CN117956991A

CN117956991A - N, N-dimethyltryptamine and related hallucinogens and uses thereof

Info

Publication number: CN117956991A
Application number: CN202280059019.6A
Authority: CN
Inventors: M·A·J·邓克顿; S·克拉克
Original assignee: Human Bioscience Co ltd
Current assignee: Human Bioscience Co ltd
Priority date: 2021-07-07
Filing date: 2022-07-07
Publication date: 2024-04-30

Abstract

Described herein are compounds that are derivatives of DMT or 5-MeO-DMT and are capable of being metabolically converted to N, N-dimethyltryptamine or an analog thereof upon administration to a subject. In certain embodiments, the compounds described herein are useful for treating disorders associated with neurological diseases.

Description

N, N-dimethyltryptamine and related hallucinogens and uses thereof

Cross reference to related applications

The present application claims the benefit of U.S. provisional patent application Ser. No. 63/219,312, filed 7 at 2021, and U.S. provisional patent application Ser. No. 63/276,516, filed 11 at 2021, the contents of each of which are incorporated herein by reference in their entirety.

Background

In the united states, almost 1 of 5 adults suffer from mental disorders, and more than 50% of americans will be diagnosed with mental disorders at some point in their lives. Every 25 americans have 1 suffering from a severe mental disorder, such as major depressive disorder, schizophrenia, or bipolar disorder.

Disclosure of Invention

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

Wherein:

r ¹ is methoxy or hydrogen;

R ² is -C(O)OR³、-C(O)R⁴、-CH(R⁵)OR⁶、-C(O)OCH(R⁵)OC(O)R⁶、-C(O)OCH(R⁵)OC(O)OR⁶、-CH(R⁵)C(O)R⁶、-CH(R⁵)OC(O)R⁶、-CH(R⁵)OC(O)OR⁶、-S(O)₂OR⁷、-P(O)OR⁸[N(R⁹)R¹⁰]、-P(O)[N(R⁹)R¹⁰][N(R¹¹)R¹²]、-C(O)N(R⁹)R¹⁰、-P(O)OR¹¹(OR¹²)、-CH(R⁵)OP(O)OR⁸[N(R⁹)R¹⁰] or-CH (R ⁵)OP(O)OR¹¹(OR¹²);

R ³、R⁴、R⁵、R⁶、R⁷ and R ⁸ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A;

R ⁹ and R ¹⁰ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently 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 that is unsubstituted or substituted with one or more R ^A;

R ¹¹ and R ¹² are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A, or R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring that is 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 each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, amino acid side chain, aryl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

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

R ¹⁸ and R ¹⁹ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently 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 that is unsubstituted or substituted with one or more R ^B;

R ²⁰ and R ²¹ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^B, or R ²⁰ and R ²¹ together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^B; and

Each R ^B is independently halogen, amino, cyano, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, -C (O) CH ₃, -C (O) Ph, or heteroarylalkyl, wherein each cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halogen, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl,

With the proviso that when R ¹ is hydrogen then R ³ is not tert-butyl.

In some embodiments, a compound of formula (I) having the structure of formula (Ia):

Wherein R ¹ is methoxy or hydrogen and R ³ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl, each independently being unsubstituted or substituted with one or more R ^A.

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

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1、R^A2、R^A3 and R ^A4 are each independently hydrogen OR alkyl which is independently unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹, and

R ^A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, OR -C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵ OR-OC (O) OR ¹⁶, wherein each heteroalkyl, heterocyclylalkyl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halo, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

In some embodiments are compounds of formula (I) having the structure of formula (Ib-1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 are each independently hydrogen OR alkyl which is independently unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹, and

R ^A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, OR -C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹ OR-OC (O) OR ¹⁶, wherein each heteroalkyl, heterocyclylalkyl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halo, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

In some embodiments, the compound of formula (I) or (Ib) has the structure of formula (Ib 1), or a pharmaceutically acceptable salt thereof:

in some embodiments, the compound of formula (I) has the structure of formula (Ic), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy, and R ¹⁸ and R ¹⁹ are each independently hydrogen, alkyl, cycloalkyl, or heteroalkyl, wherein each alkyl, cycloalkyl, and heteroalkyl is independently 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 that is unsubstituted or substituted with one or more R ^B.

In some embodiments, the compound of formula (I) has the structure of formula (Id), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy; r ⁵ is alkyl or cycloalkyl, each independently unsubstituted or substituted with one or more R ^A or hydrogen; and R ^A6 is hydrogen OR alkyl, which is unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹).

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

Wherein R ¹ is hydrogen or methoxy and R ⁵ is hydrogen, alkyl or cycloalkyl, wherein each alkyl and cycloalkyl is independently unsubstituted or substituted with one or more R ^A.

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

Wherein R ¹ is methoxy or hydrogen, and R ⁹ and R ¹⁰ are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, and heterocyclylalkyl is independently 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 that is unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (If) has the structure of formula (If 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ¹⁰ is hydrogen, alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl, wherein each of alkyl, heteroalkyl, cycloalkyl, and heterocyclylalkyl is unsubstituted or substituted with one or more R ^A; and

X ¹ and X ² are each independently selected from-CH ₂-、-O-、-NH-、-S-、-S(O)-、-S(O)₂ or-N (Y ¹) -, wherein each Y ¹ is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl.

In some embodiments, the compound of formula (I) has the structure of formula (Ig), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1、R^A2、R^A3 and R ^A4 are each independently hydrogen OR alkyl, which alkyl is unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

R ¹⁰ is hydrogen, alkyl, heteroalkyl, or cycloalkyl, wherein each of alkyl, heteroalkyl, and cycloalkyl is unsubstituted or substituted with one or more R ^A; and

R ^A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, OR -C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵ OR-OC (O) OR ¹⁶, where the heteroalkyl, heterocyclylalkyl, heteroaryl are each unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

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

Wherein:

r ¹ is hydrogen or methoxy;

R ¹⁸ and R ¹⁹ are each independently hydrogen, alkyl, cycloalkyl or heteroalkyl, wherein each alkyl, cycloalkyl or heterocyclylalkyl is independently 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 that is unsubstituted or substituted with one or more R ^B.

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

Wherein:

r ¹ is hydrogen or methoxy; and

R ⁵ and R ¹⁰ are each independently hydrogen, alkyl, heteroalkyl, or cycloalkyl, wherein each alkyl, heteroalkyl, and cycloalkyl is independently unsubstituted or substituted with one or more RA; and

R ^A6 is independently hydrogen, alkyl, heteroalkyl, OR cycloalkyl, wherein each alkyl, heteroalkyl, OR cycloalkyl is unsubstituted OR substituted with one OR more alkyl, aryl, halo, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

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

Wherein R ¹ is hydrogen or methoxy, and R ⁵ and R ¹⁰ are each hydrogen, alkyl or heteroalkyl, wherein each alkyl and heteroalkyl is independently unsubstituted or substituted with one or more RA.

In some embodiments, the compound of formula (I) has the structure of formula (Ik), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy, and R ⁴ is alkyl, heterocyclylalkyl, aryl, heteroaryl, or heteroalkyl, each of which is unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (Ik) has the structure of formula (Ik 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ^A1、R^A2、R^A3 and R ^A4 are each independently hydrogen, alkyl OR amino acid side chains, wherein each alkyl OR amino acid side chain is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

R ^A5 is heteroalkyl, heterocyclylalkyl, heteroaryl 、-C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵, OR-OC (O) OR ¹⁶, where the heteroalkyl, heterocyclylalkyl, heteroaryl are each unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

In some embodiments, the compound of formula (I) or (Ik) has the structure of formula (Ik 2), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ¹³ is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl, wherein each of the alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, and heterocyclylalkyl is unsubstituted or substituted with one or more R ^B; and

P is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In some embodiments, the compound of formula (I) or (Ik) has the structure of formula (Ik 3), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1 is alkyl OR amino acid side chain, each of which is unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹), and

R ^A5 is-N (R ¹⁸)R¹⁹ or-N (R ¹³)C(O)R¹⁴).

In some embodiments, the compound of formula (I) has the structure of formula (Il), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ⁵ is hydrogen, alkyl, or cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one or more R ^A; and

R ⁶ is alkyl, cycloalkyl, heterocyclylalkyl or heteroalkyl, wherein each alkyl, cycloalkyl, heterocyclylalkyl or heteroalkyl is unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) has the structure of formula (Im), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ⁵ is hydrogen, alkyl, cycloalkyl, or heteroalkyl, wherein each of alkyl, cycloalkyl, and heteroalkyl is unsubstituted or substituted with one or more R ^A; and

R ¹¹ and R ¹² are each independently hydrogen, cycloalkyl, aryl, heteroaryl or alkyl, wherein alkyl, cycloalkyl and heteroalkyl are each independently unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (Im) has the structure of formula (Im 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1、R^A3 and R ⁵ are each independently hydrogen, alkyl or cycloalkyl; and

R ^A2 and R ^A4 are each independently of the other alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl OR heteroaryl, -OC (O) R ¹⁵ OR-OC (O) OR ¹⁶,

Wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

In some embodiments, the compound of formula (I), (Im) or (Im 1) has the structure of formula (Im 1 a), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1、R^A3 and R ⁵ are each independently hydrogen, alkyl OR cycloalkyl, where alkyl and cycloalkyl are each independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹; and

R ^B1 and R ^B2 are each independently hydrogen or alkyl, which alkyl is unsubstituted or substituted by one or more halogen, amino, cyano, hydroxy, alkyl, acetyl or benzoyl.

In some embodiments, the compound of formula (I) has the structure of formula (In), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl;

R ⁸ is hydrogen, alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl,

Wherein each cycloalkyl, aryl, heterocyclylalkyl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (In) has the structure of formula (In 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1 is hydrogen, alkyl OR cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted OR substituted with alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

R ⁵ and R ⁸ are each hydrogen, alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl, wherein alkyl, cycloalkyl, aryl, heterocyclylalkyl, and heteroaryl are independently unsubstituted or substituted with one or more R ^A; and

R ¹³ is hydrogen or alkyl which is unsubstituted or substituted by one or more R ^B.

In some embodiments, the compound of formula (I) has the structure of formula (Io), or a pharmaceutically acceptable salt thereof:

Wherein:

R ¹ is methoxy or hydrogen; and

R ¹¹ and R ¹² are each independently selected from hydrogen, cycloalkyl, aryl, heteroaryl, or alkyl, wherein each cycloalkyl, aryl, heteroaryl, and alkyl is independently unsubstituted or substituted with one or more R ^A, or R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (Io) has the structure of formula (Io 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ^A1 and R ^A3 are each independently hydrogen, alkyl or cycloalkyl; and

R ^A2 and R ^A4 are each independently of the other alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, -OC (O) R ¹⁵ OR-OC (O) OR ¹⁶,

In some embodiments, the compound of formula (I) or (Io) has the structure of formula (Io 2), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is methoxy or hydrogen; and R ^A1 is aryl OR heteroaryl, each of which is unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹).

In some embodiments, the compound of formula (I), (Io) or (Io 1) has the structure of formula (Io 1 a), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1 and R ^A3 are each independently hydrogen, alkyl OR cycloalkyl, wherein each alkyl and cycloalkyl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹; and

In some embodiments, the compound of formula (I) has the structure of formula (Ip), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ⁸ is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl,

Wherein each alkyl, cycloalkyl, aryl, heterocyclylalkyl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (Ip) has the structure of formula (Ip 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1 is hydrogen, alkyl OR cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

R ⁸ is hydrogen, alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclylalkyl, and heteroaryl is unsubstituted or substituted with one or more R ^A; and

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

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl; and

R ⁶ is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl or heteroaryl,

Wherein each alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A.

In some embodiments, the compound of formula (I) or (Iq) has the structure of formula (Iq 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted or substituted with one or more R ^A; and

Q ¹ isWherein the method comprises the steps of

Y ¹、Y² or Y ³ are each independently-O-, -S-, -S (O) -, -S (O) ₂-、-N(R^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently hydrogen, alkyl, heteroalkyl, or heteroaryl.

In some embodiments, the compound of formula (I) has the structure of formula (Ir), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl; and

R ⁶ is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl or heteroaryl,

In some embodiments, the compound of formula (I) or (Ir) has the structure of formula (Ir 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

Q ¹ isWherein the method comprises the steps of

In some embodiments, the compound of formula (I) has the structure of formula (Is), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy, and R ¹⁵ is alkyl, heteroalkyl, cycloalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with one or more R ^B.

In some embodiments, the compound of formula (I) has the structure of formula (It), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy, and R ¹³ is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted with one or more R ^B.

In some embodiments, the compound of formula (I) has the structure of formula (Iu), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy;

R ^A1 is hydrogen, alkyl OR cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹), and

R ²⁰ and R ²¹ are each independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclylalkyl or heteroaryl, wherein each alkyl, cycloalkyl, aryl, heterocyclylalkyl and heteroaryl is independently unsubstituted or substituted with one or more R ^B, or R ²⁰ and R ²¹ together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^B.

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

Wherein:

r ¹ is hydrogen or methoxy;

r ⁹ and R ¹⁰ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently 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 that is unsubstituted or substituted with one or more R ^A; and

R ¹¹ and R ¹² are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A, or R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A. In some embodiments, the compound of formula (I) has the structure of formula (Iw):

Wherein:

r ¹ is hydrogen or methoxy;

Each R ^A1 and R ^A2 is independently hydrogen, alkyl OR cycloalkyl, wherein each alkyl and cycloalkyl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

R ^A3 is -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), and

P is 1, 2, 3,4, 5, 6, 7, 8, 9 or 10.

In another aspect, the invention provides a pharmaceutically acceptable composition comprising a compound according to any one of formulas (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

In another aspect, the invention provides a method for treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw) or a pharmaceutically acceptable salt thereof.

Drawings

Figure 1 shows the mean concentration versus time profile of DMT after oral administration of DMT (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats.

FIG. 2 shows the mean concentration versus time curve of DMT after oral administration of 5-MeO-DMT (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats.

FIG. 3 depicts the time course of plasma concentrations of N, N-Dimethyltryptamine (DMT) and the corresponding prodrug compound 20 in Shi Boge Du rats (Sprague-DAWLEY RAT) that were administered either Intravenously (IV) compound 20 at 1mg/kg (Panel A) or orally (PO) compound 20 at 10mg/kg (Panel B).

