 1, are provided in daily doses of about 2mg to about 5mg, or about 5mg to about 10mg, or about 10mg to about 100mg, or about 20 to about 200mg, or about 15 to about 300mg, or 10mg, or 15mg, or 20mg, or 25mg, or 30mg, or 35mg, or 40mg, or 45mg, or 50mg, or 55mg, or 60mg, or 65mg, or 70mg, or 75mg, or 80mg, or 85mg, or 90mg, or 95mg, or 100 mg.

In some embodiments, the compounds described herein are used to treat neurological disorders. For example, the compounds provided herein may exhibit anti-addictive properties, antidepressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disorder is an emotional or anxiety disorder. In some embodiments, the neurological disorder is migraine, headache (e.g., cluster headache), post Traumatic Stress Disorder (PTSD), anxiety, depression, neurodegenerative disease, alzheimer's disease, parkinson's disease, psychological disorders, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorders). In some embodiments, the neurological disorder is migraine or cluster headache. In some embodiments, the neurological disease is a neurodegenerative disease, alzheimer's disease, or parkinson's disease. In some embodiments, the neurological disorder is a psychological disorder, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease is a psychological disorder, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is an addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disease or neurological disease is schizophrenia.

In some embodiments, the compounds of the present disclosure are used to increase neuronal plasticity. In some embodiments, the compounds described herein are used to treat a brain disorder. In some embodiments, the compounds described herein are used to increase translation, transcription, or secretion of neurotrophic factors.

The compounds disclosed herein may also be useful for increasing neuronal plasticity in a subject. As used herein, "neuronal plasticity" may refer to the ability of the brain to change structure and/or function throughout the life of a subject. New neurons may be created and integrated into the central nervous system throughout the life of a subject. Increasing neuronal plasticity may include, but is not limited to, promoting neuronal growth, promoting neurite generation, promoting synapse generation, promoting dendritic generation, increasing dendritic shaft complexity, increasing dendritic spine density, and increasing excitatory synapses in the brain. In some embodiments, increasing neuronal plasticity includes promoting neuronal growth, promoting neurite formation, promoting synapse formation, promoting dendritic formation, increasing dendritic shaft complexity, and increasing dendritic spine density.

In some embodiments, increasing neuronal plasticity by treating a subject with a compound of the present disclosure treats neurodegenerative diseases, alzheimer's disease, parkinson's disease, psychological disorders, depression, addiction, anxiety, post-traumatic stress disorder, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

In some embodiments, the present disclosure provides a method for increasing neuronal plasticity comprising contacting a neuronal cell with a compound of the present disclosure. In some embodiments, increasing neuronal plasticity improves the brain disorders described herein.

In some embodiments, the compounds disclosed herein are useful for increasing neuronal plasticity and have, for example, anti-addiction properties, anti-depressant properties, anxiolytic properties, or a combination thereof. In some embodiments, reduced neuronal plasticity is associated with neuropsychiatric disorders. In some embodiments, the neuropsychiatric disorder is an emotional or anxiety disorder. In some embodiments, neuropsychiatric disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., drug abuse disorders). Brain disorders may include, for example, migraine, addiction (e.g., substance use disorders), depression, and anxiety.

In some embodiments, the assay or assay to determine increased neuronal plasticity resulting from administration of any of the compounds of the present disclosure is a phenotypic assay, a dendritic generation assay, a synapse generation assay, a shore (Sholl) assay, a concentration response assay, a 5-HT _2A agonist assay, a 5-HT _2A antagonist assay, a 5-HT _2A binding assay, or a 5-HT _2A blocking assay (e.g., a ketanserin blocking assay). In some embodiments, the experiment or assay to determine the fantasy potential of any of the compounds of the present disclosure is a mouse head-flick reaction (HTR) assay.

In some embodiments, the disorder is a musculoskeletal pain disorder, including fibromyalgia, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle spasms. In some embodiments, the present disclosure provides a method of treating reproductive health disorders in women, including premenstrual dysphoric disorder (PMDD), premenstrual syndrome (PMS), postnatal depression, and menopause. In some embodiments, the present disclosure provides a method of treating a brain disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the present disclosure provides a method of treating a brain disorder with a combination therapy, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure and at least one additional therapeutic agent.

In some embodiments, the compounds of the present disclosure are used to treat brain disorders. In some embodiments, the compound has, for example, an anti-addiction property, an anti-depressant property, an anti-anxiety property, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disorder is an emotional or anxiety disorder. In some embodiments, brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, panic disorder, suicidal tendencies, schizophrenia, and addiction (e.g., drug abuse disorders). In some embodiments, brain disorders include, for example, migraine, addiction (e.g., substance use disorders), depression, and anxiety.

In some embodiments, the present disclosure provides a method of treating a brain disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein. In some embodiments, the brain disorder is a neurodegenerative disease, alzheimer's disease, parkinson's disease, psychological disorders, depression, addiction, anxiety, post-traumatic stress disorder, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

In some embodiments, the brain disorder is a neurodegenerative disease, alzheimer's disease, or parkinson's disease. In some embodiments, the brain disorder is a psychological disorder, depression, addiction, anxiety, or post-traumatic stress disorder. In some embodiments, the brain condition is depression. In some embodiments, the brain disorder is addiction. In some embodiments, the brain condition is refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder. In some embodiments, the brain condition is refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, or substance-use disorder. In some embodiments, the brain disorder is stroke or traumatic brain injury. In some embodiments, the brain condition is refractory depression, suicidal ideation, major depression, bipolar disorder, or substance use disorder. In some embodiments, the brain disorder is schizophrenia. In some embodiments, the brain disorder is an alcohol use disorder.

In some embodiments, the method further comprises administering one or more additional therapeutic agents. Non-limiting examples of additional therapeutic agents suitable for administration with the compounds of the present invention may include lithium, olanzapine (representate), quetiapine (cispran), risperidone (risplal), aripiprazole (An Lifu (Abilify)), ji Pai citalone (Geodon)), clozapine (Clozaril), sodium valproate (Depakote), lamotrigine (lamotrigine) (labetan), valproic acid (valproic acid) (dypran (Depakene)), carbamazepine (carbamazepine) (carbamazepine (Equetro)), topiramate (topiramate) (Topamax), levomilnacipran (levomilnacipran) (levomilnacipran (Fetzima)), duloxetine (duxeline) (Cymbalta), duloxetine (hci), duloxetine (YINCP) and (venlafaxine) (32) and fluplazine (3283) (32), fluplazine (3283) (32) and fluplazine (37) and (67) (valproate (Depakene) Clomipramine (clomipramine) (Annofenil (ANAFRANIL)), amitriptyline (AMITRIPTYLINE) (amitriptyline hydrochloride (elafil)), desipramine (desipramine) (norbomine (Norpramin)), imipramine (imipramine) (tofubrain (Tofranil)), nortriptyline (nortriptyline) (noramitriptyline (Pamelor)), phenelzine (phenelzine) (nadir (Nardil)), strong-inner hundred Le Ming (tranylcypromine) (tranylcypromine (Parnate)), diazepam (diazepam) (diazepam (Valium)), alprazolam (alprazolam) (prandial An Nuo (Xanax)) or clonazepam (clonazepam) (knopin)).

In some embodiments, the additional therapeutic agent is a monoamine oxidase inhibitor (MAOI), which may be, for example, molobetaine (moclobemide), ka Luo Shatong (caroxazone) (acetominophen (Surodil), ti Mo Sitai ni (Timostenil)), bromaromine (brofaromine) (bromaromine (Consonar)), methylene blue (METHYLENE BLUE), pirzadil (pirlindole) (pirlindol (Pirazidol)), milnaciplin (minaprine) (Kang Duoer (Cantor)), Me Qu Yinduo (metralindole) (due to Renzan (Inkazan)), epbezamine (eprobemide), te Qu Yinduo (tetrindole), harmine (harmine), ha Ma Ling (harmaline), A Mi Fuan (amiflamine), beofloxacin (befloxatone) (MD-370,503), western Mo Shatong (cimoxat one) (MD-780,515), mechloretamine (sercloremine) (CGP-4718-A), Ethylsulfoplon (esuprone) or CX157. In some embodiments, the additional therapeutic agent is phenethylamine, such as 3, 4-methylene-dioxymethamphetamine (MDMA) and analogs thereof. Other heat transfer agents suitable for use in combination with the compounds of the present disclosure include, but are not limited to, N-allyl-3, 4-methylenedioxy-amphetamine (MDAL), N-butyl-3, 4-methylenedioxy-amphetamine (MDB U), N-benzyl-3, 4-methylenedioxy-amphetamine (MDBZ), N-cyclopropylmethyl-3, 4-methylenedioxy-amphetamine (MDCPM), N-dimethyl-3, 4-methylenedioxy-amphetamine (MDDM), N-ethyl-3, 4-methylenedioxy-amphetamine (MDE; MDEA), N- (2-hydroxyethyl) -3, 4-Methylenedioxyamphetamine (MDHOET), N-isopropyl-3, 4-Methylenedioxyamphetamine (MDIP), N-methyl-3, 4-ethylenedioxyamphetamine (MDMC), N-methoxy-3, 4-methylenedioxyamphetamine (MDMEO), N- (2-methoxyethyl) -3, 4-methylenedioxyamphetamine (MDMEOET), alpha, N-trimethyl-3, 4-methylenedioxyphenethylamine (MDMP), 3, 4-methylenedioxy-N-methylbenzenebutylamine, N-hydroxy-3, 4-Methylenedioxyamphetamine (MDOH), 3, 4-Methylenedioxyphenethylamine (MDPEA), α -dimethyl-3, 4-methylenedioxyphenethylamine (MDPH; 3, 4-methylenedioxybenzene butylamine), N-propargyl-3, 4-methylenedioxybenzene propylamine (MDPL), methylenedioxy-2-aminoindan (MD AI), 1, 3-benzodioxolyl-N-Methylbutylamine (MBDB), N-methyl-1, 3-benzodioxolyl butylamine, 3, 4-methylenedioxy-N-methyl-alpha-ethylphenylethylamine, 3, 4-methylenedioxybenzene propylamine (MDA), methanone (3, 4-methylenedioxy-N-methylcarbazepine), ethanone (3, 4-methylenedioxy-N-ethylcarbazepine), GHB or gamma hydroxybutyrate or sodium hydroxybutyrate, N-propyl-3, 4-Methylenedioxyamphetamine (MDPR) and the like.

In some embodiments, the compounds of the present disclosure are used in combination with standard care therapies for neurological diseases described herein. Non-limiting examples of standard care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, aripiprazole (ariprazole), ji Pai cilone, clozapine, sodium divalproex (divalproex sodium), lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, cardiac internal bailamine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of standard care therapies for depression are sertraline, fluoxetine, escitalopram, venlafaxine or aripiprazole. Non-limiting examples of standard care therapies for depression are citalopram (citralopram), escitalopram, fluoxetine, paroxetine, diazepam or sertraline. Additional examples of standard care therapies are known to the average skilled artisan.

Methods of increasing at least one of translation, transcription, or secretion of a neurotrophic factor.

As used herein, the term "neurotrophic factor" may refer to a family of soluble peptides or proteins that support survival, growth, and differentiation of developing and mature neurons. Increasing at least one of translation, transcription, or secretion of a neurotrophic factor may be useful, for example, in increasing neuronal plasticity, promoting neuronal growth, promoting neurite generation, promoting synapse generation, promoting dendritic generation, increasing dendritic shaft complexity, increasing dendritic spine density, and increasing excitatory synapses in the brain. In some embodiments, increasing at least one of translation, transcription, or secretion of the neurotrophic factor increases neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of a neurotrophic factor promotes neuronal growth, promotes neurite formation, promotes synapse formation, promotes dendritic formation, increases dendritic shaft complexity, and/or increases dendritic spine density.

In some embodiments, a 5-HT _2A modulator (e.g., a 5-HT _2A agonist) is used to increase at least one of translation, transcription, or secretion of a neurotrophic factor. In some embodiments, the compounds of the present disclosure are used to increase translation, transcription, or secretion of neurotrophic factors. In some embodiments, increasing translation, transcription, or secretion of a neurotrophic factor is sufficient to treat migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disease, alzheimer's disease, parkinson's disease, psychological disorders, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or addiction (e.g., substance use disorder).

Experiments or assays useful for detecting increased translation of neurotrophic factors include, for example, ELISA, western blot, immunofluorescence assay, proteomic experiments, and mass spectrometry. In some embodiments, the assay or assay for detecting increased transcription of a neurotrophic factor is a gene expression assay, PCR, or microarray. In some embodiments, the assay or assay for detecting increased secretion of a neurotrophic factor is an ELISA, western blot, immunofluorescent assay, proteomic assay, or mass spectrometry assay.

In some embodiments, the present disclosure provides a method for increasing translation, transcription, or secretion of a neurotrophic factor, wherein the method comprises contacting a neuronal cell with a compound disclosed herein.

Examples

The following examples are intended to illustrate the invention and should not be construed as limiting the invention. The temperature is given in degrees celsius. If not mentioned otherwise, all the evaporation is carried out in vacuo, preferably between about 15mm Hg and 100mm Hg (=20-133 mbar). The structures of the final product, intermediates and starting materials are confirmed by standard analytical methods (e.g., MS and NMR). Abbreviations used are those conventional in the art. If undefined, the term has its commonly accepted meaning.

Preparation of selected compounds and intermediates.

The following preparations of the compounds and intermediates are given to enable those skilled in the art to more clearly understand and practice the present invention. It is not to be taken as limiting the scope of the disclosure, but rather as being illustrative and representative only.

Abbreviations (abbreviations)

App appearance

Boc carbamic acid tert-butyl ester

Boc-Lys (Boc) -OSu nα, nε -di-Boc-L-lysine hydroxysuccinimide ester

Boc-Phe-OSu Boc-L-phenylalanine N-hydroxysuccinimide ester

Boc-Pro-OSu Boc-L-proline N-hydroxysuccinimide ester

Boc-Val-OSu Boc-L-valine hydroxysuccinimide ester

Br broad peak

CCl ₄ Tetracarbonyl chloride

CDCl ₃ d-chloroform

CD ₃ OD methanol-d 4

D ₂ O deuterium oxide

D double peak

Dd bimodal

DCM dichloromethane

DIPEA diisopropylethylamine

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EDCI. HCl N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride

Et ₂ O diethyl ether

EtOAc ethyl acetate

HCl hydrochloric acid or hydrogen chloride

H six-fold state; six-fold peak

HBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

HPLC high pressure liquid chromatography

LC-MS liquid chromatography and mass spectrometry

MeOH methanol

MeCN acetonitrile

MgSO ₄ magnesium sulfate

MS mass spectrometry

M multiple peaks

Min(s) min

ML of

Mu L microliters

Mass to charge ratio of m/z

Mol

NHS N-hydroxysuccinimide

P five-peak

Q quartet

N ₂ Nitrogen

NaHCO ₃ sodium bicarbonate

NaOH sodium hydroxide

Na ₂SO₄ sodium sulfate

NH ₄ Cl ammonium chloride

NMP N-methyl-2-pyrrolidone

NMR nuclear magnetic resonance

Rt retention time

S single peak

T triplet

Tert-tert

TBDMSCl tertiary butyl dimethyl silyl chloride

TESCl chlorotriethylsilane

TFA trifluoroacetic acid

THF tetrahydrofuran

TIPSCl triisopropylchlorosilane

The various starting materials, intermediates and compounds of the preferred embodiments can be isolated and purified as desired using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Salts may be prepared from the compounds by known salt formation procedures. Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification.