Figure 4 shows the mean concentration versus time profile of DMT after IV or oral administration of compound 20 (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats.

Figure 5 shows the average concentration versus time curve of compound 20 after IV or oral administration of compound 20 (1 mg/kg for IV administration, 10mg/kg for oral administration) to male SD rats.

FIG. 6 depicts the time course of plasma concentrations of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and the corresponding prodrug compound 19 in Shi Boge Du rats (Sprague-DAWLEY RAT) administered Intravenously (IV) compound 19 (panel A) at 1mg/kg or orally (PO) compound 19 (panel B) at 10 mg/kg.

FIG. 7 shows the mean concentration versus time curve of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) after IV or oral administration of compound 19 (1 mg/kg for IV administration, 10mg/kg for oral administration) to male SD rats.

Figure 8 shows the average total concentration of DMT after PO administration of DMT prodrug at 10mg/kg to male Shi Boge doli rats.

Figure 9 shows the average total concentration of DMT prodrug after administration to male Shi Boge doli rats IV, PO at 1, 10 mg/kg.

FIG. 10 shows the average total concentration of 5-MeO-DMT after administration of 5-MeO-DMT prodrug at 10mg/kg to male Shi Boge Du rats PO.

FIG. 11 shows the average total concentration of 5-MeO-DMT prodrug after administration to male Shi Boge Du rats IV, PO at 1, 10 mg/kg.

FIG. 12 shows the mean concentration versus time curves of DMT CP-2 and metabolite DMT after oral administration of DMT CP-2 (10 mg/Kg) to male SD rats.

FIG. 13 shows the mean concentration versus time curves of DMT CP-3 and metabolite DMT after oral administration of DMT CP-3 (10 mg/Kg) to male SD rats.

FIG. 14 shows the mean concentration versus time curves of DMT CP-4 and metabolite DMT after oral administration of DMT CP-4 (10 mg/Kg) to male SD rats.

FIG. 15 shows the mean concentration versus time curves of DMT CP-5 and metabolite DMT after oral administration of DMT CP-5 (10 mg/Kg) to male SD rats.

FIG. 16 shows the mean concentration versus time curves of DMT AP-1 and metabolite DMT after oral administration of DMT AP-1 (10 mg/Kg) to male SD rats.

FIG. 17 shows the average concentration-time profile of 5-MeO-DMT CP-2 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT CP-2 (10 mg/Kg) to male SD rats.

FIG. 18 shows the average concentration-time profile of 5-MeO-DMT CP-3 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT CP-3 (10 mg/Kg) to male SD rats.

FIG. 19 shows the average concentration-time profile of 5-MeO-DMT CP-4 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT CP-4 (10 mg/Kg) to male SD rats.

FIG. 20 shows the average concentration-time profile of 5-MeO-DMT CP-5 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT CP-5 (10 mg/Kg) to male SD rats.

FIG. 21 shows the average concentration-time profile of 5-MeO-DMT AP-1 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT AP-1 (10 mg/Kg) to male SD rats.

FIG. 22 shows the mean concentration versus time curve of DMT benzamide and metabolite DMT after oral administration of DMT benzamide (10 mg/Kg) to male SD rats.

FIG. 23 shows the average concentration-time profile of 5-MeO-DMT prodrug and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT prodrug (10 mg/Kg) to male SD rats.

FIG. 24 shows the average concentration-time profile of 5-MeO-DMT prodrug and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT prodrug (10 mg/Kg) to male SD rats.

FIG. 25 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of methyl pivaloyl 5-MeO-DMT carbamate (10 mg/Kg) to male SD rats.

FIG. 26 shows the average concentration-time profile of metabolite DMT after oral administration of DMT methoxyethyl carbamate (10 mg/Kg) to male SD rats.

FIG. 27 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of methoxyethyl 5-MeO-DMT carbamate (10 mg/Kg) to male SD rats.

FIG. 28 shows the mean concentration-time profile of metabolite DMT after oral administration of DMT-trimethyllocked amide (10 mg/Kg) to male SD rats.

FIG. 29 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT trimethyllocked amide (10 mg/Kg) to male SD rats.

FIG. 30 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of 4-piperidinopiperidine urea 5-MeO-DMT formate (10 mg/Kg) to male SD rats.

FIG. 31 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT N, N-dimethylurea formate prodrug (10 mg/Kg) to male SD rats.

FIG. 32 shows the mean concentration-time profile of metabolite DMT after oral administration of prodrug DMT lysine tri-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 33 shows the average concentration versus time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT lysine tri-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 34 shows the mean concentration versus time curve of metabolite DMT after oral administration of the prodrug di-DMT urea (symmetrical urea) di-formate (10 mg/Kg) to male SD rats.

FIG. 35 shows the mean concentration-time profile of metabolite 5-MeO-DMT after oral administration of the prodrug di-5-MeO-DMT urea (symmetrical urea) di-formate (10 mg/Kg) to male SD rats.

FIG. 36 shows the average concentration-time profile of metabolite DMT after oral administration of the prodrug DMT valine di-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 37 shows the average concentration versus time curve of metabolite 5-MeO-DMT after oral administration of the prodrug 5-MeO-DMT valine di-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 38 shows the average concentration versus time curve of metabolite 5-MeO-DMT after oral administration of the prodrug 5-MeO-DMT N, N-dimethylglycinate (10 mg/Kg) to male SD rats.

FIG. 39 shows the average concentration-time profile of metabolite DMT after oral administration of the prodrug Phe-N-Me-Gly DMT di-hydrochloride (DMT dipeptide) (10 mg/Kg) to male SD rats.

FIG. 40 shows the mean concentration versus time curve of metabolite DMT after oral administration of the prodrug DMT alanine di-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 41 shows the average concentration versus time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT alanine di-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 42 shows the mean concentration-time profile of metabolite DMT after oral administration of the prodrug DMT tetramethyl phosphorodiamidate (10 mg/Kg) to male SD rats.

FIG. 43 shows the average concentration versus time profile of metabolite 5-MeO-DMT after oral administration of the prodrug 5-MeO-DMT tetramethyl phosphorodiamidate (10 mg/Kg) to male SD rats.

FIG. 44 shows the mean concentration versus time curve of metabolite DMT after oral administration of prodrug DMT phenylalanine di-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 45 shows the average concentration versus time curve of metabolite 5-MeO-DMT after oral administration of the prodrug 5-MeO-DMT phenylalanine di-hydrochloride (10 mg/Kg) to male SD rats.

FIG. 46 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of the prodrug 2, 2-dimethylpropyl carbamate formate (10 mg/Kg) to male SD rats.

FIG. 47 shows the mean concentration versus time curve of metabolite DMT after oral administration of prodrug DMT N, N-dimethylglycine hydrochloride (10 mg/Kg) to male SD rats.

FIG. 48 shows the average concentration-time profile of metabolite DMT after oral administration of the prodrug DMT pivalate (10 mg/Kg) to male SD rats.

FIG. 49 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of the prodrug methyl 5-MeO-DMT pivalate (10 mg/Kg) to male SD rats.

FIG. 50 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT-3, 3-dimethylbuccinate hydrochloride (10 mg/Kg) to male SD rats.

FIG. 51 shows the average concentration versus time curve of metabolite DMT after oral administration of the prodrug DMT valproate 2, 2-dimethylpropyl carbamate formate (10 mg/Kg) to male SD rats.

FIG. 52 shows the mean concentration-time profile of metabolite DMT after oral administration of prodrug DMT methanol (10 mg/Kg) to male SD rats.

FIG. 53 shows the mean concentration-time profile of the metabolite 5-MeO-DMT after oral administration of the prodrug 5-MeO-DMT methanol (10 mg/Kg) to male SD rats.

FIG. 54 shows the average concentration-time profile of metabolite 5-MeO-DMT after oral administration of the prodrug 5-MeO-DMT di-trifluoroacetic acid valine carboxy-isopropyl ester (10 mg/Kg) to male SD rats.

FIG. 55 shows the average concentration-time profile of metabolite DMT after oral administration of the prodrug DMT succinate (10 mg/Kg) to male SD rats.

FIG. 56 shows the average concentration-time profile of the metabolite 5-MeO-DMT after oral administration of the prodrug methyl 5-MeO-DMT succinate (10 mg/Kg) to male SD rats.

FIG. 57 shows the mean concentration-time profile of metabolite DMT after oral administration of the prodrug DMT carbamate formate (10 mg/Kg) to male SD rats.

FIG. 58 shows the mean concentration versus time curve of metabolite DMT after oral administration of glutarate prodrug of DMT (10 mg/Kg) to male SD rats.

Detailed Description

Described herein are compounds that can be metabolically converted to N, N-dimethyltryptamine or an analog 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 disorders that may benefit from increasing neuronal plasticity.

And (5) defining.

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

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

Non-limiting examples of alkyl groups include straight, branched, and cyclic alkyl groups and alkylene groups. The alkyl group may be, for example, a 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 group.

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 bicyclic, bridged bicyclic, and spiro bicyclic ring systems, and higher fused systems, bridged systems, and spiro systems. Cycloalkyl groups may be substituted with any number of straight, branched or cyclic alkyl groups. Non-limiting examples of cyclic alkyl groups 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, 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, bicyclo [ 3.1.2.1 ] bicycloheptyl, 2.3.2.2 ] bicycloundecyl and bicyclo [ 2.2.3.2 ] bicyclooctyl.

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 alkinyl group may be located internally or terminally. Alkylynyl 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). A haloalkenyl group may be any alkenyl group substituted with any number of halogen atoms. Haloalkynyl can be any alkynyl group substituted with any number of halogen atoms.

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

The heterocyclic ring may be any ring containing a non-carbocyclic atom (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 and halogen atoms). The heterocycle may be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, butanediamide, 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, isoxazolinyl, thiazolidinyl, isothiazolinyl, 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) heterocyclic units having 2 or more rings, one of which is a heterocyclic ring, non-limiting examples of which include hexahydro-1H-pyrazinyl (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) heteroaryl rings 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 chain saturated hydrocarbon or an optionally substituted branched saturated hydrocarbon having one to about ten carbon atoms or 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, tert-pentyl and hexyl, and longer alkyl groups such as heptyl, octyl, and the like. Whenever present 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, but the present definition also covers the occurrence of the term "alkyl" where no numerical range is specified. 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 specifically stated otherwise in this specification, alkyl is optionally substituted with, for example, 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 chain hydrocarbon or an optionally substituted branched chain 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 around 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 a numerical range such as "C ₂-C₆ alkenyl" is presented herein, meaning that the alkenyl may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the presentation of the term "alkenyl" without a specified numerical range.

"Alkynyl" refers to an optionally substituted straight chain hydrocarbon or an optionally substituted branched chain hydrocarbon having one or more carbon-carbon triple bonds and having 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 appearing herein, a numerical range such as "C ₂-C₆ alkynyl" means that an alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. 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 specifically stated otherwise in this specification, alkynyl groups are optionally substituted with, for example, 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 defined as alkyl. Unless specifically stated otherwise in the specification, an alkoxy group may be optionally substituted with, for example, 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 group 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 (when fused to a cycloalkyl or heterocyclylalkyl ring, the aryl groups are bonded via an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6 to 10 membered aryl. In some embodiments, the aryl is a 6 membered aryl. Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene,Fluoranthene, fluorene, as-dicyclopentadiene acene (as-indacene), s-dicyclopentadiene acene, indane, indene, naphthalene,Phenanthrene, obsidian (pleiadene), pyrene and benzophenanthrene. In some embodiments, the aryl group is phenyl. Unless specifically stated otherwise in the specification, aryl groups may be optionally substituted with, for example, 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 (cycloalkyl bonded via a non-aromatic ring atom when fused to an aryl or heteroaryl ring), bridged 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 carbocycle groups 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] heptanyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in this specification, cycloalkyl is optionally substituted with, for example, 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 groups include, for example CD₃、CH₂D、CHD₂、CH₂CD₃、CD₂CD₃、CHDCD₃、CH₂CH₂D or CH ₂CHD₂. In some embodiments, the 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 atoms other than carbon, such as 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, such as 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, for example, -CH₂OCH₃、-CH₂CH₂OCH₃、-CH₂CH₂OCH₂CH₂OCH₃ or-CH (CH ₃)OCH₃. Unless specifically stated otherwise in this specification, heteroalkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclylalkyl, heteroaryl, and the like.

"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 one to 8 heteroatoms selected from the group consisting of: nitrogen, oxygen, phosphorus and sulfur. Unless specifically stated otherwise in this specification, heterocyclylalkyl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused to an aryl or heteroaryl ring, heterocyclylalkyl groups are bonded via 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 two to fifteen carbon atoms (C2-C15 heterocyclylalkyl), two to ten carbon atoms (C2-C10 heterocyclylalkyl), two to eight carbon atoms (C2-C8 heterocyclylalkyl), two to six carbon atoms (C2-C6 heterocyclylalkyl), two to five carbon atoms (C2-C5 heterocyclylalkyl), or two to four carbon atoms (C2-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, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 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 the 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 specifically stated otherwise in this specification, heterocyclylalkyl groups are optionally substituted with, for example, 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, halo, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or-NO 2. In some embodiments, the heterocyclylalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF3, -OH, or-OMe. In some embodiments, the heterocyclylalkyl is optionally substituted with halo.

"Heteroaryl" refers to 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 (when fused to a cycloalkyl or heterocyclylalkyl ring, heteroaryl groups are bonded via 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, azetidinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl (benzodioxolyl), benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ] [1,4] dioxazolyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzopyranyl benzopyronyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl), benzotriazole, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl dibenzothienyl, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and the like isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, isoindolyl, isoindolinyl, isoindolizinyl, isoindolyl, isoxazolyl, isoindolizinyl, isoxazolyl, isoindolyl, isoxazolyl, isoindolor isoxazol,Pyridyl, oxadiazolyl, 2-oxoazetidinyl, oxazolyl, oxiranyl, 1-oxolanyl pyridyl, 1-oxolanyl pyrimidinyl, 1-oxolanyl pyrazinyl, 1-oxolanyl pyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, pyridyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in this specification, heteroaryl is optionally substituted with, for example, 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, -CF3, -OH, -OMe, -NH2, or-NO 2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -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% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 19% pure at least 37% purity, at least 38% purity, at least 39% purity, at least 40% purity, at least 41% purity, at least 42% purity, at least 43% purity, at least 44% purity, at least 45% purity, at least 46% purity, at least 47% purity, at least 48% purity, at least 49% purity, at least 50% purity, at least 51% purity, at least 52% purity, at least 53% purity, at least 54% purity, at least 55% purity, at least 56% purity, at least 57% purity, at least 58% purity, at least 59% purity, at least 60% purity, at least 61% purity, at least 62% purity, at least 63% purity, at least 64% purity, at least 65% purity, at least 66% purity, at least 67% purity, at least 68% purity, at least 69% purity, at least 70% purity, at least 71% purity, at least 72% purity, 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 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 invention provides the use of a pharmaceutically acceptable salt of any of the compounds described herein. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt may be an organic acid or an inorganic acid. The base 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 salts may be produced by adding an inorganic base to the compounds of the present invention. The inorganic base consists of a metal cation paired with a basic counter ion such as hydroxide, carbonate, bicarbonate or phosphate. 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 invention. 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 be produced by adding an acid to the compounds of the present invention. 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 (GENTISIC ACID), gluconic acid, glucuronic acid, glucaric acid (SACCHARIC ACID), formic acid, benzoic acid, glutamic acid, pantothenic 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, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

Pharmaceutical compositions.

According to another embodiment, the present invention provides a composition comprising a compound of the present invention 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 invention 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 agent 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; a buffer substance; such as phosphate, glycine, sorbic acid, potassium sorbate; a partial glyceride mixture 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; a cellulose-based material; polyethylene glycol; sodium carboxymethyl cellulose; a polyacrylate; a wax; a polyethylene-polyoxypropylene block polymer; polyethylene glycol; and lanolin.

The compositions of the invention may be administered orally, parenterally, enterally, intracisternally, intraperitoneally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" 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 invention 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 nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable vehicles and solvents may be used including 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 delivering the composition, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) and natural pharmaceutically-acceptable oils (such as olive oil or castor oil, especially in their polyoxyethylated versions) are useful in the preparation of injectables. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tween, span and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms 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, suitable 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 suppositories 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 will therefore 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 food. In some embodiments, the pharmaceutically acceptable composition is not administered with food. In other embodiments, the pharmaceutically acceptable composition is administered with food.

It will also be appreciated that the particular dosage and treatment regimen of 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 diagnosis 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 form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, such as ethanol, isopropanol, 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, for example 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 1, 3-butanediol. Acceptable vehicles and solvents that may be used include 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 find use in the preparation of injectables.

The injectable formulations 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.

In order to prolong the effect of the compounds of the invention, it is desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. Thus, the absorption rate of a compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Or by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of a compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound may be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations can also be prepared by encapsulation of the compounds in liposomes or microemulsions compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention 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) Binding agents such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) Humectants, such as glycerin; d) Disintegrants, 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 accelerators such as quaternary ammonium compounds; g) Humectants such as 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-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules having a coating and a shell, such as enteric coatings and other coatings well known in the pharmaceutical formulating arts, can be prepared. It may optionally contain an opacifying agent and may also have a composition which releases the active ingredient in a certain part of the intestinal tract, optionally in a delayed manner, only or preferentially. 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-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.

The therapeutic agent may also be present in microencapsulated form together with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules having a coating and shell layer (such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical formulation arts) may be prepared. In such solid dosage forms, the active compound may be admixed with at least one inert diluent, such as sucrose, lactose or starch. As in common practice, such dosage forms may also contain other substances besides 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 in a certain part of the intestinal tract, optionally in a delayed manner, only or preferentially. 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 invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers as may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated as falling within the scope of the present invention. Furthermore, the present invention encompasses the use of transdermal patches that have the additional advantage of delivering compounds to the body in a controlled manner. Such dosage forms may be manufactured by dissolving or partitioning the compound in an appropriate medium. Absorption enhancers may also be used to increase the transdermal amount of the compound. The rate may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compounds of the invention.

Described herein are compounds that can be metabolically converted to N, N-dimethyltryptamine or an analog thereof upon administration to a subject. In certain embodiments, the compounds described herein are useful for treating disorders associated with any brain disease.

In some embodiments, the compounds described herein are prodrugs of Dimethyltryptamine (DMT) or prodrugs of 5-MeO-DMT. In some embodiments, the compounds described herein are hallucinogens having improved pharmacokinetic properties (e.g., longer half-life, longer tmax, and/or longer tlast, etc.) compared to DMT or 5-MeO-DMT.

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

Wherein:

r ¹ is methoxy or hydrogen;

R ³、R⁴、R⁵、R⁶、R⁷ and R ⁸ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A; r ⁹ and R ¹⁰ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently 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 that is unsubstituted or substituted with one or more R ^A;

Each R ^B is independently halogen, amino, cyano, hydroxy, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, -C (O) CH ₃, -C (O) Ph, or heteroarylalkyl, wherein each cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more halogen, amino, cyano, hydroxy, alkyl, acetyl, or benzoyl.

In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is -C(O)OR³、-C(O)R⁴、-CH(R⁵)OR⁶、-C(O)OCH(R⁵)OC(O)R⁶、-C(O)OCH(R⁵)OC(O)OR⁶、-CH(R⁵)C(O)R⁶、-S(O)₂OR⁷、-P(O)OR⁸[N(R⁹)R¹⁰]、--C(O)N(R⁹)R¹⁰、-P(O)OR¹¹(OR¹²)、-CH(R⁵)OP(O)OR⁸[N(R⁹)R¹⁰] or-CH (R ⁵)OP(O)OR¹¹(OR¹²).

In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

r ³、R⁴、R⁶、R⁷ and R ⁸ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl; and

Each R ⁵ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl,

Wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A.

In some embodiments are compounds of formula (I) or pharmaceutically acceptable salts thereof, R ³、R⁴、R⁵、R⁶、R⁷ and R ⁸ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more R ^A.

In some embodiments is a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is unsubstituted alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is heteroalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is unsubstituted heteroalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is ethyl.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with heterocyclylalkyl. In some embodiments, a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with-N (R ¹³)C(O)OR¹⁴).

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is heteroalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is heteroalkyl substituted with cycloalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is heteroalkyl substituted with alkyl.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is cycloalkyl. In some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is cycloalkyl substituted with N (R ¹⁸)R¹⁹), in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ¹⁸ and R ¹⁹ are each hydrogen, alkyl, OR heteroalkyl, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form a heterocycloalkyl ring, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form a heterocycloalkyl ring, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form an unsubstituted heterocycloalkyl ring.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is heteroaryl substituted with one OR more R ^B. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is heterocyclylalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is unsubstituted heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is unsubstituted heterocyclylalkyl.

In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁴ and R ⁵ together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A.

In some embodiments are compounds of formula (I) having the structure of formula (Ia):

Wherein R ¹ is methoxy or hydrogen and R ³ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl, each independently being unsubstituted or substituted with one or more of R ^A. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl or heteroalkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted alkyl or unsubstituted heteroalkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy and R ³ is alkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy and R ³ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen and R ³ is alkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen and R ³ is unsubstituted alkyl.

In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is heteroalkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted heteroalkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, n-pentyl or 3-methyl-1-butyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is aryl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is phenyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is heterocyclylalkyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is ethyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen and R ³ is ethyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy and R ³ is ethyl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ is alkyl substituted with heteroaryl. In some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ³ isIn some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy and R ³ isIn some embodiments are compounds of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen and R ³ is

In some embodiments is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments are compounds of formula (I) or (Ia), or pharmaceutically acceptable salts thereof, provided that when R ¹ is hydrogen then R ³ is not tert-butyl. In some embodiments is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt thereof, wherein if R ¹ is hydrogen and R ³ is alkyl, R ³ is bonded to the atom to which it is attached via a primary or secondary carbon.

In some embodiments are compounds of formula (I) having the structure of formula (Ib):

Wherein:

r ¹ is methoxy or hydrogen;

R ^A5 is heteroalkyl, heterocyclylalkyl, heteroaryl, OR -C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵ OR-OC (O) OR ¹⁶, wherein each heteroalkyl, heterocyclylalkyl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halo, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹), in some embodiments a compound of formula (Ib) OR a pharmaceutically acceptable salt thereof, wherein one of R ^A1、R^A2、R^A3 and R ^A4 is alkyl and each of R ^A1、R^A2、R^A3 and R ^A4 is hydrogen, in some embodiments a compound of formula (Ib) OR a pharmaceutically acceptable salt thereof, wherein both of R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 and R ^A4 is not alkyl is hydrogen, in some embodiments a compound of formula (Ib) OR a pharmaceutically acceptable salt thereof, wherein each of R ^A1、R^A2、R^A3 and R ^A4 is hydrogen, in some embodiments a compound of formula (Ib) OR a pharmaceutically acceptable salt thereof, wherein one of R ^A1、R^A2、R^A3 and R ^A4 is alkyl and each of R ^A1、R^A2、R^A3 and R ^A4 is hydrogen, in some embodiments a compound of formula (Ib) OR a pharmaceutically acceptable salt thereof, wherein both of R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 is alkyl and each of R ^A4 is hydrogen, in some embodiments a compound of formula (Ib) OR a pharmaceutically acceptable salt thereof, wherein each of R ^A1、R^A2、R^A3 and R ^A4 is hydrogen, in some embodiments a pharmaceutically acceptable salt thereof is hydrogen, in one of R52 and R52 is methyl and tert-butyl and each of R52 is methyl and each of R52 and each of R35 is methyl and each of methyl and is methyl and independently OR tert-butyl, wherein R ^A5 is heterocyclylalkyl. In some embodiments is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵. In some embodiments is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl. In some embodiments is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is methyl, ethyl, isopropyl, n-propyl, t-butyl, isobutyl, or n-butyl. In some embodiments is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is isobutyl.

Wherein:

r ¹ is methoxy or hydrogen;

In some embodiments is a compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof, wherein one of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 is alkyl and each of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7, which is not alkyl, is hydrogen. In some embodiments are compounds of formula (Ib-1) or a pharmaceutically acceptable salt thereof, wherein both of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 are alkyl and each of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7, which is not alkyl, is hydrogen. In some embodiments is a compound of formula (Ib-1), or a pharmaceutically acceptable salt thereof, wherein R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 are each hydrogen. In some embodiments is a compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof, wherein one of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 is alkyl and each of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 is other than alkyl is hydrogen, wherein alkyl is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments are compounds of formula (Ib-1) or a pharmaceutically acceptable salt thereof, wherein R ^A3 and R ^A4 are each independently alkyl and R ^A1、R^A2,R^A6 and R ^A7 are each hydrogen. In some embodiments are compounds of formula (Ib-1) or a pharmaceutically acceptable salt thereof, wherein both of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 are alkyl groups and each of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7, which are not alkyl groups, is hydrogen, wherein each alkyl group is independently methyl, ethyl, isopropyl, or tert-butyl. In some embodiments is a compound of formula (Ib-1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heterocyclylalkyl. In some embodiments is a compound of formula (Ib-1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵. In some embodiments is a compound of formula (Ib-1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl. In some embodiments is a compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is methyl, ethyl, isopropyl, n-propyl, t-butyl, isobutyl, or n-butyl. In some embodiments is a compound of formula (Ib-1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is isobutyl.

In some embodiments is a compound of formula (I) or (Ib-1), or a pharmaceutically acceptable salt thereof, wherein the compound is:

in some embodiments are compounds of formula (I) or (Ib) having the structure of formula (Ib 1):

In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heteroalkyl or heterocyclylalkyl. In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heteroalkyl. In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is unsubstituted heteroalkyl. In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heterocyclylalkyl. In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is unsubstituted heterocyclylalkyl. In some embodiments are compounds of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is methoxy, ethoxy, cyclopropyloxy, methylamino, or dimethylamino. In some embodiments are compounds of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is

In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵.

In some embodiments are compounds of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments are compounds of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is phenyl. In some embodiments are compounds of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

In some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴), in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴), wherein R ¹³ is hydrogen or alkyl, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴), wherein R ¹³ is hydrogen, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is alkyl, in some embodiments is a compound of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is unsubstituted alkyl, in some embodiments is a compound of formula (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴, wherein R ¹⁴ is methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, N-pentyl, or 3-methyl-1-butyl).

In some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴. In some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴), wherein R ¹³ is hydrogen or alkyl, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴), wherein R ¹³ is hydrogen, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴), wherein R ¹³ is alkyl, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹³ is unsubstituted alkyl, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, N-pentyl or 3-methyl-1-butyl, in some embodiments a compound of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴), wherein R ¹⁴ is phenyl. In some embodiments are compounds of formula (Ib) or (Ib 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl).

In some embodiments are compounds of formula (I), (Ib) or (Ib 1), or a pharmaceutically acceptable salt thereof, wherein the compounds are:

in some embodiments are compounds of formula (I) having the structure of formula (Ic):

Wherein R ¹ is hydrogen or methoxy and R ¹⁸ and R ¹⁹ are each independently hydrogen, alkyl, cycloalkyl or heteroalkyl, wherein each alkyl, cycloalkyl and heteroalkyl is independently 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 that is unsubstituted or substituted with one or more R ^B.

In some embodiments are compounds of formula (I) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ and R ¹⁹ are each independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH ₂CH₂ OMe, or-CH ₂CH₂SO₂ Me. In some embodiments are compounds of formula (I) or (Ic) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ is hydrogen and R ¹⁹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH ₂CH₂ OMe, or-CH ₂CH₂SO₂ Me. In some embodiments are compounds of formula (I) or (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁸ and R ¹⁹ are each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH ₂CH₂ OMe, or-CH ₂CH₂SO₂ Me.

In some embodiments are compounds of formula (I) or (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form a substituted or unsubstituted heterocyclylalkyl ring. In some embodiments are compounds of formula (I) or (Ic), or pharmaceutically acceptable salts or solvates thereof, wherein R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring, each of which is substituted or unsubstituted.

In some embodiments is a compound of formula (I) or (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (Id):

Wherein:

r ¹ is hydrogen or methoxy;

R ⁵ is hydrogen, alkyl or cycloalkyl, wherein each of the alkyl and cycloalkyl groups is independently unsubstituted or substituted with one or more R ^A; and

R ^A6 is hydrogen OR alkyl, which is unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹).