General conditions for characterization:

Mass spectrometry was run on LC-MS systems using electrospray ionization. These were run using Waters Acquity Classic UPLC with PDA and SQ quality detection or Waters Acquity H-Class UPLC with PDA and QD a quality detection. [ M+H ] ⁺ refers to the monoisotopic molecular weight.

NMR analysis

The NMR spectra were run on Bruker Ultrashield MHz or 500MHz NMR spectrometers. Unless otherwise indicated, spectra were recorded at 298K and solvent peaks were used as reference. The offset (d) of each signal is measured in parts per million (ppm) relative to the residual solvent peak and the multiplicity is reported along with the associated coupling constant (J) as needed.

If not explicitly indicated, analytical HPLC conditions were as follows:

Instrument: LC-MS-1:

Method 2A

Column: acquity UPLC BEH C18.2.1X105 mm 1.7 μm

Column temperature: 50 DEG C

Flow rate: 0.8mL/min.

Eluent: a: h ₂ O, 0.1% formic acid, B: meCN (MeCN)

Gradient: 0.0-1.8 min 2% -98% B,1.8-2.1 min 98% B, 2.1-2.5% A.

Method 2B

Column: acquity UPLC BEH C18.2.1X105 mm 1.7 μm

Column temperature: 50 DEG C

Flow rate: 0.8mL/min.

Eluent: a: h ₂ O, 0.1% ammonia, B: meCN (MeCN)

Gradient: 0.0-1.8 min 2% -98% B,1.8-2.1 min 98% B, 2.1-2.5% A.

Instrument: LC-MS-2:

Method 2A

Column: acquity UPLC BEH C18.2.1X105 mm 1.7 μm

Column temperature: 50 DEG C

Flow rate: 0.8mL/min.

Eluent: a: h ₂O,B：MeCN,C：50％H₂ O/50% MeCN+2.0% formic acid

Gradient: 0.0-1.7 min 0% to 95% b,5% c; 95% B,5% C for 1.7-2.1 min

95% A,5% C for 2.1-2.5 minutes.

Method 2B

Column: acquity UPLC BEH C18.2.1X105 mm 1.7 μm

Column temperature: 50 DEG C

Flow rate: 0.8mL/min.

Eluent A is H2O, B: meCN, C:50% H2O/50% MeCN+2.0% Ammonia (aqueous)

Gradient: 0.0-1.7 min 0% -95% B,5% D; 95% B,5% D in 1.7-2.1 min

95% A,5% D for 2.1-2.5 minutes.

Example 1: 4-methylpiperazine-1-carboxylic acid [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] ester

A suspension of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (201 mg,0.98 mmol) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (196 mg,0.98 mmol) in pyridine (4 mL) was stirred overnight at room temperature under N ₂. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with 5% -15% meoh in CHCl ₃ and then a gradient of 15% meoh and 1% tea in CH Cl ₃ to give a solid. The solid was dissolved in H ₂ O (2 mL) and freeze-dried to give 4-methylpiperazine-1-carboxylic acid [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] ester (50 mg,15% yield) as a solid. LC-MS (LCMS 2: method 2B): rt 1.20 minutes ;MS m/z 331.1＝[M+H]⁺;¹H NMR(400MHz,DMSO-d6)δ10.96(br.s,1H),7.19(d,J＝7.8Hz,1H),7.10(d,J＝2.3Hz,1H),7.00(t,J＝7.8Hz,1H),6.61(d,J＝7.8Hz,1H),3.66(br.s,2H),3.44(br.s,2H),2.80–2.75(m,2H),2.46–2.35(m,6H),2.23(s,3H),2.19(s,6H).

Alternatively, the compound may be purified by KP-amino D silica column chromatography eluting with a gradient of gasoline in EtOAc to MeOH to give the product as a diformate (14.7 mg). LC-MS (+ve mode) )：m/z＝331.20[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.20(s,2H,HCO),7.13(m,2H,2×ArH),6.92(s,1H,ArH),6.78(d,J＝7.5Hz,1H,ArH),3.80(br.s,2H,CH₂),3.64(br.s,2H,CH₂),2.96(m,2H,CH₂),2.64(m,2H,CH₂),2.49(br.s,4H,2×CH₂),2.36(s,3H,NMe)2.32(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ154.2,144.8,138.6,128.1,122.1,120.4,112.5,108.9,108.8,68.0,60.5,46.2,45.3,45.3,24.5.

Example 2: sulfamic acid [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] ester

Sulfamoyl chloride (135 mg,1.17 mmol) was added in one portion to a stirred suspension of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (199mg, 0.97 mmol) and K ₂CO₃ (404 mg,2.92 mmol) in THF (2 mL) at room temperature under N ₂. The mixture was stirred at room temperature overnight, then the liquid was decanted from the solid and the solid was purified directly by silica gel column chromatography eluting with 10% meoh in DCM and then 15% meoh and 2% tea in DCM to give a solid. The solid was dissolved in H ₂ O (2 mL) and freeze-dried to give [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] sulfamate (19 mg,7% yield) as a solid. LC-MS (LCMS 2: method 2B): no NH was observed for Rt 0.85 min ;MS m/z 283.9＝[M+H]⁺;¹H NMR(400MHz,D₂O)δ7.48(d,J＝7.9Hz,1H),7.36(s,1H),7.26(t,J＝7.9Hz,1H),7.19(d,J＝7.9Hz,1H),3.50(t,J＝7.5Hz,2H),3.36(t,J＝7.5Hz,2H),2.94(s,6H). and no NH ₂ was observed for NH₂;¹H NM R(400MHz,DMSO-d6)δ11.27(br.s,1H),7.29(d,J＝7.8Hz,1H),7.24(d,J＝2.3Hz,1H),7.08(t,J＝7.8Hz,1H),7.02(d,J＝7.8Hz,1H),3.16(s,6H),3.00–2.95(m,2H),2.63–2.60(m,2H)..

Example 3: [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] phosphoric acid di-tert-butyl ester hydrochloride

NaOH (40 mg,1.0 mmol) was added at once to a stirred solution of di-tert-butyl phosphite (194 mg,1.00mmol, 195. Mu.L) and DMAP (123 mg,1.00 mmol) in THF (1.5 mL) and CCI ₄ (0.50 mL) under an atmosphere of N ₂ at 0deg.C. The mixture was warmed to room temperature and stirred for 10min and then a solution of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (205 mg,1.00 mmol) in THF (1.5 mL) was added dropwise over 5 min. The mixture was heated to 50 ℃ and stirred overnight, then cooled, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% meoh and 2% tea in CHCl ₃ to give a solid. The solid was triturated with Et ₂ O (3 x 5 ml) and then dried under vacuum to give [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] phosphate di-tert-butyl hydrochloride as a solid (40 mg,9% yield). LC-MS (LCMS 2: method 2B): no NH and NH groups were observed at Rt 1.62 min ;MS m/z 397.3＝[M+H]⁺;¹H NMR(400MHz,D₂O)δ7.30–7.24(m,2H),7.18(t,J＝7.9Hz,1H),7.07(d,J＝7.9Hz,1H),3.52(t,J＝7.4Hz,2H),3.36(t,J＝7.4Hz,2H),2.93(s,6H),1.45(s,9H),1.25(s,9H). HCl;¹H NMR(400MHz,DMSO-d₆)δ11.17(br.s,1H),9.60(br.s,1H),7.25(d,J＝2.4Hz,1H),7.18(d,J＝7.9Hz,1H),7.05(t,J＝7.9Hz,1H),6.93(d,J＝7.9Hz,1H),3.30–3.24(m,2H),3.21–3.14(m,2H),2.82(s,6H),1.42(s,18H).

Example 4: [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] hydrogen phosphate tert-butyl ester

NaOH (81 mg,2.04 mmol) was added in one portion to a stirred solution of di-tert-butyl phosphite (216 mg,1.12mmol, 217. Mu.L) and DMAP (12 mg,0.10 mmol) in THF (1 mL) and CCI ₄ (0.50 mL) at 0deg.C under an atmosphere of N ₂. The mixture was stirred at room temperature for 10 min and then a solution of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (208 mg,1.02 mmol) in THF (2 mL) was added dropwise over 5 min. The mixture was heated to 50 ℃ and stirred overnight, then cooled to room temperature, filtered and the filtrate concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and then purified by reverse phase chromatography eluting with a gradient of 5% -95% mecn in H ₂ O and 0.1% ammonia to give a solid. The solid was purified by chromatography on silica, eluting with 5% -10% meoh in DCM, and then a gradient of 15% meoh and 2% tea in DCM to give the product as a solid (41 mg, 10%). LC-MS (LCMS 2: method 2B): no P (=o) OH was observed at Rt 0.95 min ;MS m/z 341.1＝[M+H]⁺;¹H NMR(400MHz,DMS O-d₆)δ10.78(br.s,1H),7.03(d,J＝2.2Hz,1H),7.00(d,J＝7.8Hz,1H),6.93(t,J＝7.8Hz,1H),6.66(d,J＝7.8Hz,1H),3.24–3.20(m,2H),3.18–3.12(m,2H),2.71(s,6H),1.39(s,9H)..

Example 5: chloromethyl isopropyl carbonate

Chloromethyl chloroformate (2.29 g,17.8mmol,1.58 mL) was added dropwise to a stirred solution of isopropanol (785 mg,13.1mmol,1.00 mL) and pyridine (1.54 g,19.4mmol,1.57 mL) in DCM (15 mL) at room temperature under an atmosphere of N ₂ over 15 minutes. The mixture was warmed to room temperature and stirred overnight, then diluted with DCM (15 mL) and washed with 1M aqueous HCl (30 mL) and H ₂ O (2 x 30 mL). The organic layer was dried over Na ₂SO₄ and concentrated in vacuo to give crude chloromethyl isopropyl carbonate (1.93 g,97% yield) as an oil. The title compound was used without further purification. ¹H NMR(400MHz,CDCl₃ ) Delta 5.72 (s, 2H), 4.96 (hept, j=6.3 hz, 1H), 1.33 (d, j=6.3 hz, 6H).

The compounds of the following table examples (table example 5) were prepared in analogy to example 5 from chloromethyl chloroformate and the appropriate alcohols.

Table example 5

Example 6: [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] oxymethyl tetrahydropyran-4-yl carbonate

A solution of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (209 mg,1.02 mmol), tetrabutylammonium bromide (330 mg,1.02 mmol) and TEA (310 mg,3.07mmol, 428. Mu.L) in MeCN (5 mL) was stirred at room temperature under an atmosphere of N ₂ for 15 minutes and then chloromethyl tetrahydropyran-4-yl carbonate (3998 mg,2.05 mmol) in MeCN (5 mL) was added dropwise over 10 minutes. The mixture was stirred at room temperature for 30min and then NaI (15 mg,0.10 mmol) was added in one portion. The mixture was stirred at room temperature for 2 days, then concentrated in vacuo. EtOAc (50 mL), H ₂ O (50 mL) and brine (50 mL) were added to the residue. The separated aqueous phase was extracted with EtOAc (50 mL) and then the combined organic layers were dried over MgSO ₄, filtered and the filtrate concentrated in vacuo to give the crude [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] oxymethyltetrahydropyran-4-yl carbonate as an oil. LC-MS (LCMS 2: method 2B): rt 1.31 min; MS M/z 363.2 = [ m+h ] ⁺.

Alternative procedure:

Potassium carbonate (149 mg,1.08 mmol) and potassium iodide (18 mg,0.11 mmol) were added to a stirred solution of nupharmoreus dephosphorylation (220 mg,1.08 mmol) in anhydrous DMF (3 mL) at room temperature under an atmosphere of N ₂. The resulting suspension was stirred at room temperature for 15 min, then a solution of chloromethyl carbonate (tetrahydro-2H-pyran-4-yl) ester (210 mg,1.08 mmol) in anhydrous DMF (3 mL) was added dropwise to the suspension and the mixture was stirred at room temperature for 16H. The solvent was removed under reduced pressure and the residual material was purified by column chromatography on silica gel eluting with a gradient of MeOH in EtOAc to provide fraction product a (54 mg) as a semi-solid and a fraction (192 mg) containing 3- (2- (dimethylamino) ethyl) -4- ((((((tetrahydro-2H-pyran-4-yl) oxy) carbonyl) oxy) methoxy) -1H-indole-1-carboxylic acid tetrahydro-2H-pyran-4-yl ester (B) as a semi-solid. LC-MS (+ve mode): m/z= 363.10 (a) and 491.10 (B) [ m+h ] ⁺. The product a fraction (54 mg) was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in H ₂ O to give the desired product (9 mg) as a solid. LC-MS (+ve mode): m/z=363.15 [ m+h ] ⁺.

Example 7: [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] oxymethyl isopropyl carbonate

A solution of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (201 mg,0.98 mmol), bu ₄ NBr (317 mg,0.98 mmol) and TEA (298 mg,2.95mmol, 411. Mu.L) in MeCN (5 mL) was stirred at room temperature under an atmosphere of N ₂ for 15 minutes and then a solution of chloromethyl isopropyl carbonate (300 mg,1.97 mmol) in MeCN (5 mL) was added dropwise over 10 minutes. The mixture was stirred at room temperature for 30 min and then NaI (15 mg,0.10 mmol) was added in one portion. The mixture was stirred at room temperature for 3 days, then concentrated in vacuo. EtOAc (50 mL), H ₂ O (50 mL) and brine (50 mL) were added to the residue. The separated aqueous phase was extracted with EtOAc (50 mL) and then the combined organic layers were dried over MgSO ₄, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel with 10% -20% meoh in DCM and then a gradient of 20% meoh and 2% tea in DCM to give the product as a solid (5 mg, 2%). LC-MS (LCMS 2: method 2B): no NH was observed at Rt 1.35 min ;MS m/z 321.1＝[M+H]⁺;¹H NMR(400MHz,CD₃OD)δ7.42(d,J＝8.0Hz,1H),7.23–7.14(m,2H),6.90(d,J＝8.0Hz,1H),5.55(s,2H),4.98(hept,J＝6.2Hz,1H),3.06–2.95(m,4H),2.59(s,6H),1.38(d,J＝6.2Hz,6H)..

Example 8: chloromethyl succinic acid tert-butyl ester

Chloromethyl chlorosulfate (3.41 g,20.7mmol,2.09 mL) was added dropwise to a vigorously stirred biphasic mixture of 4-tert-butoxy-4-oxo-butyric acid (3.00 g,17.2 mmol), sodium bicarbonate (5.79 g,68.9 mmol) and tetrabutylammonium bisulfate (585 mg,1.72 mmol) in DCM (45 mL) and H ₂ O (30 mL) at room temperature under an atmosphere of N ₂ over 10 min. The mixture was stirred vigorously at room temperature overnight, then diluted with DCM (40 mL) and H ₂ O (40 mL). The separated organic phase was washed with saturated aqueous NaHCO ₃ (40 mL), dried over Na ₂SO₄, filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0% -15% etoac in petroleum ether to give tert-butyl chloromethylsuccinate (3.15 g,82% yield) as an oil. ¹H NMR(400MHz,CDCl₃ ) Delta 5.71 (s, 2H), 2.69-2.61 (m, 2H), 2.62-2.54 (m, 2H), 1.45 (s, 9H).

The compounds of the following table examples (table example 8) were prepared from the appropriate carboxylic acids in analogy to example 8.

Table example 8

Example 9: [1,4 '-bipiperidine ] -1' -carboxylic acid chloromethyl ester hydrochloride

A solution of chloromethyl chloroformate (500 mg,3.88mmol, 345. Mu.L) in DCM (3 mL) was added dropwise to a stirred solution of 1,4' -bipiperidine (544 mg,3.23 mmol) in DCM (3 mL) at 5℃under an atmosphere of N ₂ over 15 min. The mixture was stirred at 5 ℃ for 30 minutes and then warmed to room temperature and stirred overnight. H ₂ O (0.2 mL) was added to the mixture and the mixture was then vigorously stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue azeotroped with THF (2 x 4 ml) and then dried under vacuum to give chloromethyl [1,4 '-bipiperidine ] -1' -carboxylate hydrochloride as a solid (960 mg, assuming 100% yield). The title compound was used .¹H NMR(400MHz,CD₃OD)δ5.93–5.73(m,2H),4.41–4.22(m,2H),3.55–3.46(m,2H),3.42(tt,J＝12.2,3.8Hz,1H),3.09–2.83(m,4H),2.22–2.07(m,2H),2.03–1.95(m,2H),1.89–1.62(m,5H),1.58–1.46(m,1H). without further purification, was not observed HCl;¹H NM R(400MHz,DMSO-d6)δ10.20(br.s,1H),5.95–5.81(m,2H),4.17–4.02(m,2H),3.42–3.35(m,3H),2.98–2.82(m,4H),2.16–2.05(m,2H),1.87–1.53(m,7H),1.44–1.32(m,1H).

Example 10: {3- [2- (dimethylamino) ethyl ] -4-indolyloxy } methyl-hexanedioic acid tert-butyl ester

Aqueous NaOH (3.75 m,4.73mmol,1.26 mL) was added dropwise to a stirred suspension of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (322 mg,1.58 mmol) and tetrabutylammonium bisulfate (107 mg,0.32 mmol) in DCM (3 mL) at room temperature under an atmosphere of N ₂ over 5 min. The mixture was stirred vigorously at room temperature for 5min and then a solution of t-butyl chloromethyladipate (399mg, 1.58 mmol) in DCM (2 mL) was added dropwise over 2 min. The mixture was stirred vigorously at room temperature for 15min, then diluted with DCM (20 mL) and H ₂ O (20 mL). The separated aqueous phase was extracted with DCM (2×15 mL) and then the combined organic layers were washed with brine (20 mL), dried over Na ₂SO₄, filtered and the filtrate concentrated in vacuo to give crude {3- [2- (dimethylamino) ethyl ] -4-indolyloxy } methyl-adipate as a gum. LC-MS (LCMS 2: method 2B): rt 1.72 min; MS M/z 419.3= [ m+h ] ⁺. A sample of the material was purified by column chromatography on silica gel eluting with MeOH in DCM (with 0.1% et ₃ N) to provide the product as a semi-solid (41 mg). LC-MS (+ve mode) )：m/z＝419.20[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.12(t,J＝7.9Hz,1H,ArH),6.94(dd,J＝8.2,0.9Hz,1H,ArH),6.90(s,1H,ArH),6.61(dd,J＝7.7,0.9Hz,1H,ArH),5.98(s,2H,CH₂),2.93(m,2H,CH₂),2.74(m,2H,CH₂),2.40(s,6H,2×NCH₃),2.31(t,J＝7.1Hz,2H,CH₂),2.18(t,J＝7.0Hz,2H,CH₂),1.59(m,4H,2×CH₂),1.42(s,9H,3×CH₃).

The compounds of the following table examples (table example 10) were prepared in analogy to example 10 from 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol and the appropriate chloride.

Table example 10

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Example 11: [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] oxetan-3-yl carbonate

Oxetan-3-ol (145 mg,1.96mmol,124 μl) was added dropwise to a stirred solution of bis (4-nitrophenyl) carbonate (328 mg,1.08 mmol) and DMAP (12 mg,0.10 mmol) in DCM (3 mL) at room temperature under an atmosphere of N ₂ over 2 min. The mixture was stirred at room temperature for 1 hour, then 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (200 mg,0.98 mmol) was added to the mixture at room temperature in one portion followed by the dropwise addition of DIPEA (127 mg,0.98mmol,171 μl) over 2 minutes. The mixture was stirred at room temperature for 2 days, then H ₂ O (4 mL) and EtOAc (4 mL) were added to the mixture. The separated organic layer was washed with brine (10 mL), dried over Na ₂SO₄ and concentrated in vacuo to give crude [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] oxetan-3-yl carbonate as a gum. LC-MS (LCMS 2: method 2B): rt 1.29 min; MS M/z 305.2= [ m+h ] ⁺.

Example 12: [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] oxymethyl phosphate di-tert-butyl ester

Sodium hydride, 60% dispersion in mineral oil (60 mg,1.51 mmol) was added in one portion to a stirred solution of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (205 mg,1.00 mmol) in anhydrous DMF (2.5 mL) at room temperature under an atmosphere of N ₂. The mixture was stirred at room temperature for 10 minutes, then di-tert-butyl chloromethyl phosphate (317 mg,1.10mmol, 305. Mu.L) was added dropwise over 2 minutes, followed by potassium iodide (500 mg,3.01 mmol) in one portion. The mixture was stirred at room temperature overnight, then H ₂ O (1 mL) and EtOAc (20 mL) were added and then the mixture was washed with 90% brine solution (20 mL), 50% brine solution (3 x 20 mL) and saturated aqueous sodium thiosulfate solution (20 mL). The organic layer was dried over Na ₂SO₄, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel with a gradient of 0% -5% meoh in DCM, and then a gradient of 5% -10% meoh and 0.5% tea in DCM to give the product as a gum (76 mg, 16%). LC-MS (LCMS 2: method 2B): rt 1.82 min ;MS m/z 427.3＝[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ8.24(br.s,1H),7.09–7.01(m,2H),6.95–6.88(m,1H),6.80(dd,J＝6.6,1.9Hz,1H),5.76(d,J＝11.4Hz,2H),3.13–3.04(m,2H),2.79–2.69(m,2H),2.42(s,6H),1.44(s,18H);¹H-³¹P coupling: ³¹P NMR(162MHz,CDCl₃)δ-11.83(t,J＝11.4Hz);¹H-³¹ P decoupling: ³¹P NMR(162MHz,CDCl₃ ) Delta-11.83(s).

Example 13:5- ({ 3- [2- (dimethylamino) ethyl ] -4-indolyloxycarbonyl } -N-methylamino) pentanoic acid tert-butyl ester

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Triphosgene (109 mg,0.37 mmol) was added in one portion to a stirred suspension of 3- [2- (dimethylamino) ethyl ] -1H-indol-4-ol (203 mg,0.99 mmol) and DM AP (389 mg,3.18 mmol) in DCM (10 mL) at room temperature under an atmosphere of N ₂. The mixture was stirred at room temperature for 1 hour, then tert-butyl 5- (methylamino) valerate hydrochloride (222 mg,0.99 mmol) was added to the mixture at room temperature in one portion, followed by dropwise addition of TEA (211 mg,2.09mmol, 291. Mu.L) over 2 minutes. The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a gradient of 0% -10% meoh in DCM to give an oil. The crude material was dissolved in DMSO (1.5 mL) and repurified by reverse phase chromatography eluting with a gradient of 10% -40% mecn in H ₂ O and 0.1% formic acid to give tert-butyl 5- ({ 3- [2- (dimethylamino) ethyl ] -4-indolyloxycarbonyl } -N-methylamino) pentanoate as a gum (63 mg,13% yield). The spectroscopic data for the title compound were obtained as a mixture of rotamers. LC-MS (LCMS 2: method 2A): no CO ₂ H was observed at Rt 1.17 min ;MS m/z418.2＝[M+H]⁺;MS m/z 418.2＝[M+H]⁺;¹H NMR(400MHz,DMSO-d₆)δ10.99(br.s,1H),8.19(s,1H),7.19(d,J＝8.0Hz,1H),7.13(d,J＝2.3Hz,1H),7.00(t,J＝8.0Hz,1H),6.62–6.55(m,1H),3.47(t,J＝7.0Hz,0.8H),3.30(t,J＝6.6Hz,1.2H),3.10(s,1.8H),2.91(s,1.2H),2.84–2.78(m,2H),2.62–2.54(m,2H),2.30–2.21(m,8H),1.69–1.49(m,4H),1.39(s,5.4H),1.38(s,3.6H)..

Example 14:5- ({ 3- [2- (dimethylamino) ethyl ] -4-indolyloxycarbonyl } -N-methylamino) pentanoic acid formate trifluoroacetate salt

TFA (1.48 g,13.0mmol,1.00 mL) was added dropwise to a stirred solution of tert-butyl 5- ({ 3- [2- (dimethylamino) ethyl ] -4-indolyloxycarbonyl } -N-methylamino) pentanoate (38 mg,0.08 mmol) in DCM (1 mL) at room temperature under an atmosphere of N ₂ over 5 minutes. The mixture was left at room temperature for 1 hour, then concentrated in vacuo to give the product as a gum (43 mg, 94%). The spectroscopic data for the title compound were obtained as a mixture of rotamers. LC-MS (LCMS 1: method 2A): rt 0.76 minutes; MS (MS)

m/z 362.4＝[M+H]⁺;¹H NMR(400MHz,DMSO-d₆)δ12.07(br.

s,1H),11.20(s,1H),9.37(br.s,1H),7.29–7.21(m,2H),7.05(t,J＝7.9Hz,1H),6.68–6.61(m,1H),3.52–3.47(m,0.8H),3.38–3.29(m,3.2H),3.12(s,1.8H),3.07–2.99(m,2H),2.93(s,1.2H),2.85–2.77(m,6H),2.32–2.24(m,2H),1.67–1.48(m,4H). No two CO ₂H;¹⁹ F NMR (37MHz, DMSO-d 6) delta-73.9(s) were observed.

The compounds of the following table examples (table example 14) were prepared from the appropriate tert-butyl protected compounds in analogy to example 14.

Table example 14

Example 15:4- (((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) methoxy) -4-oxobutanoic acid trifluoroacetate salt

To tert-butyl (((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) methyl) succinate (68 mg,0.17 mmol) in DCM (5 mL) was added TFA (0.69 mL,0.96g,8.5 mmol) and the mixture was stirred at room temperature for 3H. The mixture was concentrated under reduced pressure and the residue was azeotroped with MeOH (3×10 mL) to afford the product as a semi-solid (122 mg). LC-MS (+ve mode): m/z=335.15 [ m+h ] ⁺.

Example 16: (S) -2-amino-3-methylbutanoic acid ((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) methyl ester

(S) -2- (tert-Butoxycarbonylamino) -3-methyl-butanoic acid {3- [2- (dimethylamino) ethyl ] -4-indolyloxy } methyl ester (16 mg, 40. Mu. Mol) was dissolved in anhydrous dichloromethane (0.5 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature under nitrogen. After 5 minutes, the mixture turned dark blue. LC-MS (+ve mode): m/z=334.18 [ m+h ] ⁺.

The following UPLC-MS methods and conditions were used in examples 17-45.

UPLC-MS analysis was performed on a Waters Acquity UPLC system consisting of an Acquisy I-Class sample manager-FL, an Acquisy I-Class binary solvent manager, and an Acquisy UPLC column manager. UV detection is provided using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whereas mass detection is achieved using an Acquity Quad detector (scanning from 100-1250Da mass; simultaneous positive and negative modes), and ELS detection is achieved using an Acquity UPLC ELS detector. Waters Acquity UPLC BEH C18 columns (2.1X105 mm,1.7 mm) were used for separating the analytes.

Samples were prepared by dissolution (with or without sonication) in 1mL of 50% (v/v) MeCN in water. The resulting solution was then filtered through a 0.2mm syringe filter and then presented for analysis. All solvents (including formic acid and 36% ammonia solution) were purchased as HPLC grade.

Conditions (2 minutes acid): 0.1% v/v formic acid in water [ eluent A ];0.1% v/v formic acid in MeCN [ eluent B ]; the flow rate is 0.8mL/min; column oven 50 ℃; sample manager 20 ℃; an equilibration time of 1.5 minutes between 2mL injection volume and sample. Gradient parameters are provided in table 2:

TABLE 2

Time (minutes)	Eluent A (%)	Eluent B (%)
			0.00	95	5
0.25	95	5
			1.25	5	95
1.55	5	95
			1.65	95	5
2.00	95	5

Conditions (acid 4 min): 0.1% v/v formic acid in water [ eluent A ];0.1% v/v formic acid in MeCN [ eluent B ]; the flow rate is 0.8mL/min; column oven 50 ℃; sample manager 20 ℃; injection volume 2mL and 1.5 min equilibration time between samples. Gradient parameters are provided in table 3.

Table 3.

Time (minutes)	Eluent A (%)	Eluent B (%)
			0.00	95	5
0.25	95	5
			2.75	5	95
3.25	5	95
			3.35	95	5
4.00	95	5

Conditions (acid 6 min): 0.1% v/v formic acid in water [ eluent A ];0.1% v/v formic acid in MeCN [ eluent B ]; the flow rate is 0.8mL/min; column oven 50 ℃; sample manager 20 ℃; injection volume 2mL and 1.5 min equilibration time between samples. Gradient parameters are provided in table 4.