In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl or cycloalkyl. In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl. In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen, methyl, ethyl, or isopropyl. In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A6 is alkyl. In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl and R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.

In some embodiments is a compound of formula (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Ie):

In some embodiments is a compound of formula (I) or (Ie) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments is a compound of formula (I) or (Id) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments are compounds of formula (I) or (Ie) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl. In some embodiments is a compound of formula (I) or (Ie) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is methyl, ethyl or isopropyl.

In some embodiments is a compound of formula (I) or (Ie) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments is a compound of formula (I) having the structure of formula (If):

Wherein:

r ¹ is methoxy or hydrogen, and

R ⁹ and R ¹⁰ are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl, wherein each alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, and heterocyclylalkyl is independently 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 that is unsubstituted or substituted with one or more R ^A.

In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently alkyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently unsubstituted alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ⁹ and R ¹⁰ are each independently unsubstituted alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ⁹ and R ¹⁰ are each independently unsubstituted alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently heteroalkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently unsubstituted heteroalkyl. In some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, t-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, or 3-methyl-1-butyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently CH ₂CHF₂、CH₂CF₃ or CH ₂ cPr. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each phenyl. In some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each ethyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ⁹ and R ¹⁰ are each ethyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ⁹ and R ¹⁰ are each ethyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each methyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ⁹ and R ¹⁰ are each methyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ⁹ and R ¹⁰ are each methyl.

In some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy or hydrogen, R ⁹ is hydrogen and R ¹⁰ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁹ is hydrogen and R ¹⁰ is alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is alkyl. In some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is heteroalkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁹ is hydrogen and R ¹⁰ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is unsubstituted heteroalkyl. In some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, t-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl, or 3-methyl-1-butyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is-CH ₂CHF₂、-CH₂CF₃ or-CH ₂ cPr. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is phenyl. In some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is ethyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is ethyl. In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁹ is hydrogen and R ¹⁰ is ethyl. In some embodiments is a compound of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ isIn some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁹ is hydrogen and R ¹⁰ isIn some embodiments are compounds of formula (I) or (If) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁹ is hydrogen and R ¹⁰ is

In some embodiments is a compound of formula (I) or (If), or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments a compound of formula (I) or (If) having the structure of formula (If 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

X ¹ and X ² are each independently selected from-CH ₂-、-O-、-NH-、-S-、-S(O)-、-S(O)₂ -or-N (Y ¹) -, wherein each Y ¹ is independently hydrogen, cycloalkyl, heteroalkyl, or alkyl.

In some embodiments is a compound of formula (If 1) or a pharmaceutically acceptable salt thereof, wherein each Y ¹ is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, or CH ₂CH₂ OMe. In some embodiments is a compound of formula (If 1), or a pharmaceutically acceptable salt thereof, wherein X ¹ is-CH ₂ -and X ² is-N (Y ¹) -. In some embodiments is a compound of formula (If 1), or a pharmaceutically acceptable salt thereof, wherein X ² is-CH ₂ -and X ¹ is-N (Y ¹) -. In some embodiments is a compound of formula (If 1), or a pharmaceutically acceptable salt thereof, wherein X ¹ is-CH ₂ -and X ² is-N (Y ¹) -, wherein Y ¹ is hydrogen, methyl, ethyl, N-propyl, isopropyl, cyclopropyl, or-CH ₂CH₂ OMe. In some embodiments is a compound of formula (If 1), or a pharmaceutically acceptable salt thereof, wherein X ² is-CH ₂ -and X ¹ is-N (Y ¹) -, wherein Y ¹ is hydrogen, methyl, ethyl, N-propyl, isopropyl, cyclopropyl, or-CH ₂CH₂ OMe. In some embodiments is a compound of formula (If 1), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each-O-or-NH-. In some embodiments is a compound of formula (If 1), or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is hydrogen.

In some embodiments are compounds of formula (I) having the structure of formula (Ig):

Wherein:

r ¹ is methoxy or hydrogen;

In some embodiments are compounds of formula (Ig), or pharmaceutically acceptable salts or solvates thereof, wherein one R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 and R ^A4, which is not alkyl, is hydrogen. In some embodiments are compounds of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein both of R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 and R ^A4, which is not alkyl, is hydrogen. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen. In some embodiments are compounds of formula (Ig), or pharmaceutically acceptable salts thereof, wherein one R ^A1、R^A2、R^A3 and R ^A4 are alkyl groups and each of R ^A1、R^A2、R^A3 and R ^A4, which are not alkyl groups, is hydrogen, wherein each alkyl group is independently methyl, ethyl, t-butyl, or isopropyl. In some embodiments are compounds of formula (Ig), or pharmaceutically acceptable salts or solvates thereof, wherein both of R ^A1、R^A2、R^A3 and R ^A4 are alkyl groups and each of R ^A1、R^A2、R^A3 and R ^A4, which is not alkyl, is hydrogen, wherein each alkyl is independently methyl, ethyl, tert-butyl, or isopropyl.

In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is heteroalkyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is unsubstituted heteroalkyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is heterocyclylalkyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is unsubstituted heterocyclylalkyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is methoxy, ethoxy, cyclopropyloxy, methylamino, or dimethylamino. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is

In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is-CH ₂CH₂ OMe or-CH ₂CH₂SO₂ Me.

In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-OC (O) R ¹⁵. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is phenyl. In some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

In some embodiments, a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is N (R ¹³)C(O)OR¹⁴), in some embodiments, a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is hydrogen or alkyl, in some embodiments, a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is hydrogen, in some embodiments, a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is alkyl, in some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴, wherein R ¹³ is unsubstituted alkyl, in some embodiments is a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴, wherein R ¹⁴ is methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, N-pentyl, or 3-methyl-1-butyl).

In some embodiments, a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴), in some embodiments, a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹³ is hydrogen or alkyl, in some embodiments, a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹³ is hydrogen, in some embodiments, a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹³ is alkyl, in some embodiments a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹³ is unsubstituted alkyl, in some embodiments a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is alkyl, in some embodiments a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is unsubstituted alkyl, in some embodiments a compound of formula (Ig) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or 3-methyl-1-butyl. In some embodiments a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is phenyl, in some embodiments a compound of formula (Ig), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴, wherein R ¹⁴ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl).

In some embodiments is a compound of formula (I) or (Ig), or a pharmaceutically acceptable salt thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (Ih):

Wherein:

r ¹ is hydrogen or methoxy;

In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen. In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen, methyl, ethyl, n-propyl or isopropyl. In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ and R ¹⁹ are each independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, t-butyl, CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me. In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ is hydrogen and R ¹⁹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, t-butyl, CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me. In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ and R ¹⁹ are each methyl, ethyl, n-propyl, isopropyl, cyclopropyl, t-butyl, CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form a heterocyclylalkyl ring. In some embodiments is a compound of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form an azetidine ring,An tourmaline ring, a pyrrolidine ring, or a piperidine ring, each of which is substituted or unsubstituted. In some embodiments are compounds of formula (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form an azetidine ring,An tourmaline ring, a pyrrolidine ring or a piperidine ring.

In some embodiments is a compound of formula (I) or (Ih) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Ii):

Wherein:

r ¹ is hydrogen or methoxy; and

R ⁵ and R ¹⁰ are each independently hydrogen, alkyl, heteroalkyl, or cycloalkyl, wherein each alkyl, heteroalkyl, and cycloalkyl is independently unsubstituted or substituted with one or more R ^A; and

In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is methyl, ethyl, or isopropyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen, methyl, ethyl, or isopropyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A6 is hydrogen. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A6 is alkyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl and R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl and R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.

In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is alkyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen, methyl, ethyl, n-propyl or isopropyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵、R¹⁰ and R ^A6 are each independently hydrogen, alkyl, heteroalkyl, or cycloalkyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵、R¹⁰ and R ^A6 are each independently hydrogen, alkyl or cycloalkyl. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵、R¹⁰ and R ^A6 are each hydrogen. In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵、R¹⁰ and R ^A6 are each independently hydrogen, methyl, ethyl, n-propyl or isopropyl.

In some embodiments is a compound of formula (Ii) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (Ij):

Wherein R ¹ is hydrogen or methoxy and R ⁵ and R ¹⁰ are each hydrogen, alkyl or heteroalkyl, wherein each alkyl and heteroalkyl is independently unsubstituted or substituted with one or more R ^A.

In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl. In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is methyl, ethyl, or isopropyl.

In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen. In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments is a compound of formula (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁰ is CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

In some embodiments is a compound of formula (I) or (Ij) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Ik):

Wherein R ¹ is hydrogen or methoxy and R ⁴ is alkyl, heterocyclylalkyl, aryl, heteroaryl or heteroalkyl, each of which is unsubstituted or substituted with one or more R ^A.

In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is heteroalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is heterocyclylalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ⁴ is heteroalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ⁴ is heterocyclylalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ⁴ is heteroalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ⁴ is heterocyclylalkyl.

In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is alkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is CH ₂CF₃. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is unsubstituted alkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or n-nonyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is cycloalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is unsubstituted cycloalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, or cyclooctyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ or aryl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ or phenyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ or heteroaryl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 3-pyrimidinyl, or 6-pyrimidinyl.

In some embodiments is a compound of formula (I) or (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is heterocyclylalkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is 。

In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ isWherein R ¹⁴ is alkyl, cycloalkyl, or aryl, each independently being unsubstituted or substituted with one or more R ^B. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ isWherein R14 is methyl, ethyl, n-propyl, isopropyl or CH ₂CH₂ OMe. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ isWherein R14 is phenyl.

In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is Wherein R ^A7 is hydrogen OR alkyl which is unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹), in some embodiments a compound of formula (Ik) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ⁴ isWherein R ^A7 is hydrogen. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ isWherein R ^A7 is alkyl which is unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹), in some embodiments, a compound of formula (Ik) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ⁴ isWherein R ^A7 is unsubstituted alkyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ isWherein R ^A7 is methyl, ethyl, n-propyl, isopropyl or n-butyl. In some embodiments is a compound of formula (Ik) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ isWherein R ^A7 is benzyl.

in some embodiments are compounds of formula (I) or (Ik) having the structure of formula (Ik 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

In some embodiments are compounds of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen or alkyl. In some embodiments are compounds of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heteroalkyl or heterocyclylalkyl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heterocyclylalkyl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is heteroalkyl. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is alkoxy. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is methoxy. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is alkylsulfonyl. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is methylsulfonyl.

In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵. In some embodiments are compounds of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl. In some embodiments are compounds of formula (Ik 1) or pharmaceutically acceptable salts thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is unsubstituted alkyl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ or aryl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is unsubstituted aryl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is phenyl. In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-OC (O) R ¹⁵, wherein R ¹⁵ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

In some embodiments are compounds of formula (I) or (Ik) having the structure of formula (Ik 2) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

P is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In some embodiments are compounds of formula (I), (Ik) or (Ik 2) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl. In some embodiments are compounds of formula (I), (Ik) or (Ik 2) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is hydrogen or alkyl. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is hydrogen. In some embodiments are compounds of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is alkyl. In some embodiments are compounds of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is unsubstituted alkyl. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl. In some embodiments are compounds of formula (I), (Ik) or (Ik 2) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or 3-methyl-1-butyl. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is methyl. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is hydrogen or methyl. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is aryl. In some embodiments are compounds of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is unsubstituted aryl. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is phenyl. In some embodiments are compounds of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments are compounds of formula (I), (Ik) or (Ik 2) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1,2, 3,4 or 5. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 4. In some embodiments is a compound of formula (I), (Ik) or (Ik 2), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 5.

In some embodiments is a compound of formula (Ik 1) or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments is a compound of formula (Ik 2) or a pharmaceutically acceptable salt thereof, wherein the compound is:

in some embodiments are compounds of formula (I) or (Ik) having the structure of formula (Ik 3) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

R ^A5 is-N (R ¹⁸)R¹⁹ or-N (R ¹³)C(O)R¹⁴).

In some embodiments a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹⁸)R¹⁹. In some embodiments a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein R ^A1 is-N (R ¹⁸)R¹⁹, wherein R ¹⁸ and R ¹⁹ are each hydrogen, in some embodiments a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹⁸)R¹⁹, wherein R ¹⁹ is alkyl, cycloalkyl or aryl, in some embodiments a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹⁸)R¹⁹, wherein R ¹⁸ is hydrogen and R ¹⁹ is alkyl, cycloalkyl or aryl, in some embodiments a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein R ¹⁸ is hydrogen and R95 is unsubstituted alkyl, cycloalkyl or an unsubstituted aryl, in some embodiments an unsubstituted cycloalkyl or an unsubstituted tert-butyl, R9732 is phenyl or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴.

In some embodiments is a compound of formula (Ik 3) or a pharmaceutically acceptable salt thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (Il):

Wherein:

r ¹ is methoxy or hydrogen;

In some embodiments is a compound of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is methyl, ethyl, isopropyl, t-butyl, 2-dimethylaminoethyl or cyclopropyl. In some embodiments are compounds of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁵ is hydrogen and R ⁶ is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl or cyclopropyl. In some embodiments are compounds of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁵ is hydrogen and R ⁶ is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl or cyclopropyl. In some embodiments are compounds of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁵ is hydrogen and R ⁶ is tert-butyl. In some embodiments are compounds of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, R ⁵ is hydrogen. In some embodiments are compounds of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁵ is hydrogen and R ⁶ is tert-butyl.

In some embodiments is a compound of formula (I) or (Il) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Im):

Wherein:

r ¹ is methoxy or hydrogen;

In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each independently cycloalkyl, aryl, heteroaryl, or alkyl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is hydrogen and R ¹² is cycloalkyl, aryl, heteroaryl or alkyl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is hydrogen and R ¹² is alkyl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is hydrogen and R ¹² is tert-butyl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or heteroaryl-substituted alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is hydrogen and R ¹² is cycloalkyl, aryl, heteroaryl or alkyl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is hydrogen and R ¹² is alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is heterocyclylalkyl substituted with alkyl or arylalkyl.

In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is hydrogen. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ¹¹ and R ¹² are each alkyl, heterocyclylalkyl or cycloalkyl. In some embodiments is a compound of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁴ is hydrogen, and R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁵ is hydrogen, and R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁵ is hydrogen, and R ¹¹ and R ¹² are each tert-butyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁵ is hydrogen, and R ¹¹ and R ¹² are each tert-butyl.