Table 4.

Time (minutes)	Eluent A (%)	Eluent B (%)
			0.00	95	5
0.30	95	5
			6.00	5	95
6.10	95	5
			7.00	95	5

Conditions (alkaline 2 min): 0.1% ammonia in water [ eluent a ];0.1% ammonia in MeCN [ eluent B ]; the flow rate is 0.8mL/min; column oven 50 ℃; sample manager 20 ℃; injection volume 2mL and 1.5 min equilibration time between samples. Gradient parameters are provided in table 5.

Table 5.

Conditions (alkaline 4 min): 0.1% ammonia in water [ eluent a ];0.1% ammonia in MeCN [ eluent B ]; the flow rate is 0.8mL/min; column oven 50 ℃; sample manager 20 ℃; injection volume 2mL and 1.5 min equilibration time between samples. Gradient parameters are provided in table 6.

TABLE 6

Conditions (alkaline 6 min): 0.1% ammonia in water [ eluent a ];0.1% ammonia in MeCN [ eluent B ]; the flow rate is 0.8mL/min; column oven 50 ℃; sample manager 20 ℃; injection volume 2mL and 1.5 min equilibration time between samples. Gradient parameters are provided in table 7.

TABLE 7

Example 17: tetrahydro-2H-pyran-4-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester hydrochloride

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To a mixture of dephosphorized nupharmor-ol (170 mg,0.83 mmol) in anhydrous pyridine (10 mL) was added DMAP (10 mg,0.08 mmol) and the mixture was cooled to 0 ℃. Dioxane-3-carbonyl chloride (117 mg,97 μl,0.79 mmol) was carefully added and the mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of acetonitrile in 0.02% hydrochloric acid to provide the product as a glassy solid (231 mg, 84%). LC-MS (+ve mode) )：m/z＝317.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.23(m,2H,2×ArH),7.07(t,J＝9.0Hz,1H,ArH),6.67(dd,J＝7.7,0.8Hz,1H,ArH),3.97(m,2H,CH₂),3.54(td,J＝11.5,2.5Hz,2H,CH₂),3.43(t,J＝7.3Hz,2H,CH₂),3.15(t,J＝7.2Hz,2H,CH₂),2.86(s,6H,2×NMe),2.03(m,2H,CH₂),1.87(m,2H,CH₂);¹³C NMR(75.5MHz,CDCl₃)δ200.5,174.0,143.9,139.3,123.9,121.7,111.7,109.4,107.0,66.6,58.2,42.4,39.9,28.6,21.6.

Example 18: oxetan-3-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester

Oxetane-3-carboxylic acid (79 mg,0.77 mmol) was dissolved in anhydrous DMF (5 mL) under N ₂ and N, N-diisopropylethylamine (108 mg, 146. Mu.L, 0.84 mmol) was added followed by the addition of nupharmorin dephosphorylation (132 mg,0.65 mmol) and HBTU (267 mg,0.71 mmol). The mixture was stirred at room temperature for 20 hours, then volatiles were removed under reduced pressure and saturated aqueous NaHCO ₃ (20 mL) was added. The resulting mixture was extracted with EtOAc (50 mL) and the organic layer was washed with H ₂ O (20 mL), saturated brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give the product (200 mg). LC-MS (+ve mode): m/z=289.15 [ m+h ] ⁺.

Example 19: tetrahydrofuran-3-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester hydrochloride

Tetrahydrofuran-3-carbonyl chloride (184 mg,145 μl,1.37 mmol) was added to a stirred solution of nupharmoreus dephosphorylation (200 mg,0.98 mmol) in anhydrous pyridine (2.4 mL) at room temperature. The mixture was heated to 40 ℃ and stirred for 16 hours, then volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of acetonitrile in 0.02% hydrochloric acid to provide the product as a solid (284 mg, 86%). LC-MS (+ve mode) )：m/z＝303.10[M+H]⁺;¹H NMR(300MHz,D₂O)δ7.46(dd,J＝8.3,0.6Hz,1H,ArH),7.30(s,1H,ArH),7.25(t,J＝8.0Hz,1H,ArH),6.87(dd,J＝7.7,0.7Hz,1H,ArH),4.23(dd,J＝9.1,4.7Hz,1H,CH),4.05(m,2H,CH₂),3.90(m,1H,CH),3.63(m,1H,CH),3.45(t,J＝7.0Hz,2H,CH₂),3.10(d,J＝7.0Hz,2H,CH₂),2.86(s,6H,2×NCH₃),2.40(m,2H,CH₂).

Example 20: 1-Methylazetidine-3-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester

N, N-diisopropylethylamine (278 mg, 384. Mu.L, 2.15 mmol), dimethylaminopyridine (27 mg,0.22 mmol) and 1-methylazetidine-3-carboxylic acid (248 mg,2.15 mmol) were added to a stirred mixture of desphosphoric acid oudemansin (220 mg,1.08 mmol) in DCM (5 mL) under an atmosphere of N ₂. The resulting suspension was stirred at room temperature for 15 minutes, then N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (454 mg,2.37 mmol) was added to this suspension and the reaction mixture was heated to 35 ℃ and stirred for 16 hours. The solvent was removed under reduced pressure to yield a crude residue containing the product. LC-MS (+ve mode): m/z=302.10 [ m+h ] ⁺.

Example 21:3- (2-Acetyloxy-4, 6-dimethylphenyl) -3-methylbutanoic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Step 1: preparation of 2- (4-chloro-2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene acetate

Oxalyl chloride (255 mg,152 μl,1.78 mmol) was added to a mixture of 3- (2-acetoxy-4, 6-dimethylphenyl) -3-methylbutanoic acid (311 mg,1.78 mmol) in anhydrous DCM (10 mL) at 0deg.C under N ₂ atmosphere. The mixture was warmed to room temperature and stirred for 2 hours 45 minutes, then volatiles were removed under reduced pressure to provide the product as a semi-solid, which was used directly in the next step.

Step 2: preparation of 3- (2-acetoxy-4, 6-dimethylphenyl) -3-methylbutanoic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

To a mixture of dephosphorylated ouabain (200 mg,0.98 mmol) and DMAP (12 mg,0.098 mmol) in anhydrous pyridine (5 mL) was added a solution of 3- (2-acetoxy-4, 6-dimethylphenyl) -3-methylbutanoic acid chloride (1.78 mmol) in anhydrous pyridine (5 mL). The mixture was stirred at room temperature for 16 hours and then concentrated to give a semi-solid (0.75 g). The crude product was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of 0.1% formic acid in acetonitrile in water to provide the product as a solid (274 mg, 62%). LC-MS (+ve mode) )：m/z＝451.20[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.41(s,1H,HCO),7.23(m,2H,2×ArH),7.04(t,J＝8.1Hz,1H,ArH,),6.89(s,1H,ArH),6.69(s,1H,ArH),6.42(dd,J＝7.3,0.7Hz,1H,ArH,)3.34(t,J＝7.1Hz,2H,CH₂),3.20(s,2H,CH₂),3.04(t,J＝6.9Hz,2H,CH₂),2.81(s,6H,2×NMe),2.61(s,3H,CH₃),2.32(s,3H,CH₃),2.24(s,3H,CH ₃)1.73(s,6H,2×CH₃);¹³C NMR(75.5MHz,CD₃OD)δ171.2,170.3,167.2,149.8,143.6,139.3,138.3,136.3,132.9,131.9,124.0,123.0,121.6,119.0,111.7,109.3,106.8,58.3,42.3,39.0,30.9,24.3,21.5,20.5,18.8.

Example 22: dipalmitic acid 2- ((((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) carbonyl) oxy) propane-1, 3-diyl ester

To 2-hydroxypropionate-1, 3-diyl dipalmitate (200 mg,0.35 mmol) in DCM (10 mL) was added DMAP (136 mg,1.13 mmol) and triphosgene (40 mg,0.13 mmol), and the mixture was stirred at room temperature for 1 hour. To a mixture of the resulting 2- ((chlorocarbonyl) oxy) propane-1, 3-diyl dipalmitate (0.35 mmol) was added a solution of nula agenda dephosphorylation (71 mg,0.35 mmol) and TEA (40 mg,55 μl,0.42 mmol) in MeC N (5 mL), and the mixture was stirred for 16 hours. The mixture was filtered through Celite (Celite), the filter cake was washed with DCM (3×20 mL), and the combined filtrates were concentrated to give a solid. The crude product was purified by column chromatography on silica gel eluting with a gradient of EtOAc in petrol, then further purified by column chromatography on silica gel eluting with a gradient of EtOAc in MeOH to afford the product as a semi-solid (47.3 mg, 16%). LC-MS (+ve mode) )：m/z＝799.55[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.24(dd,J＝8.7,0.7Hz,1H,ArH),7.07(m,2H,2×ArH),6.84(m,1H,ArH),5.24(m,1H,CH),4.48(dd,J＝12.2,3.7Hz,2H,CH₂),4.26(dd,J＝12.0,6.3Hz,2H,CH₂),2.93(m,2H,CH₂),2.68(m,2H,CH₂),2.34(s,6H,2×NMe),1.60(m,4H,2×CH₂)1.26(m,42H,21×CH₂),0.89(t,J＝6.5Hz,6H,2×CH₃).

Example 23:6- ((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) -6-oxohexanoic acid hydrochloride

Adipic anhydride (technical grade, 90%,143mg,1.00 mmol) was added to a suspension of dephosphorized nuphar mushroom extract (158 mg,0.77 mmol) in anhydrous DCM (7.5 mL) containing DMAP (19 mg,0.16 mmol) under an atmosphere of N ₂, and the mixture was stirred at room temperature for 20 hours. The volatiles were removed under reduced pressure and the residue was purified using C ₁₈ column reverse phase chromatography eluting with a gradient of acetonitrile in H ₂ O to provide after freeze drying a solid (158 mg) which was further purified in the same manner to give the free base of the title compound as a very hygroscopic solid. The free base was dissolved in a mixture of 1, 4-dioxane (5 mL) and H ₂ O (0.5 mL) and treated with 4M HCl in 1, 4-dioxane (193. Mu.L) at room temperature. Volatiles were removed under reduced pressure to provide the desired product as a solid (153 mg, 54%). LC-MS (+ve mode) )：m/z＝333.10[M+H]⁺;¹H NMR(300MHz,D₂O)δ7.46(dd,J＝8.3,0.8Hz,1H,ArH),7.32(s,1H,ArH),7.25(t,J＝8.0Hz,1H,ArH)6.45(dd,J＝7.7,0.8Hz,1H,ArH),3.46(t,J＝7.0Hz,2H,CH₂),3.12(t,J＝7.0Hz,2H,CH₂),2.87(s,6H,2×NCH₃),2.79(m,2H,CH₂),2.47(m,2H,CH₂),1.78(m,4H,2×CH₂);¹³C NMR(75.5MH z,D₂O)δ178.6,175.8,142.9,138.8,125.2,122.4,118.5,112.1,110.5,106.5,58.2,42.9,33.4,23.7,23.5,21.3.

Example 24: (3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) hexanedioic acid tert-butyl ester

A mixture of dephosphorized nupharbitis (155 mg,0.76 mmol), HBTU (345 mg,0.91 mmol), 6- (tert-butoxy) -6-oxohexanoic acid (184 mg,0.91 mmol) and Cs ₂CO₃ (294 mg,0.91 mmol) in anhydrous DMF (10 mL) was stirred overnight at room temperature under nitrogen. The mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of H ₂ O (30 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2X 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give an oil (1.13 g) which was purified by column chromatography on silica gel eluting with MeOH in DCM (containing 0.1% et ₃ N) to give the product as an oil (180 mg, 61%). LCMS (+ve mode) )：m/z＝389.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.79(br.s,1H,NH),7.24(dd,J＝8.2,0.8Hz,1H,ArH),7.11(app t,1H,ArH),6.92(d,J＝1.7Hz,1H,ArH),6.78(dd,J＝7.6,0.8Hz,1H,ArH),3.04(m,2H,CH₂),2.84(m,2H,CH₂)2.72(m,2H,CH₂),2.49(s,6H,2×NCH₃),2.30(t,J＝7.2Hz,2H,CH₂),1.78(m,4H,2×CH₂),1.45(s,9H,C(CH₃)₃);¹³C NMR(75.5MHz,CDC l₃)δ172.9,172.6,143.9,138.6,123.2,122.2,119.5,112.4,110.5,109.5,80.3,59.6,44.2,35.2,34.1,28.1,24.6,24.3,23.2.

Example 25: n- ((tert-Butoxycarbonyl) -L-phenylalanyl) -N-methylglycine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

N-Boc-L-phenylalanine-sarcosine (120 mg,0.36 mmol), HBTU (164 mg,0.43 mmol) and Cs ₂CO₃ (190 mg,0.58 mmol) were dissolved in anhydrous DMF (4 mL) under N ₂. The mixture was stirred at room temperature for 30 min, then a mixture of des-phosphoric acid nupharicin (35 mg,0.16 mmol) in anhydrous DMF (0.5 mL) was added. The mixture was stirred at room temperature for 20 hours, then filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of 0.1% acetonitrile in formic acid in H ₂ O to provide the product as a semi-solid (32.5 mg, 39%). LC-MS (+ve mode) )：m/z＝523.30[M+H]⁺;¹H NM R(300MHz,CD₃CN)δ9.55(s,1H,NH⁺),8.36(s,1H,HCO),7.35(m,1H,ArH),7.26(m,5H,5×ArH),7.12(m,2H,2×ArH),6.76(dd,J＝7.7,0.8Hz,1H,ArH),5.88(d,J＝8.8Hz,1H,NH),4.82(m,1H,CH),4.43(s,2H,CH₂),3.11(7H,NCH₃,2×CH₂),2.75(s,6H,2×NCH₃),1.31(s,9H,3×Bo c CH₃).

Example 26: (tert-Butoxycarbonyl) -L-valine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

To a mixture of dephosphorylated nupharmor (200 mg,0.98 mmol) in MeCN (10 mL) was added K ₂CO₃ (149 mg,1.08 mmol) and Boc-Val-OSu (292 mg,0.93 mmol). The mixture was heated to 80 ℃ and stirred for 1 hour, allowed to cool to room temperature and stirred for 16 hours. The mixture was filtered through celite and the filter pad was washed with Me CN (2 x 20 mL) and the combined filtrates were concentrated. The crude product was purified using reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.1% formic acid in H ₂ O to provide the product as a foam (184 mg, 46%). LC-MS (+ve mode) )：m/z＝404.25[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.42(s,1H,HC O),7.32(dd,J＝8.2,0.8Hz,1H,ArH),7.26(s,1H,ArH),7.14(t,J＝7.9Hz,1H,ArH),6.76(dd,J＝7.7,0.8Hz,1H,ArH),4.36(d,J＝5.9Hz,1H,CH),3.50(m,2H,CH₂),3.26(t,J＝7.5Hz,2H),2.99(s,6H,2×NMe),2.42(m,1H,CH),1.50(s,9H,3×Boc CH₃),1.19(d,J＝6.9Hz,3H,CH₃),1.15(d,J＝6.9Hz,3H,CH₃);¹³C NMR(75.5MHz,CD₃OD)δ210.6,202.1,174.1,167.4,159.0,145.6,141.2,126.3,123.4,121.0,113.2,111.5,109.4,81.3,61.5,60.4,44.2,32.3,29.4,23.3,20.4,19.2.

Example 27: l-valine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester dihydrochloride

A mixture of (tert-butoxycarbonyl) -L-valine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate (140 mg,0.35 mmol) in DCM (10 mL) was treated with TFA (1.33 mL,17.4 mmol) under an atmosphere of N ₂. The mixture was stirred at room temperature for 3 hours, then volatiles were removed under reduced pressure and the crude residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.02% hydrochloric acid to provide the product as a semi-solid (19 mg, 14%). LC-MS (+ve mode) )：m/z＝304.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.34(dd,J＝8.2,0.8Hz,1H,ArH),7.26(s,1H,ArH),7.13(t,J＝8.0Hz,1H,ArH),6.80(dd,J＝7.8,0.8Hz,1H,ArH),4.75(d,J＝4.0Hz,1H,CH),3.47(m,2H,CH₂),3.29(m,2H,CH₂),2.93(s,3H,NCH₃),2.92(s,3H,NCH₃),2.62(m,1H,CH),1.27(dd,J＝7.8,1.7Hz,6H,2×CH₃).

Example 28: (tert-Butoxycarbonyl) -L-phenylalanine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

A suspension of Boc-Phe-OSu (0.67 mg,1.84 mmol), dephosphorylated ouabain (348 mg,1.68 mmol) and K ₂CO₃ (254 mg,1.84 mmol) in anhydrous MeCN (10 mL) was stirred under N ₂ at room temperature for 1 hour, then heated to reflux and stirred for 30 minutes, then stored at room temperature for 20 hours. The mixture was poured into H ₂ O (40 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with saturated brine (40 mL), dried (MgSO ₄), filtered and the filtrate was concentrated to an oil (804 mg). The residue was purified by column chromatography on silica gel eluting with a gradient of MeOH in DCM to provide a mixture of the desired product (as its free base) and dephosphorylated ouabain (130 mg). This material was further purified using reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.1% formic acid in H ₂ O to provide the product as a solid (174 mg, 21%). LC-MS (+ve mode) )：m/z＝452.25[M+H]⁺;¹H NMR(300MHz,DMSO-d₆)δ11.05(s,1H,NH),8.21(s,1H,HCO),7.71(d,J＝8.5Hz,1H,ArH),7.32(m,4H,ArH),7.24(m,2H,ArH+NH⁺),7.16(d,J＝2.1Hz,1H,ArH),7.03(m,1H,ArH),6.60(d,J＝7.4Hz,1H,ArH),4.58(m,1H,CH),3.30(dd,J＝13.7,4.7Hz,1H,CH_aH_b(Phe)),3.05(dd,J＝13.7,10.4Hz,1H,CH_aH_b(Phe)),2.85(m,2H,CH₂),2.59(m,2H,CH₂),2.27(s,6H,2×NCH₃),1.34(s,9H,C(CH₃)₃);¹³C NMR(75.5MHz,DMSO-d₆)δ171.7,164.2,156.0,144.2,139.1,138.1,129.7,128.7,127.0,124.1,121.4,119.8,111.5,111.4,109.9,78.9,60.6,55.8,45.3,40.8,28.6.

Example 29: l-phenylalanine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester 2HCl salt

(Tert-Butoxycarbonyl) -L-phenylalanine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate (110 mg,0.22 mmol) is dissolved in anhydrous DCM (2 mL) and TFA (0.5 mL) is added dropwise. The mixture was stirred for 30min, then volatiles were removed under reduced pressure and the residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of acetonitrile in 0.02% hydrochloric acid to provide the product as a solid (70 mg, 75%). LC-MS (+ve mode) )：m/z＝352.20[M+H]⁺;¹H NMR(300MHz,D₂O)δ7.45(m,6H,ArH),7.35(s,1H,ArH),7.28(m,1H,ArH),6.93(d,J＝0.6Hz,1H,ArH),4.82(m,1H,CH),3.62(dd,J＝14.3,7.2Hz,1H,CH_aH_b(Phe)),3.50(dd,J＝14.3,6.9Hz,1H,CH_aH_b(Phe)),3.35(m,2H,CH₂),3.09(m,2H,CH₂),2.86(s,3H,NCH₃),2.79(s,3H,NCH₃);¹³C NMR(75.5MHz,D₂O)δ169.5,142.2,139.0,133.8,129.5,129.3,128.2,125.5,122.3,117.7,111.6,111.1,106.3,58.0,54.2,43.2,42.6,35.9,21.2.

Example 30:2- (3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) L-pyrrolidine-1, 2-dicarboxylic acid 1- (tert-butyl) ester formate salt

A suspension of Boc-Pro-OSu (261 mg,0.84 mmol), dephosphorylated ouabain (155 mg,0.76 mmol) and K ₂CO₃ (115 mg,0.84 mmol) in anhydrous MeCN (5 mL) was heated to 90℃and stirred for 18 hours. The mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with saturated brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give crude oil which was purified using reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.1% formic acid in H ₂ O to provide the product as a semi-solid (54 mg, 16%). LC-MS (+ve mode): m/z=402.25 [ m+h ] ⁺;¹H NMR(300MHz,CD₃ CN) (mixture of two rotamers) )δ9.45(br.s,1H,NH⁺),8.36(s,1H,HC O),7.34(m,1H,ArH),7.15(m,2H,ArH),6.89-6.77(m,1H,ArH),4.63(m,1H,CH),3.47(m,2H,CH₂),3.10(m,4H,2×CH₂),2.69(s,3H,NCH₃),2.48(s,3H,NCH₃),2.28(m,2H,CH₂),2.04(obs m,2H,CH₂),1.47(s,9H,C(CH₃)₃).

Example 31: l-proline 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester dihydrochloride

Boc-Pro-dephosphorylated nupharin formate (242 mg,0.54 mmol) was dissolved in anhydrous DCM (4 mL) and TFA (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, then volatiles were removed under reduced pressure and the residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.02% hydrochloric acid to provide the product as a semi-solid (178 mg, 70%). LC-MS (+ve mode) )：m/z＝302.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ7.50(d,,J＝8.2Hz,1H,ArH),7.36(s,1H,ArH),7.27(t,J＝7.8Hz,1H,ArH),6.98(d,J＝7.8Hz,1H,ArH),4.92(t,J＝8.2Hz,1H,CH),3.52(m,4H,2×CH₂),3.19(t,J＝6.7Hz,2H,CH₂),2.89(s,6H,2×NCH₃),2.72(m,1H,0.5×CH₂),2.45(m,1H,0.5×CH₂),2.23(m,2H,CH₂);¹³C NMR(75.5MHz,D₂O)δ169.6,142.5,139.0,125.4,122.3,117.9,111.7,111.0,106.4,59.6,58.0,46.3,42.9,42.8,28.3,23.5,21.4.

Example 32: n2, N6-bis (t-butoxycarbonyl) -L-lysine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester hydrochloride

To a mixture of dephosphorylated nupharmor (200 mg,0.98 mmol) in anhydrous MeCN (10 mL) was added K ₂CO₃ (149 mg,1.08 mmol), followed by the addition of Boc-Lys (Boc) -OSu (413 mg,0.93 mmol) in portions. The mixture was stirred at room temperature for 16 hours, the solvent was removed under reduced pressure and the crude residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.02% hydrochloric acid to provide the product as a solid (243 mg, 47%). LC-MS (+ve mode): m/z=533.35 [ m+h ] ⁺.

Example 33: l-lysine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester tri-hydrochloride

A mixture of N2, N6-bis (t-butoxycarbonyl) -L-lysine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester hydrochloride (243 mg,0.46 mmol) in DCM (10 mL) was treated with TFA (1.76 mL,23.0 mmol) under an atmosphere of N ₂. The mixture was stirred at room temperature for 16 hours, then volatiles were removed under reduced pressure and the crude residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.02% hydrochloric acid to provide the product as a solid (141 mg, 70%). LC-MS (+ve mode) )：m/z＝333.20[M+H]⁺;¹H NMR(300MHz,D₂O)δ7.43(d,J＝8.2Hz,1H,ArH),7.30(s,1H,ArH),7.20(t,J＝8.0Hz,1H,ArH),6.85(d,J＝7.8Hz,1H,ArH),4.57(m,1H,CH),3.44(t,J＝7.8Hz,2H,CH₂),3.13(t,J＝6.0Hz,2H,CH₂),3.00(t,J＝7.5Hz,2H,CH₂),2.82(d,J＝6.0Hz,6H,2×NMe),2.22(m,2H,CH₂),1.69(m,4H,2×CH₂);¹³C NMR(75.5MHz,CDCl₃)δ170.1,142.4,139.0,125.5,122.4,118.0,111.7,111.2,106.8,58.1,52.7,43.1,42.7,39.0,29.4,26.4,21.7,21.3.

Example 34: dimethylglycine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester diformate

A suspension of N, N-dimethylglycine (113 mg,1.10 mmol), N-hydroxysuccinimide (139 mg,1.21 mmol), N-diisopropylethylamine (156 mg, 211. Mu.L, 1.21 mmol) and HBTU (417 mg,1.10 mmol) in a mixture of EtOAc (10 mL) and DMF (5 mL) was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residual material was dissolved in anhydrous MeCN (10 mL) and placed under an atmosphere of N ₂. K ₂CO₃ (167 mg,1.21 mmol) and dephosphorylated ouabain (202 mg,0.99 mmol) were added and the mixture was heated to reflux and stirred for 30min, followed by stirring at room temperature for 18 h. The mixture was filtered through celite and the filter cake was washed with MeCN. The combined filtrates were concentrated under reduced pressure and the residue was purified using reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.1% formic acid in H ₂ O to provide the product as an oil (79 mg, 21%). LC-MS (+ve mode) )：m/z＝290.15[M+H]⁺;¹HNMR(300MHz,D₂O)δ8.35(br.s,2H,2×HCO),7.42(d,J＝8.2Hz,1H,ArH),7.29(s,1H,ArH),7.20(m,1H,ArH),6.93(d,J＝7.8Hz,1H,ArH),4.50(s,2H,CH₂),3.43(m,2H,CH₂),3.11(m,2H,CH₂),3.00(s,6H,2×NCH₃),3.81(s,6H,2×NCH₃).

Example 35: 2-oxa-6-azaspiro [3.3] heptane-6-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Step 1: preparation of 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl chloroformate (de-phosphate nupharmic acid ester)

To a solution of dephosphorylated ouabain (200 mg,0.98 mmol) in DCM (10 mL) was added DMAP (338 mg,3.2 mmol) and triphosgene (85 mg,0.36 mmol). The reaction mixture was stirred at room temperature for 1 hour and used directly in the next step.

Step 2: preparation of 2-oxa-6-azaspiro [3.3] heptane-6-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

To the solution of the des-phosphate bare cap fungus ester of chloroformate were added 2-oxa-azaspiro [3,3] heptane (194 mg,196 mmol) and TEA (118 mg, 156. Mu.L, 1.17 mmol) and the mixture was stirred at room temperature for 16 hours. H ₂ O (1 mL) was added and the mixture was filtered through celite, washing the filter cake with DCM (10 mL) and MeCN (10 mL). The combined filtrates were concentrated to give a solid (0.80 g) which was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.1% formic acid in H ₂ O to provide the product as a semi-solid (167 mg, 51%). LC-MS (+ve mode) )：m/z＝330.10[M+H]⁺;¹H NMR(300MHz,DMSO-d₆)δ8.24(s,1H,HCO),7.20(dd,J＝8.1,0.9Hz,1H,ArH),7.13(d,J＝2.4Hz,1H,ArH),7.00(t,J＝7.8Hz,1H,ArH),6.67(dd,J＝7.6,0.8Hz,1H,ArH),4.72(s,4H,2×CH₂),4.43(br.s,2H,CH₂),4.18(br.s,2H,CH₂),2.86(m,2H,CH₂),2.61(m,2H,CH₂),2.34(s,6H,2×NMe);¹³C NMR(75.5MHz,DMSO-d₆)δ164.5,154.5,154.3,144.4,138.9,123.9,121.4,112.1,110.9,109.5,80.3,80.0,60.5,59.4,58.7,44.8,38.1,24.1.

Example 36: morpholine-4-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester hydrochloride

Pyridine (0.79 g, 809. Mu.L, 10.0 mmol) was added dropwise to triphosgene (294 mg,1.00 mmol) in anhydrous DCM (5 mL) at 0deg.C under an atmosphere of N ₂. After stirring until the precipitate dissolved (about 20 minutes), morpholine (93 mg,92 μl,1.07 mmol) was introduced dropwise into the flask. The mixture was stirred at 0 ℃ for 15min and at room temperature for 1 hour, then the DCM was removed under reduced pressure and additional pyridine (3 mL) was added followed by the addition of nupharin dephosphorylation (204 mg,1.00 mmol). The mixture was heated to 80 ℃ and stirred for 16 hours, then volatiles were removed under reduced pressure and the residue was dissolved in MeOH (5 mL). EtOAc (20 mL) was added to give a solid, which was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.02% hydrochloric acid to give the product as a solid (75 mg, 22%). LC-MS (+ve mode) )：m/z＝318.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ7.44(d,J＝8.2Hz,1H,ArH),7.32(s,1H,ArH),7.24(t,J＝7.7Hz,1H,ArH),6.85(d,J＝7.7Hz,1H,ArH),3.83(br.s,6H,3×CH₂),3.59(m,2H,CH₂),3.44(m,2H,CH₂),3.13(m,2H,CH₂),2.87(s,6H,2×NCH₃);¹³C NMR(75.5MHz,D₂O)δ155.8,143.5,138.78,125.1,122.5,119.1,112.3,110.3,106.6,66.2,58.2,44.6,43.9,42.8,21.3.