In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are eachIn some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl or 3-methyl-1-butyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each phenyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each 4-nitrophenyl. In some embodiments are compounds of formula (I) or (Im) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each benzyl.

In some embodiments a compound of formula (I) or (Im) having the structure of formula (Im 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

r ^A1、R^A3 and R ⁶ are each independently hydrogen, alkyl or cycloalkyl; and

In some embodiments is a compound of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments is a compound of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen. In some embodiments is a compound of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1 and R ^A3 are each hydrogen.

In some embodiments is a compound of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵. In some embodiments is a compound of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵; and R ^A1、R^A3 and R ⁴ are each independently hydrogen, methyl, ethyl, isopropyl or tert-butyl. In some embodiments is a compound of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁵ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁵ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is benzyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁵ is benzyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl. In some embodiments are compounds of formula (Im 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl.

In some embodiments is a compound of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶. In some embodiments is a compound of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶; and R ^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl or tert-butyl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁶ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁶ is isopropyl. In some embodiments is a compound of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein each R ^A2 and R ^A4 is-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is phenyl or 4-nitrophenyl. In some embodiments is a compound of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein each R ^A2 and R ^A4 is-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁶ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is benzyl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each hydrogen; and each R ¹⁶ is benzyl. In some embodiments are compounds of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl. In some embodiments is a compound of formula (Im 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶; each of R ^A1、R^A3 and R ⁵ is hydrogen; and each R ¹⁶ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl.

In some embodiments is a compound of formula (I), (Im) or (Im 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments are compounds of formula (I), (Im) or (Im 1) having the structure of formula (Im 1 a) or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^B1 and R ^B2 are each independently hydrogen or alkyl, which alkyl is unsubstituted or substituted by one or more hydrogen, amino, cyano, hydroxy, alkyl, acetyl or benzoyl.

In some embodiments is a compound of formula (Im 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^B1 and R ^B2 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pent-3-yl or benzyl. In some embodiments is a compound of formula (Im 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl or tert-butyl. In some embodiments is a compound of formula (Im 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1、R^A3 and R ⁵ are each hydrogen. In some embodiments is a compound of formula (Im 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and R ^B1 and R ^B2 are each hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pent-3-yl or benzyl.

In some embodiments is a compound of formula (I), (Im 1) or (Im 1 a), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (In):

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl;

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl,

In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen, methyl, ethyl, or t-butyl. In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is hydrogen. In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is alkyl or cycloalkyl. In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments are compounds of formula (I) or (In) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is phenyl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is 4-nitrophenyl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is benzyl. In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 4-pyrimidinyl. In some embodiments is a compound of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen. In some embodiments are compounds of formula (I) or (In), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is alkyl.

In some embodiments are compounds of formula (I) or (In) having the structure of formula (In 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1 is hydrogen, alkyl OR cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted OR substituted with alkyl, aryl, hydrogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

R ¹³ is hydrogen or alkyl, which is unsubstituted or substituted with one or more R ^B.

In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen or alkyl. In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen, methyl, ethyl, or tert-butyl. In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen. In some embodiments is a compound of formula (In 1), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is alkyl or cycloalkyl. In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments is a compound of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments is a compound of formula (In 1), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is phenyl. In some embodiments is a compound of formula (In 1), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is 4-nitrophenyl. In some embodiments is a compound of formula (In 1), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is benzyl. In some embodiments is a compound of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 4-pyrimidinyl. In some embodiments is a compound of formula (In 1), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is alkyl. In some embodiments is a compound of formula (In 1), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is unsubstituted alkyl. In some embodiments is a compound of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or-CH ₂CH(Et)₂. In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen or alkyl; and R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or-CH ₂CH(Et)₂. In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen or unsubstituted alkyl; and R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or-CH ₂CH(Et)₂. In some embodiments are compounds of formula (In 1) or a pharmaceutically acceptable salt thereof, wherein R ⁵ and R ^A1 are each hydrogen; and R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or-CH ₂CH(Et)₂.

In some embodiments is a compound of formula (I), (In) or (In 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (Io):

Wherein:

R ¹ is methoxy or hydrogen; and

R ¹¹ and R ¹² are each independently selected from hydrogen, cycloalkyl, aryl, heteroaryl, or alkyl, wherein each cycloalkyl, aryl, heteroaryl, and alkyl is independently unsubstituted or substituted with one or more R ^A or R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A.

In some embodiments, a compound of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each independently selected from cycloalkyl, aryl, heteroaryl, or alkyl; or R ¹¹ and R ¹² together with the atoms to which they are attached form a heterocyclylalkyl ring. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ is hydrogen and R ¹² is alkyl, cycloalkyl, aryl, heteroaryl, or alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is heterocyclylalkyl substituted with alkyl or arylalkyl.

In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl, heterocyclylalkyl, or cycloalkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy and R ¹¹ and R ¹² are each tert-butyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen and R ¹¹ and R ¹² are each tert-butyl.

In some embodiments are compounds of formula (I) or (Io) or pharmaceutically acceptable salts or solvates thereof, wherein R ¹¹ and R ¹² are eachIn some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each phenyl. In some embodiments are compounds of formula (I) or (Io) or pharmaceutically acceptable salts or solvates thereof, wherein R ¹¹ and R ¹² are each 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each 4-nitrophenyl. In some embodiments are compounds of formula (I) or (Io) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each benzyl.

In some embodiments, a compound of formula (I) or (Io) having the structure of formula (Io 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

r ^A1 and R ^A3 are each independently hydrogen, alkyl or cycloalkyl; and

R ^A2 and R ^A4 are each independently of the other alkyl, heteroalkyl OR cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, -OC (O) R ¹⁵ OR-OC (O) OR ¹⁶,

In some embodiments is a compound of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments is a compound of formula (Io 1), or a pharmaceutically acceptable salt thereof, wherein R ^A1 and R ^A3 are each hydrogen.

In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵; and R ^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl or tert-butyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each hydrogen; and each R ¹⁵ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each hydrogen; and each R ¹⁵ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is benzyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each hydrogen; and each R ¹⁵ is benzyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl. In some embodiments are compounds of formula (Io 1) or a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵;R^A1 and R ^A3 are each hydrogen; and each R ¹⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl.

In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶; and R ^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl or tert-butyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is alkyl, cycloalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1 and R ^A3 are each hydrogen; and each R ¹⁶ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, 3-methyl-1-butyl, cyclopropyl or cyclobutyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein each R ^A2 and R ^A4 is-OC (O) OR ¹⁶;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein each R ^A2 and R ^A4 is-OC (O) OR ¹⁶;R^A1 and R ^A3 are each hydrogen; and each R ¹⁶ is phenyl or 4-nitrophenyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶; each R ^A1 and R ^A3 is independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and each R ¹⁶ is benzyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1 and R ^A3 are each hydrogen; and each R ¹⁶ is benzyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶;R^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, OR tert-butyl; and each R ¹⁶ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl. In some embodiments are compounds of formula (Io 1) OR a pharmaceutically acceptable salt thereof, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶; each of R ^A1 and R ^A3 is hydrogen; and each R ¹⁶ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl.

In some embodiments is a compound of formula (I), (Io) or (Io 1), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments is a compound of formula (I), (Io) or (Io 1), or a pharmaceutically acceptable salt or solvate thereof, wherein:

in some embodiments, a compound of formula (I) or (Io) having the structure of formula (Io 2) or a pharmaceutically acceptable salt thereof,

In some embodiments is a compound of formula (Io 2), or a pharmaceutically acceptable salt thereof, wherein R ^A1 is aryl. In some embodiments is a compound of formula (Io 2), or a pharmaceutically acceptable salt thereof, wherein R ^A1 is aryl substituted with halo. In some embodiments is a compound of formula (Io 2) or a pharmaceutically acceptable salt thereof, wherein R ^A1 isWherein Z ¹、Z² and Z ³ are each independently hydrogen or halogen. In some embodiments is a compound of formula (Io 2), or a pharmaceutically acceptable salt thereof, wherein R ^A1 isWherein Z ¹、Z² and Z ³ are each independently hydrogen, fluorine, chlorine, bromine or iodine. In some embodiments is a compound of formula (Io 2), or a pharmaceutically acceptable salt thereof, wherein R ^A1 is

In some embodiments is a compound of formula (Io 2), or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments are compounds of formula (I), (Io) or (Io 1) having the structure of formula (Io 1 a) or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

In some embodiments is a compound of formula (Io 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^B1 and R ^B2 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pent-3-yl, or benzyl. In some embodiments is a compound of formula (Io 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl. In some embodiments is a compound of formula (Io 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 and R ^A3 are each independently hydrogen. In some embodiments is a compound of formula (Io 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl; and R ^B1 and R ^B2 are each hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pent-3-yl or benzyl.

In some embodiments is a compound of formula (Io 1 a) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments are compounds of formula (I) having the structure of formula (Ip):

Wherein:

r ¹ is methoxy or hydrogen;

R ⁸ is alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl,

In some embodiments are compounds of formula (I) or (Ip) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is alkyl or cycloalkyl. In some embodiments are compounds of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments are compounds of formula (I) or (Ip) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In some embodiments is a compound of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is aryl. In some embodiments is a compound of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is phenyl. In some embodiments is a compound of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is 4-nitrophenyl. In some embodiments is a compound of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is benzyl. In some embodiments is a compound of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁸ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 4-pyrimidinyl. In some embodiments is a compound of formula (I) or (Ip), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen. In some embodiments are compounds of formula (I) or (Ip) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen and R ¹⁰ is alkyl.

In some embodiments are compounds of formula (I) or (Ip) having the structure of formula (Ip 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1 is hydrogen, alkyl OR cycloalkyl, wherein each of the alkyl and cycloalkyl is unsubstituted OR substituted with one OR more of alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1 is hydrogen or alkyl. In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein R ^A1 is hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1 is hydrogen, methyl, ethyl, or t-butyl. In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein R ^A1 is hydrogen. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is alkyl or cycloalkyl. In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is unsubstituted alkyl or unsubstituted cycloalkyl. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is phenyl. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is 4-nitrophenyl. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is benzyl. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ⁸ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 4-pyrimidinyl. In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is alkyl. In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein R ¹³ is unsubstituted alkyl. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or-CH ₂CH(Et)₂. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1 is hydrogen or unsubstituted alkyl; and R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or-CH ₂CH(Et)₂. In some embodiments is a compound of formula (Ip 1) or a pharmaceutically acceptable salt thereof, wherein R ^A1 is hydrogen; and R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or-CH ₂CH(Et)₂.

In some embodiments is a compound of formula (Ip 1), or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Iq):

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl; and

R ⁶ is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl or heteroaryl,

In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (I) or (Iq), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heterocyclylalkyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroalkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroalkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heterocyclylalkyl substituted with arylalkyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is methyl, isopropyl, tert-butyl, or-CH (Et) ₂.

In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl and R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ⁶ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl and R ⁶ is unsubstituted alkyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is methyl, ethyl, isopropyl, tert-butyl or cyclopropyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ⁶ is methyl, ethyl, isopropyl, tert-butyl or cyclopropyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ⁶ is tert-butyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is hydrogen, R ⁵ is hydrogen and R ⁶ is tert-butyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ is methoxy, R ⁵ is hydrogen and R ⁶ is tert-butyl.

In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is cycloalkyl. In some embodiments are compounds of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is methyl, ethyl, n-propyl, t-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is phenyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is 4-nitrophenyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is benzyl. In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroaryl. In some embodiments is a compound of formula (I) or (Iq), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, or 4-pyrimidinyl.

In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroalkyl. In some embodiments is a compound of formula (I) or (Iq), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me. In some embodiments a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is- (CH ₂)_rCO₂ H wherein R is 1,2,3, 4, 5 or 6, in some embodiments a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is- (CH ₂)_sCO₂R¹³) wherein s is 1,2,3, 4, 5 or 6, in some embodiments a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is- (CH ₂)_sCO₂R¹³), wherein R ¹³ is alkyl, in some embodiments is a compound of formula (I) or (Iq), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is- (CH ₂)_sCO₂R¹³), wherein R ¹³ is unsubstituted alkyl, in some embodiments is a compound of formula (I) or (Iq), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is- (CH ₂)_sCO₂R¹³), wherein R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or-CH (Et) ₂.

In some embodiments, a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is-CH (R ^A1)NH₂, wherein R ^A1 is hydrogen, alkyl, heteroalkyl, or an amino acid side chain, in some embodiments, a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is-CH (R ^A1)NH₂, wherein R ^A1 is an amino acid side chain, in some embodiments, a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is-CH (R ^A1)NH₂, wherein R ^A1 is methyl, ethyl, n-propyl, isopropyl, t-butyl, CH (Me) Et, CH ₂CH(Me)₂, or CH ₂CH₂ sme.

In some embodiments is a compound of formula (I) or (Iq) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments are compounds of formula (I) or (Iq) having the structure of formula (Iq 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

Q ¹ isWherein the method comprises the steps of

In some embodiments are compounds of formula (Iq 1), or a pharmaceutically acceptable salt thereof, wherein each of Y ¹、Y² or Y ³ is-N (R ^Y1) -. In some embodiments are compounds of formula (Iq 1), or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -, wherein R ^Y1 is hydrogen. In some embodiments are compounds of formula (Iq 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, CH (Et) ₂、CH₂CH₂OMe、CH₂CH₂SO₂ Me or CH ₂CF₃. In some embodiments are compounds of formula (Iq 1), or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each phenyl. In some embodiments are compounds of formula (Iq 1), or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each benzyl. In some embodiments are compounds of formula (Iq 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

In some embodiments is a compound of formula (Iq) or (Iq 1), or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments are compounds of formula (Iq 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently Wherein R ^Z1 is hydrogen or alkyl. In some embodiments are compounds of formula (Iq 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independentlyWherein R ^Z1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or CH (Et) ₂. In some embodiments are compounds of formula (Iq 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independentlyWherein R ^Z1 is benzyl.

In some embodiments is a compound of formula (Iq 1) or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Ir):

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl; and

R ⁶ is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl or heteroaryl,

In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl, cycloalkyl, heterocyclylalkyl, aryl or heteroaryl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroalkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroalkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heterocyclylalkyl substituted with arylalkyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is methyl, ethyl, isopropyl, t-butyl, or-CH (Et) ₂.