Example 37: ((5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl) carbonic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester

To a solution of des-phosphate bare cap fungus chloroformate (containing about 1mmol chloride) was added a solution of 4- (hydroxymethyl) -5-methyl-1, 3-dioxol-2-one (127 mg,0.98 mmol) and TEA (118 mg,156 μl,1.17 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 16 hours, then filtered through celite, and the filter cake was washed with DC M (10 mL) and MeCN (10 mL). The combined filtrates were concentrated to give the product (0.63 g). LC-MS (+ve mode): m/z=361.10 [ m+h ] ⁺.

Example 38:2- (4- ((tert-butyldimethylsilyl) oxy) -1H-indol-3-yl) -N, N-dimethylethan-1-amine

A solution of desphosphoric acid oudemansiella radicata (98 mg,0.48 mmol) in anhydrous DMF (3.5 mL) was treated with imidazole (65 mg,0.96 mmol) and TBDMSCl (174 mg,1.15 mmol) under an atmosphere of N ₂ followed by dropwise addition of N, N-diisopropylethylamine (149 mg, 200. Mu.L, 1.15 mmol). The mixture was stirred at room temperature for 24 hours, then the volatiles were removed under reduced pressure and EtOAc (50 mL) and saturated aqueous NaHCO ₃ (20 mL) were added. The organic layer was separated, washed with H ₂ O (20 mL), saturated brine (20 mL), dried (MgSO ₄) and concentrated to give a solid which was purified by column chromatography on silica gel, eluting with a gradient of MeOH in DCM to provide the product as a solid (112 mg, 73%). LC-MS (+ve mode) )：m/z＝319.20[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.98(br.s,1H,NH),6.94(m,3H,3×ArH),6.47(dd,J＝7.2,1.3Hz,1H,ArH),3.12(m,2H,CH₂),2.68(m,2H,CH₂),2.32(s,6H,2×NCH₃),1.04(s,9H,C(CH₃)₃),0.34(s,6H,2×CH₃);¹³C NMR(75.5MHz,CDCl₃)δ150.6,138.8,122.5,120.2,119.6,115.0,107.8,104.5,60.8,45.7,26.3,25.2,18.8,-3.6.

Example 39: n, N-dimethyl-2- (4- ((triisopropylsilyl) oxy) -1H-indol-3-yl) ethan-1-amine

A mixture of desphosphoric acid oudemansiella radiata (155 mg,0.76 mmol) in anhydrous DMF (3.5 mL) was treated with imidazole (103 mg,1.52 mmol) and TIPSCl (351 mg, 390. Mu.L, 1.82 mmol) under an atmosphere of N ₂ followed by dropwise addition of N, N-diisopropylethylamine (235 mg, 317. Mu.L, 1.82 mmol). The mixture was stirred at room temperature for 24 hours, then the volatiles were removed under reduced pressure and EtOAc (50 mL) and saturated aqueous NaHCO ₃ (20 mL) were added. The organic layer was separated, washed with H ₂ O (20 mL), saturated brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give a solid, which was purified by column chromatography on silica gel, eluting with a gradient of MeOH in DCM to provide the product as a solid (255 mg, 92%). LC-MS (+ve mode )：m/z＝361.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.96(br.s,1H,NH),6.94(m,3H,3×ArH),6.46(dd,,J＝7.2,1.3Hz,1H,ArH),3.19(m,2H,CH₂),2.76(m,2H,CH₂),2.35(s,6H,2×NCH₃),1.41( seven peak) ,J＝7.5Hz,3H,3×CH(CH₃)₂),1.04(d,J＝7.5Hz,18H,3×CH(CH₃)₂);¹³C NMR(75.5MHz,CDCl₃)δ151.0,138.8,122.6,120.2,119.7,114.7,107.5,104.4,60.5,45.5,24.9,18.3,13.7.

Example 40: n, N-dimethyl-2- (4- ((triethylsilyl) oxy) -1H-indol-3-yl) ethan-1-amine

Imidazole (127 mg,1.86 mmol) and TESCl (336 mg, 375. Mu.L, 2.23 mmol) were added to a mixture of dephosphorized nupharin (190 mg,0.93 mmol) in anhydrous DM F (4.2 mL) under an atmosphere of N ₂, followed by dropwise addition of N, N-diisopropylethylamine (288 mg, 388. Mu.L, 2.23 mmol). The mixture was stirred at room temperature for 18 hours, then the volatiles were removed under reduced pressure and EtOAc (75 mL) and saturated aqueous NaHCO ₃ (20 mL) were added. The organic layer was separated, washed with H ₂ O (20 mL), saturated brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give crude oil (324 mg). This material was purified by column chromatography on silica gel eluting with a gradient of MeOH in DCM to provide the product as a semi-solid (236 mg, 80%). LC-MS (+ve mode) )：m/z＝319.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.00(br.s,1H,NH),6.93(m,3H,3×ArH),6.45(br.d,J＝7.2Hz,1H,ArH),3.10(m,2H,CH₂),2.68(m,2H,CH₂),2.33(s,6H,2×NCH₃),1.02(m,9H,3×CH₂CH₃),0.87(m,6H,3×CH₂CH₃);¹³C NMR(75.5MHz,CDCl₃)δ150.5,138.8,122.6,120.4,119.5,115.0,107.2,104.6,61.2,45.7,25.2,6.9,5.4.

Example 41: (3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) methyl ethyl carbonate formate salt

Chloromethyl ethyl carbonate (234 mg,196 μl,1.69 mmol) was added to a suspension of nugesso de-phosphate (157 mg,0.77 mmol) and K ₂CO₃ (265 mg,1.92 mmol) in anhydrous DMF (6 mL) at room temperature under an atmosphere of N ₂. The mixture was stirred at room temperature for 24 hours, the solids were removed by filtration through celite, and the filter cake was washed with MeC N. The combined filtrates were concentrated to give an oil (265 mg), which was dissolved in 5% aqueous formic acid and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified using reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.1% formic acid in H ₂ O to give the product as a semi-solid (127 mg, 47%). LC-MS (+ve mode) )：m/z＝307.10[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.42(br.s,1H,HCO),7.53(d,J＝8.3Hz,1H,ArH),7.34(m,2H,ArH),7.05(d,J＝7.8Hz,1H,ArH),5.63(s,2H,OCH₂O),4.40(q,J＝7.1Hz,2H,CH₂),3.44(m,2H,CH₂),3.14(m,2H,CH₂),2.92(s,6H,2×NCH₃),1.38(t,J＝7.1Hz,3H,CH₃);¹³C NMR(75.5MHz,D₂O)δ170.3,154.9,143.4,138.3,128.3,123.0,119.6,112.7,108.9,107.7,68.3,66.4,58.2,42.7,21.1,13.4.

Example 42: methyl pivalate ((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy)

Potassium carbonate (406 mg,2.94 mmol), potassium iodide (49 mg,0.29 mmol) and chloromethyl pivalate (443 mg, 424. Mu.L, 2.94 mmol) were added to a stirred mixture of nuphar rugoso-annulata dephosphorylation (0.60 g,2.94 mmol) in anhydrous DMF (15 mL) at room temperature under an atmosphere of N ₂. The mixture was stirred at room temperature for 16 hours, then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient of MeOH in EtOAc to provide 3- (2- (dimethylamino) ethyl) -1- ((pivaloyloxy) methyl) -1H-indol-4-yl pivalate C (192 mg, 16%), methyl (3- (2- (dimethylamino) ethyl) -4-hydroxy-1H-indol-1-yl) pivalate B (117 mg, 13%) as a solid (117 mg) and a fraction containing impure pivalic acid ((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) methyl ester a (170 mg) as an oil. The fraction containing compound a (170 mg) was purified by column chromatography on silica gel eluting with a gradient of MeOH in EtOAc to give a fraction containing compound a (82 mg) as an oil. This material (82 mg) was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in water to provide the title compound as a semi-solid (22 mg, 2%). LC-MS (+ve mode) )：m/z＝319.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.12(t,J＝7.9Hz,1H,ArH),6.94(dd,J＝8.2,0.8Hz,1H,ArH),6.89(s,1H,ArH),6.61(dd,J＝7.7,0.9Hz,1H,ArH),5.96(s,2H,CH₂),2.91(m,2H,CH₂),2.70(m,2H,CH₂),2.38(s,6H,2×NCH₃),1.15(s,9H,3×Boc CH₃).

Data for (3- (2- (dimethylamino) ethyl) -4-hydroxy-1H-indol-1-yl) methyl pivalate (B)

LC-MS (+ve mode) )：m/z＝319.15[M+H]⁺;¹H NMR(300MH z,CDCl₃)δ7.37(dd,J＝8.3,0.5Hz,1H,ArH),7.15(t,J＝8.0Hz,1H,ArH),6.98(s,1H,ArH),6.68(dd,J＝7.7,0.6Hz,1H,ArH),5.52(s,2H,CH₂),2.86(t,J＝7.3Hz,2H,CH₂),2.63(t,J＝7.3Hz,2H,CH₂),2.25(s,6H,2×NCH₃),1.41(s,9H,3×Boc CH₃);¹³C NMR(75.5MHz,CDCl₃)δ177.9,144.9,138.5,126.3,122.5,121.1,112.7,110.5,108.3,70.0,58.9,44.7,39.4,27.5,23.4.

Data for 3- (2- (dimethylamino) ethyl) -1- ((pivaloyloxy) methyl) -1H-indol-4-yl pivalate (C)

LC-MS (+ve mode) )：m/z＝403.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.30(dd,J＝8.2,0.8Hz,1H,ArH),7.19(t,J＝8.0Hz,1H,ArH),7.03(s,1H,ArH),6.75(dd,J＝7.7,0.8Hz,1H,ArH),6.01(s,1H,CH₂),2.92(m,2H,CH₂),2.64(m,2H,CH₂),2.30(s,6H,2×NCH₃),1.43(s,9H,3×BocCH₃),1.14(s,9H,3×Boc CH₃);¹³C NMR(75.5MHz,CDCl₃)δ178.4,177.7,145.1,139.0,126.15,122.9,121.5,114.2,113.3,107.4,68.9,59.9,45.7,39.4,39.1,27.5,27.1,24.7.

Example 43: di- (hydroxymethyl isopropyl) phosphate 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester

Cesium carbonate (88 mg,0.27 mmol) was added to a stirred suspension of oudemansiella radiata (70 mg,0.25 mmol) in DMF (3 mL) at room temperature under an atmosphere of N ₂. After 15 minutes chloromethyl isopropyl carbonate (56 mg,49 μl,0.37 mmol) was added to the suspension and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residual material was purified by reverse phase chromatography on C ₁₈ silica eluting with a gradient of MeCN in 0.02% hydrochloric acid to provide the product as a semi-solid (17 mg). LC-MS (+ve mode): m/z=517.20 [ m+h ] ⁺.

Example 44: bis (dimethyl pivalate) phosphate 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester

Bis (2, 2-dimethylpropionate) ((hydroxyphosphoryl) bis (oxy)) bis (methylene) (194 mg,0.60 mmol) was dissolved in anhydrous DCM (5 mL) containing DMF (5. Mu.L) at room temperature under an atmosphere of N ₂ and a solution of (COCl) ₂ (457 mg, 306. Mu.L, 3.57 mmol) in anhydrous DCM (5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, then volatiles were removed under reduced pressure. The residue was dissolved in DCM (5 mL) and added to a mixture of nupharicin dephosphorylation (101 mg,496 μmol) in anhydrous pyridine at 0 ℃. The mixture was warmed to room temperature and stirred for 18 hours, then concentrated under reduced pressure to give an oil containing the product (359 mg). LC-MS (+ve mode): m/z=513.25 [ m+h ] ⁺.

Alternative procedure:

cesium carbonate (161 mg,0.49 mmol) was added to a stirred suspension of oudemansiella radicata (70 mg,0.25 mmol) in anhydrous DMF (3 mL) under an atmosphere of N ₂. After 15 minutes, chloromethyl pivalate (74 mg,71 μl,0.49 mmol) was added to the suspension and the mixture was heated to 50 ℃ and stirred for 16 hours. The solvent was removed under reduced pressure to provide a semi-solid containing the cultural compound. LC-MS (+ve mode): m/z= 513.25 (a), 399.15 (B), 597.30 (C), 483.20 (D), and 389.30 (E) [ m+h ] ⁺.

Example 45:3- ((((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) sulfonyl) oxy) -2, 2-dimethylpropionic acid ethyl ester

Ethyl 3-hydroxy-2, 2-dimethylpropionate (351 mg,2.39 mmol) and pyridine (115 mg, 118. Mu.L, 1.46 mmol) were dissolved in anhydrous Et ₂ O (3 mL) under an atmosphere of N ₂ and the mixture was cooled to-78 ℃. A solution of SO ₂Cl₂ (200 mg, 118. Mu.L, 1.46 mmol) in anhydrous Et ₂ O (10 mL) was added dropwise and the mixture stirred at-78℃for 30 min. The prepared suspension containing chlorosulfonyloxy intermediate was added dropwise to a solution of desphosphoric acid galectin (136 mg,0.664 mmol) in anhydrous pyridine (10 mL) at 0 ℃ under N ₂ atmosphere, and the mixture was warmed to room temperature and stirred for 16 hours. The precipitate was removed by filtration, the filter cake was washed with DCM, and the filtrate was concentrated to give a semi-solid. LC-MS (+ve mode): m/z=413.15 [ m+h ] ⁺.

Example 46: pharmacokinetics of the nupharicin-dephosphorylated prodrug was selected in rats after a single intravenous or oral administration.

Exemplary protocols used in PK studies are summarized in table 8 below.

Table 8. Summary of po or IV PK study protocol

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Analysis

Samples were sent via unique calibration lines and following acceptance QC for optimization and measurement of the method of both prodrug and parent compound (dephosphorylated galectin). Dose formulation concentrations were also measured and PK parameters (,Cmax(ng/mL)、Tmax(hr)、Cl(ml/min/kg)、Vdss(L/kg)、t1/2(hr)、AUC0-t(ng/mL*hr)、AUC0-inf(ng/mL*hr)、MRT(hr)、 bioavailability (% F) where necessary) were determined using WinNon Lin software. The data (including bioanalytical results and assay performance) are reported in tabular form.

Additional formulation details of PK study

Phosphoric acid. 85% phosphoric acid was diluted 8.5 times to yield a 10% solution.

Formulations for PO administration: for PO administration, the prodrug was formulated in 10% DMSO/40% PEG-400/water to a concentration of 2mg/mL dephosphorylated galectin. This provides a dose of 10mg/kg of dephosphorylated nupharicin when the prodrug is administered at 5mL/kg of dosing volume PO.

Formulations for IV administration: for IV administration, the prodrug was formulated in 10% DMSO/90% hydroxypropyl-beta-cyclodextrin (HPCD, 20% w/v in water) to a concentration of 0.5mg/mL dephosphorylated galectin. This provides a dose of 1mg/kg of dephosphorylated nupharicin when the prodrug is administered at a dosing volume IV of 2 mL/kg.