In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl and R ⁶ is alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen and R ⁶ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl and R ⁶ is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl and R ⁶ is heterocyclylalkyl. In some embodiments is a compound of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is methyl, ethyl, n-propyl, isopropyl, tert-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is aryl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is phenyl. In some embodiments are compounds of formula (I) or (Ir) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heterocyclylalkyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is oxetan-3-yl or azetidin-3-yl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is heteroaryl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, or 4-pyrimidinyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is benzyl. In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶ is

In some embodiments is a compound of formula (I) or (Ir), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments a compound of formula (I) or (Ir) having the structure of formula (Ir 1) or a pharmaceutically acceptable salt thereof,

Wherein:

r ¹ is methoxy or hydrogen;

Q ¹ isWherein the method comprises the steps of

In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -. In some embodiments are compounds of formula (Ir 1), or pharmaceutically acceptable salts thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -, wherein R ^Y1 is hydrogen. In some embodiments is a compound of formula (Ir 1), or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, CH (Et) ₂、CH₂CH₂OMe、CH₂CH₂SO₂ Me or CH ₂CF₃. In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each phenyl. In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each benzyl. In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently Wherein R ^Z1 is hydrogen or alkyl. In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independentlyWherein R ^Z1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or CH (Et) ₂. In some embodiments are compounds of formula (Ir 1) or a pharmaceutically acceptable salt thereof, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independently

In some embodiments is a compound of formula (Ir 1), or a pharmaceutically acceptable salt thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Is):

Wherein R ¹ is hydrogen or methoxy and R ¹⁵ is alkyl, heteroalkyl, cycloalkyl, aryl or heteroaryl, each of which is unsubstituted or substituted with one or more R ^B.

In some embodiments are compounds of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is alkyl. In some embodiments are compounds of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (Is) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl. In some embodiments are compounds of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is cycloalkyl. In some embodiments are compounds of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is cyclopropyl. In some embodiments are compounds of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is heteroalkyl. In some embodiments are compounds of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is-CH [ CH (Me) ₂]NH₂. In some embodiments a compound of formula (I) or (Is) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is- (CH ₂)_qCO₂ H, wherein q Is 1,2,3, 4,5, or 6, in some embodiments a compound of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is phenyl, in some embodiments a compound of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl, in some embodiments a compound of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is methyl, ethyl, isopropyl, or tert-butyl, in some embodiments a compound of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is 2-pyridyl, 3-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁵ Is methyl, ethyl, isopropyl, or tert-butyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R3462 Is methyl or a pharmaceutically acceptable salt or solvate thereof, and in some embodiments a pharmaceutically acceptable salt or solvate thereof, R Is a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or use thereof, of R35, or a pharmaceutically acceptable salt or use thereof.

In some embodiments Is a compound of formula (I) or (Is), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound Is:

in some embodiments is a compound of formula (I) having the structure of formula (It):

Wherein R ¹ is hydrogen or methoxy and R ¹³ is alkyl, cycloalkyl, heterocyclylalkyl, aryl or heteroaryl, each of which is unsubstituted or substituted with one or more R ^B.

In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is alkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is unsubstituted alkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is methyl, ethyl, isopropyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is cycloalkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is heteroalkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is-CH ₂CH₂OMe、CH₂CH₂SO₂ Me or CH2CH ₂NMe₂. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is (CH 2) _uCO₂ H, wherein u is 1, 2, 3, 4, 5, or 6. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is aryl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is phenyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is heteroaryl. In some embodiments is a compound of formula (I) or (It) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is heterocyclylalkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is oxetan-3-yl or azetidin-3-yl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is

In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein R ^B1 is hydrogen or alkyl and Z ¹ is-O-, -S-; -S (O) -, -S (O) ₂ -, or-N (R ^C1) -, wherein R ^C1 is hydrogen, alkyl, acetyl or benzoyl. In some embodiments are compounds of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein R ^C1 is alkyl. In some embodiments are compounds of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein R ^C1 is methyl, acetyl or benzoyl. In some embodiments are compounds of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is

In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein Y ¹、Y² or Y ³ are each independently-O-, -S-, -S (O) -, -S (O) ₂ -, or-N (R ^B2) -, wherein each R ^B2 is independently hydrogen, alkyl, acetyl or benzoyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein R ^B2 is alkyl. In some embodiments are compounds of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein R ^B2 is unsubstituted alkyl. In some embodiments are compounds of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ isWherein each R ^B2 is independently methyl, acetyl, or benzoyl. In some embodiments are compounds of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is

In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is-CH ₂CH₂R^B3, wherein R ^B3 is heteroaryl or heterocyclylalkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is-CH ₂CH₂R^B3, wherein R ^B3 is heterocyclylalkyl. In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is-CH ₂CH₂R^B3, wherein R ^B3 is

In some embodiments is a compound of formula (I) or (It), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

In some embodiments are compounds of formula (I) having the structure of formula (Iu), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy;

R ²⁰ and R ²¹ are each independently hydrogen, alkyl, cycloalkyl, aryl, heterocyclylalkyl or heteroaryl, wherein alkyl, cycloalkyl, aryl, heterocyclylalkyl and heteroaryl are each independently unsubstituted or substituted with one or more R ^B or R ²⁰ and R ²¹ together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^B.

In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is alkyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is unsubstituted alkyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is hydrogen. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is methyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is hydrogen. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^A1 is methyl, ethyl, isopropyl, -CH (Et) ₂, or tert-butyl.

In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each alkyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently unsubstituted alkyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methyl-1-butyl, n-pentyl, or n-hexyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each benzyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independentlyIn some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each phenyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently cycloalkyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently heteroaryl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, or 4-pyrimidinyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, R ²⁰ is hydrogen and R ²¹ is alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.

In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently alkyl or cycloalkyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently unsubstituted alkyl and R ^A1 is hydrogen. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each independently unsubstituted alkyl and R ¹ is methyl. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each tert-butyl, R ^A1 is hydrogen and R ¹ is methoxy. In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein R ²⁰ and R ²¹ are each tert-butyl, R ^A1 is hydrogen and R ¹ is hydrogen.

In some embodiments is a compound of formula (Iu), or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

in some embodiments is a compound of formula (I) having the structure of formula (Iv):

Wherein:

r ¹ is hydrogen or methoxy;

R ⁹ and R ¹⁰ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently 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 that is unsubstituted or substituted with one or more R ^A; and

R ¹¹ and R ¹² are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A or R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A.

In some embodiments are compounds of formula (Iv) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A. In some embodiments are compounds of formula (Iv) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹ and R ¹² are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one or more R ^A. In some embodiments is a compound of formula (Iv) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹、R¹⁰、R¹¹ and R ¹² are each independently alkyl, cycloalkyl, or hydrogen, wherein each alkyl and cycloalkyl is independently unsubstituted or substituted with one or more R ^A. In some embodiments is a compound of formula (Iv) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹、R¹⁰、R¹¹ and R ¹² are each independently hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl or n-butyl. In some embodiments is a compound of formula (Iv) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹、R¹⁰、R¹¹ and R ¹² are each methyl.

In some embodiments is a compound of formula (Iv) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

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

Wherein:

r ¹ is hydrogen or methoxy;

P is 1, 2, 3,4, 5, 6, 7, 8, 9 or 10.

In some embodiments is a compound of formula (Iw) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ^A1 and R ^A2 is independently hydrogen, alkyl, or cycloalkyl. In some embodiments is a compound of formula (Iw) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ^A1 and R ^A2 is independently hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl. In some embodiments is a compound of formula (Iw) or a pharmaceutically acceptable salt or solvate thereof, wherein each R ^A1 and R ^A2 is independently hydrogen.

In some embodiments is a compound of formula (Iw) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ^A3 is-C (O) OR ¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴ OR-C (O) R ¹⁴. In some embodiments is a compound of formula (Iw) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ^A3 is-C (O) OR ¹³. In some embodiments is a compound of formula (Iw) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ^A3 is-C (O) OR ¹³, wherein R ¹³ is hydrogen OR alkyl, which is unsubstituted OR substituted with one OR more R ^B. In some embodiments is a compound of formula (Iw) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ^A3 is-C (O) OR ¹³, wherein R ¹³ is hydrogen OR unsubstituted alkyl. In some embodiments is a compound of formula (Iw) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ^A3 is-C (O) OR ¹³, wherein R ¹³ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, OR tert-butyl. In some embodiments is a compound of formula (Iw) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ^A3 is-C (O) OR ¹³, wherein R ¹³ is hydrogen OR tert-butyl.

In some embodiments is a compound of formula (Iw) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1,2, 3,4, or 5. In some embodiments is a compound of formula (Iw) or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2, 3,4, or 5.

In some embodiments is a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw), or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy. In some embodiments is a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw), or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen.

In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is hydrogen or alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is hydrogen. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is unsubstituted alkyl.

In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen or unsubstituted alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is hydrogen. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁵ is unsubstituted alkyl.

In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶. In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁵ is hydrogen or alkyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁵ is hydrogen or unsubstituted alkyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH ₂OC(O)R⁶, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is alkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is alkyl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is heteroalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is alkyl, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is heteroalkyl, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)R⁶, wherein R ⁶ is arylalkyl substituted heterocyclylalkyl.

In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶. In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH ₂OC(O)OR⁶. In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶), wherein R ⁵ is alkyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁵ is hydrogen or unsubstituted alkyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is heteroalkyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is alkyl, heteroalkyl, cycloalkyl, or heterocyclylalkyl, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is alkyl, cycloalkyl, or heterocyclylalkyl, heteroalkyl or arylalkyl substituted heterocyclylalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is unsubstituted heteroalkyl, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted heterocyclylalkyl, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is a heterocyclylalkyl substituted with alkyl, heteroalkyl, or arylalkyl), in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) OCH (R ⁵)OC(O)OR⁶, wherein R ⁶ is unsubstituted heterocycloalkyl.

In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰. In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ and R ¹⁰ are each independently an alkyl group, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ and R ¹⁰ are each independently an unsubstituted alkyl group, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (H) R ¹⁰, wherein R ¹⁰ is an alkyl group, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ and R3494 are each independently an unsubstituted alkyl group, in some embodiments a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ and R ¹⁰ are each independently alkyl substituted with-N (R ¹⁸)R¹⁹ OR-C (O) OR ¹³, in some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is unsubstituted alkyl and R ¹⁰ is alkyl substituted with-N (R ¹⁸)R¹⁹ OR-C (O) OR ¹³, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (H) R ¹⁰, wherein R ¹⁰ is alkyl substituted with-N (R ¹⁸)R¹⁹ OR-C (O) OR ¹³, in some embodiments is a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is alkyl and R ¹⁰ is alkyl substituted with-N (R ¹⁰), wherein R ¹⁰ and R ¹⁰ are each alkyl, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ¹⁰ is-C (O) N (R ¹⁰, wherein R ¹⁰ is alkyl and R ¹⁰ is alkyl substituted with-N (R ¹⁰), wherein R ¹⁸ and R ¹⁹ are each unsubstituted alkyl. In some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is unsubstituted alkyl and R ¹⁰ is alkyl substituted with-N (R ¹⁸)R¹⁹), wherein R ¹⁸ and R ¹⁹ are each unsubstituted alkyl, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (H) R ¹⁰, wherein R ¹⁰ is alkyl substituted with-N (R ¹⁸)R¹⁹), wherein R ¹⁸ and R ¹⁹ are each unsubstituted alkyl, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ is alkyl and R ¹⁰ is alkyl substituted by-C (O) OR ¹³, wherein R ¹³ is alkyl OR hydrogen, in some embodiments is a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ is alkyl and R ¹⁰ is alkyl substituted by-C (O) OR ¹³, wherein R ¹³ is unsubstituted alkyl OR hydrogen, in some embodiments is a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) N (H) R ¹⁰, wherein R ¹⁰ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is unsubstituted alkyl OR hydrogen. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ and R ¹⁰ are each independently alkyl substituted with-C (O) OH, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is alkyl and R ¹⁰ is alkyl substituted with-C (O) OH, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is C (O) N (H) R ¹⁰, wherein R ¹⁰ is alkyl substituted with-C (O) OH.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ¹⁰ is alkyl or heteroalkyl, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ is hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl or unsubstituted heteroalkyl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with a heteroalkyl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with heterocyclylalkyl. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with cycloalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with an unsubstituted heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with an unsubstituted heterocycloalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is C (O) N (R ⁹)R¹⁰, each of which is hydrogen, aryl, heteroaryl, alkyl or heteroaryl, each of which is substituted with an unsubstituted heterocycloalkyl, wherein R3998 is hydrogen, aryl, N (R3998) or a pharmaceutically acceptable salt or solvate thereof, each of which is substituted with a heteroalkyl group. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with a heterocyclylalkyl group, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with a cycloalkyl group, which is substituted with an alkyl group, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰), wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with-OC (O) R ¹⁵, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each of which is substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, alkyl, aryl or heteroaryl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, aryl, heteroaryl, alkyl or heteroalkyl, each substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is hydrogen, unsubstituted alkyl, unsubstituted aryl or unsubstituted heteroaryl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, alkyl, cycloalkyl, or heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is alkyl or heteroalkyl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is alkyl or heteroalkyl, each of which is substituted with-N (R ¹³)C(O)R¹⁴, wherein R ¹³ and R ¹⁴ are each independently hydrogen, aryl, heteroaryl, alkyl, or heteroalkyl, in some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is alkyl or heteroalkyl, each of which is substituted with-C (O) N (R ¹⁸)R¹⁹), wherein R ¹⁸ and R ¹⁹ are each independently hydrogen, aryl, heteroaryl, alkyl or heteroalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is alkyl or heteroalkyl, each of which is substituted with-N (R ¹³)C(O)R¹⁴, wherein R ¹³ and R ¹⁴ are each independently hydrogen, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl or unsubstituted heteroalkyl.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, alkyl, cycloalkyl or heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl or unsubstituted heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is cycloalkyl substituted with-N (R ¹⁸)R¹⁹), wherein R ¹⁸ and R ¹⁹ are each hydrogen, alkyl, heteroalkyl, or cycloalkyl, in some embodiments are compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is cycloalkyl substituted with-N (R ¹⁸)R¹⁹), wherein R ¹⁸ and R ¹⁹ are each hydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, or unsubstituted cycloalkyl, wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form an unsubstituted heterocyclylalkyl ring.

In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, alkyl, cycloalkyl, or heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ⁹ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, or unsubstituted heteroalkyl, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) N (R ⁹)R¹⁰, wherein R ¹⁰ is alkyl substituted with-OC (O) N (R ¹⁸)R¹⁹), wherein R ¹⁸ and R ¹⁹ together with the atom to which they are attached form a heteroaryl ring or a heterocyclylalkyl ring, each substituted with alkyl, heteroalkyl, or cycloalkyl.

In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl, heteroalkyl, heterocyclylalkyl or cycloalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocyclylalkyl, or unsubstituted cycloalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl substituted with aryl or arylalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl substituted with aryl, heterocyclylalkyl or arylalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl substituted with heterocyclylalkyl.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-C (O) OR ¹³. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen, alkyl, cycloalkyl, aryl, OR heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, OR unsubstituted heteroaryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl, cycloalkyl, heteroaryl, or heterocyclylalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, or unsubstituted heterocyclylalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is heterocycloalkyl substituted with alkyl. In some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-N (R ¹³)C(O)R¹⁴), wherein R ¹³ is alkyl, cycloalkyl OR hydrogen, and R ¹⁴ is alkyl, aryl OR heteroaryl, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-N (R ¹³)C(O)R¹⁴), wherein R ¹³ is unsubstituted alkyl, unsubstituted cycloalkyl OR hydrogen, and R ¹⁴ is unsubstituted alkyl, unsubstituted aryl OR unsubstituted heteroaryl, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is alkyl substituted with-NH 42, in some embodiments a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R4395 is unsubstituted alkyl, unsubstituted aryl OR unsubstituted heteroaryl, wherein R43969 is unsubstituted alkyl, unsubstituted aryl OR a pharmaceutically acceptable salt OR solvate thereof, wherein R5343 is a pharmaceutically acceptable salt OR solvate thereof, wherein R5352 is substituted with-C (O) OR a pharmaceutically acceptable salt OR solvate thereof, wherein the aryl is substituted with alkyl OR-OC (O) OR ¹⁶, wherein R ¹⁶ is alkyl, heteroalkyl, cycloalkyl, aryl, OR heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is substituted alkylaryl, wherein the aryl is substituted with alkyl OR-OC (O) OR ¹⁶, wherein R ¹⁶ is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted aryl, OR unsubstituted heteroaryl.

In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl substituted with C (O) R ¹⁴. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is alkyl, heteroalkyl, cycloalkyl, or aryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-C (O) R ⁴, wherein R ⁴ is heterocyclylalkyl substituted with C (O) R ¹⁴, wherein R ¹⁴ is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, or unsubstituted aryl.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-P (O) OR ¹¹(OR¹²) OR CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ is hydrogen and R ¹² is 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 are compounds of formula (I) OR a pharmaceutically acceptable salt thereof, wherein R ² is-P (O) OR ¹¹(OR¹²) OR CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ is hydrogen and R ¹² is alkyl, unsubstituted OR substituted with one OR more R ^A.

In some embodiments are compounds of formula (I) or (Iu) or a pharmaceutically acceptable salt thereof, wherein R ²⁰ is hydrogen and R ²¹ is 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 ^B or R ²⁰ and R ²¹ together with the atom to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^B. In some embodiments are compounds of formula (I) or (Iu), or a pharmaceutically acceptable salt thereof, wherein R ²⁰ is hydrogen and R ²¹ is alkyl, unsubstituted or substituted with one or more R ^B.

In some embodiments a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is-CH (R ⁵)OC(O)OR⁶ in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is-CH (R ⁵)OC(O)OR⁶, wherein R ⁵ and R ⁶ are each independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl and heteroaryl is independently unsubstituted or substituted with one or more R ^A, in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is-CH (R ⁵)OC(O)OR⁶, wherein R ⁵ and R ⁶ are each independently hydrogen or alkyl, which is unsubstituted or substituted with one or more R ^A in some embodiments a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² is-CH (R ⁵)OC(O)OR⁶), wherein R42 is hydrogen or a tert-butyl compound of formula (R5332), wherein R42 is unsubstituted or substituted with one or more R ^A is n-butyl, R53 is n-butyl, R52 is n-butyl, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen and R ⁶ is ethyl.

In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²). In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ⁵ is hydrogen, alkyl, cycloalkyl or heteroalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ⁵ is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroalkyl, or substituted alkylheteroaryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each independently selected from alkyl, cycloalkyl, aryl, heteroaryl, or alkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each independently selected from unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl, or alkyl substituted with aryl or heteroaryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is alkyl, cycloalkyl, heterocyclylalkyl, aryl or heteroaryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocyclylalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein each R ¹⁵ is heterocyclylalkyl substituted with alkyl or arylalkyl.

In some embodiments, a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR⁸[N(R⁹)R¹⁰ ]. In some embodiments, a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR⁸[N(R⁹)R¹⁰ ], wherein R ⁵ is hydrogen, alkyl, cycloalkyl, heteroalkyl, OR an alkyl substituted with heteroaryl; R ⁹ is hydrogen and R ¹² is alkyl substituted with-C (O) OR ¹³ in some embodiments is a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR⁸[N(R⁹)R¹⁰) wherein R ⁸ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkyl or alkyl substituted by aryl or heteroaryl; r ⁹ is hydrogen; and R ¹² is alkyl substituted with-C (O) OR ¹³. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³ is alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-CH (R ⁵)OP(O)OR⁸[N(R⁹)R¹⁰ ], wherein R ¹² is alkyl substituted with-C (O) OR ¹³, wherein R ¹³ is unsubstituted alkyl.

In some embodiments is a compound of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹². In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each unsubstituted alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-C (O) OR ¹³. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹³ is alkyl, cycloalkyl, aryl OR heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹³ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, OR unsubstituted heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is alkyl, cycloalkyl, heteroaryl, OR heterocyclylalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, OR unsubstituted heterocyclylalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) R ¹⁵, wherein R ¹⁵ is heterocyclylalkyl substituted with alkyl OR arylalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) OR ¹⁶, wherein R ¹⁶ is alkyl, cycloalkyl, heteroaryl, OR heterocyclylalkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² are each alkyl substituted with-OC (O) OR ¹⁶, wherein R ¹⁶ is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heteroaryl, OR unsubstituted heterocyclylalkyl.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² together with the atom to which they are attached form an unsubstituted heterocyclylalkyl ring. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring substituted with aryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring substituted with unsubstituted aryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ¹¹(OR¹²), wherein R ¹¹ and R ¹² together with the atom to which they are attached form a heterocyclylalkyl ring substituted with an aryl group, wherein the aryl group is substituted with a halogen.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ]. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ], wherein R ⁸ is alkyl, aryl OR heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ], wherein R ⁸ is unsubstituted alkyl, unsubstituted aryl, OR unsubstituted heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ], wherein R ⁹ and R ¹⁰ are each independently selected from hydrogen OR alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ], wherein R ⁸ is unsubstituted alkyl, unsubstituted aryl, OR unsubstituted heteroaryl, R ⁹ is hydrogen and R ¹⁰ is alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ], wherein R ⁸ is unsubstituted alkyl, unsubstituted aryl, OR unsubstituted heteroaryl, R ⁹ is hydrogen and R ¹⁰ is alkyl substituted with-C (O) R ¹⁴. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-P (O) OR ⁸[N(R⁹)R¹⁰ ], wherein R ¹⁰ is alkyl substituted with-C (O) R ¹⁴, wherein R ¹⁴ is hydrogen OR alkyl. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹⁴ is unsubstituted alkyl.

In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-S (O) ₂OR⁷. In some embodiments is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-S (O) ₂OR⁷, wherein R ⁷ is alkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-S (O) ₂OR⁷, wherein R ⁷ is alkyl substituted with-C (O) R ¹⁴. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ is alkyl substituted with-C (O) R ¹⁴, wherein R ¹⁴ is alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-S (O) ₂OR⁷, wherein R ⁷ is alkyl substituted with-C (O) R ¹⁴. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ is alkyl substituted with-C (O) R ¹⁴, wherein R ¹⁴ is heterocyclylalkyl. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is-S (O) ₂OR⁷, wherein R ⁷ is alkyl substituted with-C (O) R ¹⁴. In some embodiments are compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁷ is alkyl substituted with-C (O) R ¹⁴, wherein R ¹⁴ is heterocyclylalkyl substituted with alkyl, -C (O) CH ₃, or C (O) Ph.

In some embodiments is a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. In some embodiments is a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw) or a pharmaceutically acceptable salt thereof, wherein R ¹ is methoxy.

In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with-OP (O) OR ²⁰(OR²¹). In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with-OP (O) OR ²⁰(OR²¹), wherein R ²⁰ and R ²¹ are each independently alkyl, cycloalkyl, aryl, heterocyclylalkyl, OR heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with-OP (O) OR ²⁰(OR²¹), wherein R ²⁰ and R ²¹ are each independently alkyl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with-OP (O) OR ²⁰(OR²¹), wherein R ²⁰ and R ²¹ are each independently unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted heterocycloalkyl, OR unsubstituted heteroaryl. In some embodiments are compounds of formula (I) OR a pharmaceutically acceptable salt OR solvate thereof, wherein R ² is-C (O) OR ³, wherein R ³ is alkyl substituted with-OP (O) OR ²⁰(OR²¹), wherein R ²⁰ and R ²¹ are each independently unsubstituted alkyl.

The pharmaceutical compositions of the invention may comprise any of the racemic, non-racemic or diastereoisomerically enriched mixtures of compounds comprising a stereogenic center described herein.

Selected compounds of the invention and corresponding simplified molecular linear input system (SMILES) strings are provided in table 1.

TABLE 1

* The SMILES string is provided for all the corresponding free bases of the compounds in salt form.

In some embodiments, the compounds described herein are selected from the compounds of table 1.

In some embodiments, the compounds described herein are selected from the compounds of table 1A below.

TABLE 1A

A method of treatment.

In another aspect, the invention provides a method for treating or preventing a disease, disorder, or condition that would benefit from increased levels of a tryptamine hallucinogen, such as DMT, comprising administering to a subject in need thereof an effective amount of a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw), or a pharmaceutically acceptable salt thereof. In some embodiments, the condition includes post-traumatic stress disorder, major depressive disorder, schizophrenia, alzheimer's disease (alzheimer's disease), frontotemporal dementia, parkinson's disease (parkinsons disease), dementia of parkinson's disease (parkinsons dementia), dementia with lewy bodies (lewy body dementia), multiple system atrophy, or substance abuse. In some embodiments, the condition comprises a musculoskeletal pain disorder, including muscle fiber pain, muscle pain, joint stiffness, osteoarthritis, rheumatoid arthritis, muscle spasms. In some embodiments, the invention provides methods for treating female reproductive health disorders, including 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., steroidogenic modulation or modulation of a biological target that activates the 5-HT _2A receptor). 5-HT _2A agonism is associated with promotion of neuroplasticity. The 5-HT _2A antagonists abrogate neurite and myelopoiesis of magic compounds, such as DMT, LSD and DOI, which have 5-HT _2A agonist 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 neural plasticity may include, for example, increasing dendritic spine growth, increasing synthesis of synaptic proteins, enhancing synaptic responses, increasing dendritic branching complexity, increasing dendritic branching content, increasing spinal cord generation, increasing neurite generation, or any combination thereof. In some embodiments, the increase in neuroplasticity comprises an increase in 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-magic. In some embodiments, a non-fanciful 5-HT _2A modulator (e.g., a 5-HT _2A agonist) is used to treat a neurological disorder, which does not cause dissociative side effects. In some embodiments, the magic potential of the compounds described herein is assessed in vitro. In some embodiments, the in vitro assessed in vitro in the compound of the present invention is the magic potential and in vitro assessed in vitro of the magic homolog of the magic potential. In some embodiments, the compounds described herein have lower in vitro induced magic potential than the magic homologs.

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 invention act 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 beneficial to administer a 5-HT _2A antagonist in combination with a compound of the invention to reduce undesirable 5-HT _2A agonism, such as potential illusion. 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, MDL-11,939, irinotecan (SR-46,349), ketanserin (ketanserin), ritanserin (ritanserin), ataanserin (altanserin), acepromazine (acepromazine), mianserin (mianserin), mirtazapine (mirtazapine), quetiapine (quetiapine), SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin (blonanserin), SB200646, RS102221, nefazodone (nefazodone), MDL-100,907, pinup Mo Fanse (PIMAVANSERIN), flibanserin (flibanserin), nepenterin (nelotanserin) and lorcaserin (lorcaserin). 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 compounds disclosed herein, such as about three or about 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-magic 5-HT2 _A modulator (e.g., a 5-HT2 _A agonist) is used to treat a neurological disorder. In some embodiments, the neurological disease comprises reduced neuroplasticity, reduced cortical structure plasticity, reduced 5-HT _2A receptor content, reduced dendritic branching complexity, reduced dendritic spine loss, reduced dendritic branching content, reduced spinal cord production, reduced neurite production, neurite retraction, or any combination thereof.

In some embodiments, the use of a non-fanciful 5-HT _2A modulator (e.g., a 5-HT _2A agonist) increases 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.

In some embodiments, the compounds herein are provided to the patient at a low dose that is insufficient to produce a discernible illusive effect, but high enough to provide therapeutic benefit. This dose range was predicted to be between 200 μg (microgram) and 2 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, anti-depressive properties, anti-anxiety properties, or combinations thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disorder is an affective or anxiety disorder. In some embodiments, the neurological disorder is migraine, headache (e.g., cluster headache), post Traumatic Stress Disorder (PTSD), anxiety, depression, neurodegenerative disorders, alzheimer's disease, parkinson's disease, psychotic disorders, refractory depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disorder is migraine or cluster headache. In some embodiments, the neurological disorder is a neurodegenerative disorder, alzheimer's disease, or parkinson's disease. In some embodiments, the neurological disorder is a psychotic 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 psychotic disorder, a refractory depression, a 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 invention 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 the 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 alter structure and/or function throughout the life of a subject. During the lifetime of the subject, new neurons may be created and integrated into the central nervous system. Increasing neuronal plasticity may include, but is not limited to, promoting neuronal growth, promoting neurite generation, promoting synapse regeneration, promoting dendrite formation, increasing dendrite branching complexity, increasing dendrite spine density, and increasing excitatory synapses in the brain. In some embodiments, increasing neuronal plasticity includes promoting neuronal growth, promoting neurite generation, promoting synapse regeneration, promoting dendrite formation, increasing dendrite branching complexity, and increasing dendrite density.