NB: the prodrug (without dephosphorylated galectin) was first dissolved in DMSO and then PEG was added, followed by water/0.5% methylcellulose, if necessary.

Measuring the concentration of the dephosphorylated ouabain after IV in vivo or oral administration of the dephosphorylated ouabain prodrug or derivative

The pharmacokinetic properties of IV or of the dephosphorylated galectin prodrug or derivative synthesized after oral administration in a rat model were evaluated. The concentration of dephosphorylated nupharicin in each rat is measured at a plurality of sampling time points after IV or oral administration of the synthetic dephosphorylated nupharicin prodrug or derivative to the rat.

Dosage formulations were prepared at equal concentrations of dephosphorylated galectin adjusted to the molecular weight of the compound tested. Nominal doses (1 mg/kg for IV and 2mg/kg for PO) were used in PK parameter determinations.

Example 2-1 dephosphorization of the parent Compound of nupharin (IV)

Chemical name: de-phosphate nupharicin

Structural category: parent body

Mechanism category: n/a-parent compounds

TABLE 2-1 dephosphorization of the parameters of the Phlomycete (IV) PK

FIG. 1 shows the average concentration-time profile of dephosphorylated ouabain after IV administration of dephosphorylated ouabain (1 mg/kg).

EXAMPLE 2-2 dephosphorization of the parent Compound of nupharin (PO)

Chemical name: de-phosphate nupharicin

Structural category: parent body

Mechanism category: n/a-parent compounds

TABLE 2 dephosphorization of the Phlomycete (PO) PK parameters

FIG. 2 shows the average concentration-time profile of dephosphorylated ouabain after oral administration of dephosphorylated ouabain (2 mg/kg).

EXAMPLES 2-3 Euonymus Alata Sieb

Chemical name: nuda cover mushroom extract

Structural category: phosphate prodrugs

Mechanism category: phosphatase enzyme

TABLE 2-3 De-phosphate nupharin PK parameters

FIG. 3 shows the average concentration-time profile of metabolite dephosphorylated ouabain after oral administration of ouabain (2 mg/kg).

Examples 2-4 dephosphorization of the Ussula Capsoides-O-TBDMS ether prodrugs

Chemical name: 2- (4- ((tert-butyldimethylsilyl) oxy) -1H-indol-3-yl) -N, N-dimethylethan-1-amine

Structural category: silyl ethers

Mechanism category: assuming non-enzymatic decomposition

TABLE 2-4 dephosphorization of the Phlomycete PK parameters

FIG. 4 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

EXAMPLES 2-5 dephosphorization of the Ulipstatin-O-TIPS Ether prodrugs

Chemical name: n, N-dimethyl-2- (4- ((triisopropylsilyl) oxy) -1H-indol-3-yl) ethan-1-amine

Structural category: silyl ethers

Mechanism category: assuming non-enzymatic decomposition

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TABLE 2-5 dephosphorization of the Phlomycete PK parameters

FIG. 5 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-6 dephosphorization of the Ussula Pubescentis extract O-adipate hydrochloride prodrug

Chemical name: 6- ((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) -6-oxohexanoic acid HCl salt

Structural category: half esters

Mechanism category: assuming esterase and/or assuming pH-dependent intramolecular cyclization

TABLE 2-6 dephosphorization of the Phlomycete PK parameters

FIG. 6 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

EXAMPLES 2-7 desphosphoric acid Eugenia-3-tetroxide hydrochloride prodrugs

Chemical name: tetrahydrofuran-3-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester HCl salt

Structural category: esters of

Mechanism category: assuming esterases

TABLE 2-7 De-phosphate nupharin PK parameters

FIG. 7 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-8 dephosphorization of the Uyghur extract trimethyl locked formate prodrug

Chemical name: 3- (2-Acetyloxy-4, 6-dimethylphenyl) -3-methylbutanoic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Structural category: esters of

Mechanism category: assuming esterase+intramolecular cyclization

TABLE 2-8 dephosphorization of the Phlomycete PK parameters

FIG. 8 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-9 dephosphorization of the Heterol 2-oxa-6-azaspiro [3.3] heptanoate formate prodrugs

Chemical name: 2-oxa-6-azaspiro [3.3] heptane-6-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Structural category: carbamates (Carbamates)

Mechanism category: assuming enzymatic hydrolysis

TABLE 2-9 dephosphorization of the Phlomycete PK parameters

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FIG. 9 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

EXAMPLES 2-10 dephosphorization of the Ussula Capsoides O-TES Ether prodrugs

Chemical name: n, N-dimethyl-2- (4- ((triethylsilyl) oxy) -1H-indol-3-yl) ethan-1-amine

Structural category: silyl ethers

Mechanism category: assuming non-enzymatic decomposition

TABLE 2-10 dephosphorization of the Phlomycete PK parameters

FIG. 10 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-11 dephosphorization of the Eugenia-D-lysine tri-hydrochloride prodrugs

Chemical name: l-lysine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester tri-hydrochloride

Structural category: esters of amino acids

Mechanism category: assuming esterases

TABLE 2-11 dephosphorization of the Phlomycete PK parameters

FIG. 11 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-12 dephosphorization of the Uyghur extract oxazolidine hydrochloride prodrugs

Chemical name: tetrahydro-2H-pyran-4-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester hydrochloride

Structural category: esters of

Mechanism category: assuming esterases

TABLE 2-12 dephosphorization of the Phlomycete PK parameters

FIG. 12 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-13 desphosphoric acid galectin morpholinocarbamate hydrochloride prodrugs

Chemical name: morpholine-4-carboxylic acid 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester HCl salt

Structural category: carbamates (Carbamates)

Mechanism category: assuming enzymatic hydrolysis

TABLE 2-13 De-phosphate nupharin PK parameters

FIG. 13 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-14 dephosphorization of the O-methylethyl formate prodrug of nupharin carbonate

Chemical name: (3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy) methyl ethyl carbonate formate salt

Structural category: methoxymethylene carbonate

Mechanism category: assuming esterase+chemical decomposition

TABLE 2-14 dephosphorization of the Phlomycetes Umbelliferae PK parameters

FIG. 14 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-15 dephosphorization of Di-tert-butyl Capsoxyphosphonate hydrochloride prodrugs

Chemical name: di-tert-butyl [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] phosphate HCl salt

Structural category: phosphonic acid esters

Mechanism category: assuming phosphatase

TABLE 2-15 dephosphorization of the Phlomycete PK parameters

FIG. 15 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg). * Plasma concentrations were below the quantitative limit (BLQ) at other time points.

Examples 2-16 dephosphorization of the Ussula galectin Boc-valine formate prodrugs

Chemical name: (tert-Butoxycarbonyl) -L-valine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Structural category: protected amino acid ester prodrugs

Mechanism category: assuming esterases

TABLE 2-16 dephosphorization of the Phlomycete PK parameters

FIG. 16 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-17 dephosphorization of the Ussula galectin Boc-proline formate prodrugs

Chemical name: l-pyrrolidine-1, 2-dicarboxylic acid 1- (tert-butyl) 2- (3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) ester formate salt

Structural category: protected amino acid esters

Mechanism category: assuming esterases

TABLE 2-17 dephosphorization of the Phlomycete PK parameters

FIG. 17 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

EXAMPLES 2-18 desphosphoric acid Eugenia decursinol phenylalanine dihydrochloride prodrugs

Chemical name: l-phenylalanine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester 2HCl salt

Structural category: amino acid esters

Mechanism category: assuming esterases

TABLE 2-18 De-phosphate nupharin PK parameters

FIG. 18 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-19 dephosphorization of the Ussula Capsoides Boc-phenylalanine formate prodrugs

Chemical name: (tert-Butoxycarbonyl) -L-phenylalanine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Structural category: protected amino acid esters

Mechanism category: assuming esterases

TABLE 2-19 dephosphorization of the Phlomycete PK parameters

FIG. 19 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-20 desphosphoric acid nupharin Pivaloyloxymethyl (POM) prodrugs

Chemical name: methyl pivalate ((3- (2- (dimethylamino) ethyl) -1H-indol-4-yl) oxy)

Structural category: pivaloyloxymethyl (POM) prodrugs

Mechanism category: assuming esterase+chemical decomposition

TABLE 2-20 De-phosphate nupharin PK parameters

FIG. 20 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-21 dephosphorization of the Ulmus-Tepsilosis O-proline ester dihydrochloride prodrugs

Chemical name: l-proline 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester 2HCl salt

Structural category: amino acid esters

Mechanism category: assuming esterases

TABLE 2-21 dephosphorization of the Phlomycete PK parameters

FIG. 21 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

EXAMPLES 2-22 dephosphorization of the Ussula galectin N-POM Ether prodrugs

Chemical name: novel methyl (3- (2- (dimethylamino) ethyl) -4-hydroxy-1H-indol-1-yl) pivalate

Structural category: N-Pivaloyloxymethyl (POM)

Mechanism category: assuming esterase+chemical decomposition

TABLE 2-22 dephosphorization of the Phlomycetes Umbelliferae PK parameters

FIG. 22 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-23 dephosphorization of the N-POM Ether O-pivaloyl prodrugs of nupharmic acid

Chemical name: 3- (2- (dimethylamino) ethyl) -1- ((pivaloyloxy) methyl) -1H-indol-4-yl pivalate

Structural category: N-Pivaloyloxymethyl (POM) and esters

Mechanism category: assuming esterase+chemical decomposition

TABLE 2-23 dephosphorization of the Phlomycete PK parameters

FIG. 23 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-24 dephosphorization of the Ulmus-Tenebrio-Volvin O-methyl glutarate ether tert-butyl ester prodrug

Chemical name: {3- [2- (dimethylamino) ethyl ] -4-indolyloxy } methylpentanedioic acid tert-butyl ester

Structural category: acyloxymethyl (AOM)

Mechanism category: assuming esterase and/or pH dependent intramolecular cyclization + chemical decomposition

TABLE 2-24 dephosphorization of the Phlomycete PK parameters

FIG. 24 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-25 dephosphorization of the Uyghur medicine O-methyl succinate ether tert-butyl ester prodrug

Chemical name: {3- [2- (dimethylamino) ethyl ] -4-indolyloxy } methyl succinic acid tert-butyl ester

Structural category: acyloxymethyl (AOM)

TABLE 2-25 dephosphorization of the Phlomycete PK parameters

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FIG. 25 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-26 dephosphorization of the Ulmus-Tepsilosis O-methylpiperazine carbamate diformate prodrugs

Chemical name: 4-methylpiperazine-1-carboxylic acid [3- [2- (dimethylamino) ethyl ] -1H-indol-4-yl ] ester diformate

Structural category: carbamates (Carbamates)

Mechanism category: assuming enzymatic hydrolysis

TABLE 2-26 dephosphorization of the Phlomycete PK parameters

* Plasma concentration BLQ-below the limit of quantification

EXAMPLES 2-27 dephosphorization of the Ulmus-Tenebrio-calico-patent O-methyl adipate ether tert-butyl ester prodrug

Chemical name: {3- [2- (dimethylamino) ethyl ] -4-indolyloxy } methyl-hexanedioic acid tert-butyl ester

Structural category: acyloxymethyl (AOM)

TABLE 2-27 dephosphorization of the Phlomycete PK parameters

FIG. 26 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

EXAMPLES 2-28 dephosphorization of the Eugenia-valine dihydrochloride prodrug

Chemical name: l-valine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester 2HCl

Structural category: amino acid esters

Mechanism category: assuming esterases

TABLE 2-28 dephosphorization of the Phlomycete PK parameters

FIG. 27 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-29 dephosphorization of the Ussula galectin N-Boc-L-phenylalanine-sarcosinate prodrugs

Chemical name: n- ((tert-Butoxycarbonyl) -L-phenylalanyl) -N-methylglycine 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl ester formate salt

Structural category: dipeptide

Mechanism category: assuming esterase and/or pH dependent intramolecular cyclization

TABLE 2-29 dephosphorization of the Phlomycete PK parameters

FIG. 28 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

Examples 2-30 dephosphorization of the Dimethylglycinate diformate prodrug of nupharin

Chemical name: 3- (2- (dimethylamino) ethyl) -1H-indol-4-yl dimethyl glycine ester diformate

Structural category: esters of

Mechanism category: assuming esterases

TABLE 2-30 dephosphorization of the Phlomycete PK parameters

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FIG. 29 shows the average concentration-time profile of metabolite dephosphorylated ouabain following oral administration of a dephosphorylated ouabain prodrug (2 mg/Kg).

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Many modifications, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims are intended to define the scope of the invention and the methods and structures within the scope of these claims and their equivalents are covered thereby.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or isotopologue thereof:

Wherein:

2. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ia):

3. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1 or claim 2, wherein R ³ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

4. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any of claims 1 to 3, wherein R ³ is unsubstituted or substituted alkyl.

5. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 4, wherein R ³ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

6. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is unsubstituted alkyl.

7. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 6, wherein R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

8. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 4 OR claim 5, wherein R ³ is alkyl substituted with-C (O) OR ¹³.

9. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 8, wherein R ¹³ is hydrogen or alkyl.

10. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 8, wherein R ¹³ is hydrogen, methyl, ethyl, or tert-butyl.

11. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

12. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

13. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, benzoyl, phenyl, or NH-Boc.

14. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

15. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is

16. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ isWherein R ^C is the side chain of a natural amino acid and R' is hydrogen or-Boc.

17. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 16, wherein R ³ is

18. A compound or pharmaceutically acceptable salt, solvate or isotopologue as claimed in any one of claims 1 to 3 wherein R ³ is heterocyclylalkyl.

19. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 18, wherein R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

20. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 4 or claim 5, wherein R ³ is

21. The compound of claim 4 or claim 5, or a pharmaceutically acceptable salt, solvate, or isotopologue thereof, wherein R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

22. A compound or pharmaceutically acceptable salt, solvate or isotopologue as claimed in any one of claims 1 to 3 wherein R ³ is heteroalkyl.

23. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any of claims 1 to 3, wherein R ³ is unsubstituted or substituted aryl (e.g., phenyl).

24. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 23, wherein R ³ is substituted phenyl.

25. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 24, wherein R ³ is phenyl substituted with-OC (O) R ¹⁸, wherein R ¹⁸ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl.

26. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ib):

27. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26, wherein R ³ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

28. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26 or claim 20, wherein R ³ is unsubstituted or substituted alkyl.

29. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of any one of claims 19 to 21, wherein R ³ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)O R¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-O P (O) OR ²⁰(OR²¹.

30. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 29, wherein R ³ is alkyl substituted with heterocyclylalkyl.

31. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 30, wherein R ³ is aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Substituted alkyl, wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

32. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 26 to 28, wherein R ³ is alkyl substituted with one or more-OC (O) R ¹⁵.

33. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 26 to 28, wherein R ³ is isopropyl substituted with two-OC (O) R ¹⁵, wherein each R ¹⁵ is alkyl.

34. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 26 to 28, wherein R ³ is unsubstituted alkyl.

35. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 34, wherein R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

36. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26 or 27, wherein R ³ is heteroalkyl.

37. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26 or 27, wherein R ³ is heterocyclylalkyl.

38. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 37, wherein R ³ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

39. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 37, wherein R ³ is oxetanyl.

40. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26 or 27, wherein R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

41. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26 or 27, wherein R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

42. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ic):

43. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 42, wherein each of R ⁶ and R ⁷ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl are unsubstituted or substituted with one or more R ^A.

44. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 42, wherein R ⁶ and R ⁷, together with the atoms to which they are attached, form a heterocyclylalkyl or heteroaryl ring that is unsubstituted or substituted with one or more R ^A.

45. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 44, wherein R ⁶ and R ⁷, together with the atoms to which they are attached, form aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

46. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 45, wherein R ⁶ and R ⁷, together with the atoms to which they are attached, form

47. The compound, or pharmaceutically acceptable salt, solvate, or isotopologue of claim 42 or 43, wherein R ⁶ is methyl.

48. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 47, wherein R ⁷ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl.

49. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 47, wherein R ⁷ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen, methyl, ethyl, OR tert-butyl.

50. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Id):

51. The compound, or pharmaceutically acceptable salt, solvate, or isotopologue of claim 50, wherein R ⁴ is hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

52. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 50 or claim 51, wherein R ⁴ is hydrogen or unsubstituted or substituted alkyl.

53. The compound, or pharmaceutically acceptable salt, solvate, or isotopologue of claim 52, wherein R ⁴ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

54. The compound, or pharmaceutically acceptable salt, solvate, or isotopologue of claim 52, wherein R ⁴ is hydrogen.

55. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 54, wherein R ⁵ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

56. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ⁵ is unsubstituted or substituted alkyl.

57. The compound, OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 56, wherein R ⁵ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(O R²¹).

58. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 56, wherein R ⁵ is unsubstituted alkyl.

59. The compound, or pharmaceutically acceptable salt, solvate, or isotopologue of claim 58, wherein R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

60. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of any one of claims 50 to 55, wherein R ⁵ is alkyl substituted with C (O) OR ¹³.

61. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 60, wherein R ¹³ is hydrogen or alkyl.

62. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 60, wherein R ¹³ is hydrogen, methyl, ethyl, or tert-butyl.

63. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ⁵ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

64. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

65. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

66. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

67. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

68. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 54, wherein R ⁵ is heterocyclylalkyl.

69. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 68, wherein R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

70. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 68, wherein R ⁵ is optionally substituted piperidinyl.

71. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 68, wherein R ⁵ is

72. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 55, wherein R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

73. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 54, wherein R ⁵ is heteroalkyl.

74. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 54, wherein R ⁵ is unsubstituted or substituted aryl (e.g., phenyl).

75. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 50 to 54, wherein R ⁵ is tert-butyl 、-CH(NH₂)CH(CH₃)₂、-CH₂N(CH₃)₂、-CH₂CH₂OCH₃、-CH₂CH₂NH(CH₃)₂、-CH₂CH₂C(CH₃)₂OC(O)CH₃、-CH₂CH₂C(CH₃)₂NHC(O)CH₃ or-CH ₂CH₂C(CH₃)₂NHC(O)OCH₂CH₃.

76. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ie):

77. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 76, wherein R ⁴ is hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

78. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 76 or claim 77, wherein R ⁴ is unsubstituted or substituted alkyl.

79. The compound, or pharmaceutically acceptable salt, solvate, or isotopologue of claim 78, wherein R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

80. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 76 or claim 77, wherein R ⁴ is hydrogen.

81. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 79, wherein R ⁵ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

82. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 81, wherein R ⁵ is unsubstituted or substituted alkyl.

83. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 82, wherein R ⁵ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(O R²¹.

84. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 82, wherein R ⁵ is unsubstituted alkyl.

85. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 84, wherein R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

86. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 83, wherein R ⁵ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

87. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 83, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

88. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 83, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

89. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 83, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

90. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 79, wherein R ⁵ is heterocyclylalkyl.

91. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 90, wherein R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

92. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claims 76 to 83, wherein R ³ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

93. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 79, wherein R ⁵ is heteroalkyl.

94. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 79, wherein R ⁵ is unsubstituted or substituted aryl (e.g., phenyl).

95. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 76 to 79, wherein R ⁵ is morpholinyl, isopropyl, or ethyl.

96. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (If):

97. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 96, wherein R ⁴ is hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

98. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 96 or claim 97, wherein R ⁴ is unsubstituted or substituted alkyl.

99. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 98, wherein R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

100. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 96 or 97, wherein R ⁴ is hydrogen.

101. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 96 to 100, wherein each of R ⁶ and R ⁷ is independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R ^A.

102. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 101, wherein R ⁶ is hydrogen or methyl, and R ⁷ is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R ^A.

103. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 96 to 100, wherein R ⁶ and R ⁷ together with the atoms to which they are attached form a heterocyclylalkyl ring or heteroaryl ring that is unsubstituted or substituted with one or more R ^A.

104. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 103, wherein R ⁶ and R ⁷, together with the atoms to which they are attached, form aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

105. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 103, wherein R ⁶ and R ⁷ together with the atoms to which they are attached form an optionally substituted piperidinyl.

106. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 103, wherein R ⁶ and R ⁷ together with the atoms to which they are attached form

107. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ig):

108. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 107, wherein each of R ⁶ and R ⁷ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl is unsubstituted or substituted with one or more R ^A.

109. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 107, wherein R ⁶ and R ⁷ are each independently hydrogen or alkyl.

110. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 107, wherein R ⁶ and R ⁷ are each independently hydrogen or methyl.

111. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 107, wherein R ⁶ and R ⁷ are each hydrogen.

112. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 107, wherein R ⁶ and R ⁷ together with the atoms to which they are attached form a heterocyclylalkyl ring or heteroaryl ring that is unsubstituted or substituted with one or more R ^A.

113. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 112, wherein R ⁶ and R ⁷, together with the atoms to which they are attached, form aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl,Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

114. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ih):

115. the compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 114, wherein each of R ¹¹ and R ¹² is independently hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

116. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 114 or 115, wherein each of R ¹¹ and R ¹² is independently hydrogen or unsubstituted or substituted alkyl.

117. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 115, wherein each of R ¹¹ and R ¹² is independently alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

118. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 114 or 115, wherein each of R ¹¹ and R ¹² is independently unsubstituted alkyl.

119. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 93, wherein each of R ¹¹ and R ¹² is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

120. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 114 or 115, wherein each of R ¹¹ and R ¹² is independently alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

121. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 114 OR 115, wherein each of R ¹¹ and R ¹² is independently alkyl substituted with-OC (O) OR ¹⁶, wherein R ¹⁶ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, OR heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted OR further substituted with one OR more halo, amino, cyano, hydroxy, alkyl, acetyl, OR benzoyl.

122. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 121, wherein R ¹⁶ is hydrogen or alkyl.

123. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 121, wherein R ¹⁶ is hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

124. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 89 or claim 114, wherein each of R ¹¹ and R ¹² is independently heteroalkyl.

125. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 89 or claim 114, wherein each of R ¹¹ and R ¹² is independently unsubstituted or substituted aryl (e.g., phenyl).

126. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 114, wherein the compound has the structure of formula (Ih'):

Wherein R ^4A and R ^4A 'are each independently hydrogen or alkyl, and R ^5A and R ^5A' are each independently hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl groups.

127. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 126, wherein R ^4A and R ^4A' are each hydrogen.

128. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 126 or 127, wherein R ^5A and R ^5A' are each methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

129. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 126 or 127, wherein R ^5A and R ^5A' are each isopropyl or tert-butyl.

130. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26, wherein the compound has the structure of formula (Ib'):

Wherein R ^6A and R ^6A' are each independently hydrogen or alkyl.

131. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 130, wherein R ^6A and R ^6A' are each independently -CH₃、-C₂H₅、C₃H₇、C₄H₉、C₅H₁₁、C₆H₁₃、C₇H₁₅、C₈H₁₇、C₉H₁₉、C₁₀H₂₁、C₁₁H₂₃、C₁₂H₂₅、C₁₃H₂₇、C₁₄H₂₉、C₁₅H₃₁、C₁₆H₃₃ or C ₁₇H₃₅.

132. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 130 or 131, wherein R ^6A and R ^6A' are the same.

133. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 26, wherein the compound has the structure of formula (Ib'):

134. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 133, wherein R ^6A is -CH₃、-C₂H₅、C₃H₇、C₄H₉、C₅H₁₁、C₆H₁₃、C₇H₁₅、C₈H₁₇、C₉H₁₉、C₁₀H₂₁、C₁₁H₂₃、C₁₂H₂₅、C₁₃H₂₇、C₁₄H₂₉、C₁₅H₃₁、C₁₆H₃₃ or C ₁₇H₃₅.

135. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 133 or 134, wherein R ^1B、R^2B and R ^3B are each independently alkyl.

136. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 135, wherein each of R ^1B、R^2B and R ^3B is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

137. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 135, wherein R ^1B、R^2B and R ^3B are each methyl.

138. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ii):

139. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 138, wherein each of R ³、R⁴ and R ⁵ is independently hydrogen, unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

140. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 138 or 139, wherein each of R ³、R⁴ and R ⁵ is unsubstituted or substituted alkyl.

141. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of any one of claims 138 to 140, wherein each of R ³、R⁴ and R ⁵ is independently alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

142. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 138-140, wherein each of R ³、R⁴ and R ⁵ is independently unsubstituted alkyl.

143. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 142, wherein each of R ³、R⁴ and R ⁵ is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂ 1.

144. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 142, wherein R ³、R⁴ and R ⁵ are the same unsubstituted alkyl.

145. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 142, wherein R ³ and R ⁴ are methyl, ethyl, or isopropyl.

146. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 145, wherein R ⁵ is ethyl, isopropyl, or tert-butyl.

147. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 142, wherein (i) R ³ and R ⁴ are methyl, R ⁵ is ethyl; (ii) R ³、R⁴ and R ⁵ are isopropyl; or (iii) R ³、R⁴ and R ⁵ are ethyl.

148. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 89 or claim 138, wherein each of R ³、R⁴ and R ⁵ is independently heteroalkyl.

149. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 89 or claim 138, wherein each of R ³、R⁴ and R ⁵ is independently unsubstituted or substituted aryl (e.g., phenyl).

150. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound has the structure of formula (Ij):

151. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 150, wherein R ⁵ is unsubstituted or substituted alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl.

152. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 150 or 151, wherein R ⁵ is unsubstituted or substituted alkyl.

153. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of claim 150 OR 151, wherein R ⁵ is alkyl substituted with one OR more substituents R ^A, and wherein each R ^A is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, amino acid side chain 、-OR¹³、-N(R¹⁸)R¹⁹、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶、-OP(O)OR¹⁷[N(R¹⁸)R¹⁹]、-C(O)N(R¹⁸)R¹⁹、-OC(O)N(R¹⁸)R¹⁹, OR-OP (O) OR ²⁰(OR²¹.

154. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 150 to 153, wherein R ⁵ is unsubstituted alkyl.

155. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 154, wherein R ⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, 3-methyl-1-butyl, or-C ₁₀H₂₁.

156. The compound OR pharmaceutically acceptable salt, solvate, OR isotopologue of any one of claims 150 to 153, wherein R ⁵ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl.

157. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 156, wherein R ⁵ is hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

158. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 150 to 153, wherein R ⁵ is alkyl substituted with-N (R ¹⁸)R¹⁹, wherein each of R ¹⁸ and R ¹⁹ is independently hydrogen or methyl.

159. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 150 to 153, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen or methyl.

160. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 150 to 153, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)R¹⁴, wherein each of R ¹³ is hydrogen or methyl, and R ¹⁴ is hydrogen, alkyl, alkenyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl are unsubstituted or further substituted with one or more halo, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

161. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 150 to 153, wherein R ⁵ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴, wherein each of R ¹³ and R ¹⁴ is independently hydrogen, methyl, or ethyl.

162. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 150 or 151, wherein R ⁵ is heterocyclylalkyl.

163. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 162 wherein R ⁵ is selected from aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl dioxide, diazacyclohexanyl, Wherein X is-CH ₂-、-O-、-S-、-SO₂, -NH-or-NMe.

164. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 1 to 163, wherein R ¹ is hydrogen.

165. A compound of formula (II), or a pharmaceutically acceptable salt, solvate or isotopologue thereof:

Wherein:

r ²¹ is CH ₃、CH₂D、CHD₂ or CD ₃;

Wherein when R ²¹ is CH ₃ and R ²² and R ²³ do not include deuterium, then at least one of Y ¹、Y²、Y³、Y⁴、Y⁵、Y⁶、Y⁷、Y⁸ and Y ⁹ is deuterium.

166. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 111, wherein R ²¹ is-CH ₃.

167. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 111, wherein R ²¹ is-CD ₃.

168. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 113, wherein R ²² and R ²³ are each independently-CH ₃、-CH₂D、-CHD₂ or-CD ₃.

169. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 113, wherein at least one of R ²² and R ²³ comprises deuterium.

170. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 113, wherein one of R ²² and R ²³ is-CD ₃.

171. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 113, wherein both R ²² and R ²³ are-CD ₃.

172. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 117, wherein Y ¹ is D.

173. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 117, wherein Y ³ is D.

174. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 117, wherein Y ¹ and Y ² are each D.

175. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 117, wherein Y ³ and Y ⁴ are each D.

176. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 117, wherein Y ¹、Y²、Y³ and Y ⁴ are each D.

177. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of any one of claims 111 to 117, wherein Y ⁶ is H.

178. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 111, wherein the compound is selected from the group consisting of:

/>

179. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound is a compound described in table 1.

180. The compound or pharmaceutically acceptable salt, solvate, or isotopologue of claim 1, wherein the compound is selected from the group consisting of:

/>

181. a pharmaceutical composition comprising a compound according to any one of claims 1-180, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

182. A method of treating or preventing a disease, disorder, or condition in which increased levels of dephosphorylated nuphar mushroom are beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt, solvate, or isotopologue of any of claims 1-180 or a pharmaceutical composition of claim 181.

183. The method of claim 182, wherein the disease, disorder, or condition is selected from post-traumatic stress disorder, major depressive disorder, schizophrenia, alzheimer's disease, frontotemporal dementia, parkinson's disease, parkinson's dementia, dementia with lewy bodies, multiple system atrophy, and abuse of drugs.