In some embodiments, increasing neuronal plasticity by treating a subject with a compound of the invention can treat neurodegenerative disorders, alzheimer's disease, parkinson's disease, psychotic 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 invention provides methods for increasing neuronal plasticity comprising contacting a neuronal cell with a compound of the invention. In some embodiments, increasing neuronal plasticity may improve the brain disorders described herein.

In some embodiments, the compounds disclosed herein are useful for increasing neuronal plasticity and have, for example, anti-addictive properties, anti-depressive properties, anxiolytic properties, or combinations thereof. In some embodiments, the reduced neuronal plasticity is associated with a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is an affective 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., substance 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 for determining the increase in neuronal plasticity caused by administration of any compound of the invention is a phenotypic assay, a dendritic formation assay, a myelopoiesis assay, a synaptogenesis assay, a 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 for determining the magic potential of any of the compounds of the invention is a mouse Head Twitch Response (HTR) assay.

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

In some embodiments, the compounds of the invention are used to treat brain disorders. In some embodiments, the compound has, for example, an anti-addiction property, an anti-depression 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 affective or anxiety disorder. In some embodiments, brain disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, panic disorder, suicidal liability, schizophrenia, and addiction (e.g., substance abuse disorders). In some embodiments, brain disorders include, for example, migraine, addiction (e.g., substance use disorders), depression, and anxiety.

In some embodiments, the invention provides methods for treating a brain disorder 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 disorder, alzheimer's disease, parkinson's disease, a psychotic disorder, 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 disorder, alzheimer's disease, or parkinson's disease. In some embodiments, the brain disorder is a psychotic 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 condition is an alcohol use disorder.

In some embodiments, the method further comprises administering one or more additional therapeutic agents. Non-limiting examples of other therapeutic agents suitable for administration with the compounds of the present invention may include lithium, olanzapine (olanzapine) (reproproxa), quetiapine (cisapride), risperidone (risperidone) (risperidal), aripiprazole (aripiprazole) (An Lifu (abily)), ziprasidone (ziprasidone) (Geodon), clozapine (clozapine) (clozapine)), divalproex sodium (divalproex sodium) (d Paco (Depakote)), lamotrigine (lamotrigine) (risperidone (lamltal)); valproic acid (debark Depakene), carbamazepine carbamazepine (Ai Ketuo (Equetro)), topiramate topiramate (tolmetin (Topamax)), levo-milnacipran levomilnacipran (Fei Sima (Fetzima)), duloxetine (duloxetine) (xinbaita (Cymbalta), yan Tefu (yentrev)), venlafaxine venlafaxine (yinopsis Effexor), sitagland citalopram (campstream Celexa), fluvoxamine fluvoxamine (lan (Luvox)), edepram (escitalopram) (lestopiram (Lexapro)), fluoxetine (fluxetine) (Prozac), paroxetine (paroxetine) (pamil), fluxil (Paxil), sertraline (levofloxacin (Zoloft)), clomipramine (clomipramine) (Annovinci (ANAFRANIL)), amitriptyline (AMITRIPTYLINE) (elaveri), desipramine (desipramine) (norbomine (Norpramin)), imipramine (imipramine) (tofubrain (Tofranil)), nortriptyline (nortriptyline) (pa Mi Le (Pamelor)), phenelzine (phenelzine) (nadir (Nardil)), tranylcypromine (tranylcypromine) (panat (Parnate)), diazepam (diazepam) (fanning (Valium)), alprazolam (alprazolam) (Zan An Nuo (Xanax)) or onazapine (clonazepam) (canola (Kloppin)).

In some embodiments, the other therapeutic agent is a monoamine oxidase inhibitor (MAOI), which may be, for example, moclobemide (moclobemide), carbo Luo Shatong (caroxazone) (Su Luodi (Surodil), themerrill (Timostenil)), bromaromine (brofaromine) (Kang Suola (Consonar)), methylene blue, pirlindol (pirlindole) (piradol (Pirazidol)), mi Nabo lin (minaprine) (Cantor), meta Qu Yinduo (metralindole) (kanzane (Inkazan)), epbemine (eprobemide), tertredol (tetrindole), wild rufin (harmine), peganine (harmaline), al Mi Fuan (amiflamine), befloxalone (befloxatone) (MD-370,503), west Mo Shatong (cimoxatone) (MD-780,515), chromochloride Lei Min (sercore) (CGP-4718-a), ethylsulprine (esuprone), or CX157.

In some embodiments, the other therapeutic agent is phenethylamine, such as 3, 4-methylene-dioxymethyl amphetamine (3, 4-methylene-dioxymethamphetamine; MDMA), and the like. Other co-temperament and interest-potency agents suitable for combination with the compounds of the present invention include, but are not limited to, N-allyl-3, 4-methylenedioxy-amphetamine (MDAL), N-butyl-3, 4-methylenedioxy-amphetamine (MDBU), 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-methylphenethylamine, N-hydroxy-3, 4-methylenedioxy-amphetamine (MDOH), 3, 4-Methylenedioxyphenethylamine (MDPEA), alpha-dimethyl-3, 4-methylenedioxyphenethylamine (PH; 3, 4-methylenedioxyphenethylamine), N-propyl-3, 4-Methylenedioxyphenethylamine (MDA), N-dimethyl-3, 4-methylenedioxyphenethylamine (62), N-dimethyl-3, 4-Methylenedioxyphenethylamine (MDA), 3, 4-methylenedioxy-N-methylenedioxyphenethylamine (62), N-hydroxy-3, 4-methylenedioxy-phenethylamine (MDA), 3, 4-methylenedioxy-dioxy-phenethylamine (MDPEA), alpha-dimethyl-3, 4-methylenedioxyphenethylamine (3, 4-methylenedioxy-p-ethylenedioxy-phenethylamine (MDA), N-2-methyl-dioxy-2-dioxy-p-amine (N-methyl-2-dioxy-2-methyl-dioxy-2-amine), methyl ketone (3, 4-methylenedioxy-N-methylcarbazedone), ethyl ketone (3, 4-methylenedioxy-N-ethylcarbazedone), GHB or gamma hydroxybutyrate or sodium hydroxybutyrate, N-propyl-3, 4-methylenedioxy-amphetamine (MDPR), and the like.

In some embodiments, the compounds of the invention 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, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, sitagliptan, fluvoxamine, edepram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, colazapine, or any combination thereof. Non-limiting examples of standard care therapies for depression are sertraline, fluoxetine, edestin, venlafaxine or aripiprazole. Non-limiting examples of standard care therapies for depression are citalopram (citralopram), edestin, fluoxetine, paroxetine, diazepam or sertraline. Other examples of standard-of-care therapeutic agents are known to those of ordinary skill in the art.

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 neurotrophic factors may be useful, for example, increasing neuronal plasticity, promoting neuronal growth, promoting neurite generation, promoting synapse regeneration, promoting dendrite formation, increasing dendrite branching 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 a neurotrophic factor may increase neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of a neurotrophic factor can promote neuronal growth, promote neurite generation, promote synapse regeneration, promote dendritic formation, increase dendritic branching complexity, and/or increase 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 use of a compound of the invention increases the translation, transcription, or secretion of a neurotrophic factor. In some embodiments, increasing the 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 disorders, alzheimer's disease, parkinson's disease, psychotic disorders, refractory depression, suicidal ideation, major depression, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

The increase in translation of the neurotrophic factor can be detected using assays or assays that can include, for example, ELISA, western blot, immunofluorescence assays, proteome experiments, and mass spectrometry. In some embodiments, the assay or assay for detecting an increase in transcription of a neurotrophic factor is a gene expression assay, PCR, or microarray. In some embodiments, the assay or assay for detecting an increase in secretion of a neurotrophic factor is an ELISA, western blot, immunofluorescence assay, proteome assay, or mass spectrometry.

In some embodiments, the invention provides methods for increasing translation, transcription, or secretion of a neurotrophic factor, wherein the methods comprise contacting a neuronal cell with a compound disclosed herein.

Pharmacokinetics.

In another aspect, the invention provides a method for treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw) or a pharmaceutically acceptable salt thereof. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 500nM to about 2500ng/mL about 0.25 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 1400nM to about 2500ng/mL about 0.5 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 1400nM to about 2500ng/mL about 0.75 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 1100nM to about 2500ng/mL about 1 hour after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 600nM to about 2500ng/mL about 2 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 50nM to about 2500ng/mL about 4 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 500nM to about 2500ng/mL about 0.25 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 1400nM to about 1800ng/mL about 0.5 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 1400nM to about 2400ng/mL about 0.75 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 1100nM to about 1600ng/mL about 1 hour after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 600nM to about 1200ng/mL about 2 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of DMT in the subject is about 50nM to about 1000ng/mL about 4 hours after administration. In some embodiments, the administration is oral administration. In some embodiments, the subject is a rat. In some embodiments, the compound is a compound of formula (I). In some embodiments, the subject is a rat. In some embodiments, the compound is a compound of formula (I), wherein R ³ is cycloalkyl or alkyl. In some embodiments, the compound is a compound of formula (I), wherein R ¹ is hydrogen.

In another aspect, the invention provides a method for treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I)、(Ia)、(Ib)、(Ib-1)、(Ib1)、(Ic)、(Id)、(Ie)、(If)、(If1)、(Ig)、(Ih)、(Ii)、(Ij)、(Ik)、(Ik1)、(Ik2)、(Ik3)、(Il)、(Im)、(Im1)、(Im1a)、(In)、(In1)、(Io)、(Io1)、(Io2)、(Io1a)、(Ip)、(Ip1)、(Iq)、(Iq1)、(Ir)、(Ir1)、(Is)、(It)、(Iu)、(Iv) or (Iw) or a pharmaceutically acceptable salt thereof. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 50nM to about 300ng/mL about 0.25 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 100nM to about 300ng/mL about 0.5 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 100nM to about 300ng/mL about 0.75 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 100nM to about 300ng/mL about 1 hour after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 30nM to about 300ng/mL about 2 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 1nM to about 300ng/mL about 4 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 50nM to about 150ng/mL about 0.25 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 100nM to about 300ng/mL about 0.5 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 100nM to about 200ng/mL about 0.75 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 100nM to about 250ng/mL about 1 hour after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 30nM to about 100ng/mL about 2 hours after administration. In some embodiments, for a dose of about 10mg/kg administered, the plasma concentration of 5-OMe-DMT in the subject is about 1nM to about 200ng/mL about 4 hours after administration. In some embodiments, the administration is oral administration. In some embodiments, the subject is a rat. In some embodiments, the compound is a compound of formula (I). In some embodiments, the subject is a rat. In some embodiments, the compound is a compound of formula (I), wherein R ³ is cycloalkyl or alkyl. In some embodiments, the compound is a compound of formula (I), wherein R ¹ is methoxy.

Examples

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

Example 1: the selected compounds and intermediates are prepared.

The following methods of preparation of the compounds and intermediates are provided to enable those skilled in the art to more clearly understand and practice the invention. It should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Abbreviations (abbreviations)

App appearance

Boc carbamic acid tert-butyl ester

Boc-Sar-OH Boc-sarcosine

Br broad peak

CDCl ₃ d₃ -chloroform

D double peak

Dd double peak

DCM dichloromethane

DIPEA diisopropylethylamine

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

HATU hexafluorophosphoric acid 3-oxidized 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridine

HCl hydrochloric acid

H six-fold peak (hextet/sextet)

Hr or hrs hours

HPLC high pressure liquid chromatography

LC-MS liquid chromatography and mass spectrometry

MeOH MeOH

MeCN acetonitrile

MS mass spectrum

M multiple peaks

Min(s) min

ML of

Mu L microliters

Mass to charge ratio of m/z

P five-peak

Q quartet

NaHCO ₃ sodium bicarbonate

Na ₂SO₄ sodium sulfate

NMP N-methyl-2-pyrrolidone

NMR nuclear magnetic resonance

Rt retention time

S single peak

Sar sarcosine

T triplet

Tert-tert

THF tetrahydrofuran

The compounds of the preferred embodiments are synthesized using the methods described herein or other methods known in the art with reference to the following examples. The various starting materials, intermediates and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Salts can 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:

And (5) NMR analysis.

¹H、¹³C、¹⁹ F and ³¹ P NMR analyses were performed on a Bruker ^TM Avance 400MHz NMR spectrometer using deuterated chloroform or deuterated dimethyl sulfoxide as solvent. The offset (d) of each signal was measured in parts per million (ppm) relative to the residual solvent peak and the multiplicity was reported with the associated coupling constant (J) as appropriate.

UPLC-MS analysis method.

The UPLC-MS analysis was performed with a Waters ^TM Acquity UPLC system consisting of an Acquity I sample manager-FL, an Acquity I binary solvent manager, and an Acquity UPLC column manager. UV detection was performed using an Acquity UPLC PDA detector (scanning from 210 to 400 nm) while mass detection was performed using a Acquity QDa detector (scanning from 100-1250Da mass; both in cationic and anionic mode) and ELS detection was performed using an Acquity UPLC ELS detector. Analytes were separated using Waters ^TM Acquity UPLC BEH C column (2.1X105 mm,1.7 mm).

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

Conditions (acidic, 2 min).

Water containing 0.1% v/v formic acid [ eluent a ]; meCN [ eluent B ] containing 0.1% v/v formic acid; 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 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 (acidic, 4 min).

Water containing 0.1% v/v formic acid [ eluent a ]; meCN [ eluent B ] containing 0.1% v/v formic acid; 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 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 (acidic, 6 min).

Water containing 0.1% v/v formic acid [ eluent a ]; meCN [ eluent B ] containing 0.1% v/v formic acid; 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 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% Aqueous ammonia [ eluent a ]; meCN with 0.1% ammonia [ 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% Aqueous ammonia [ eluent a ]; meCN with 0.1% ammonia [ 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% Aqueous ammonia [ eluent a ]; meCN with 0.1% ammonia [ 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 1-1: di-methyl primary amine (DMT)

A4% sulfuric acid solution (0.16M, 0.82mL,15.3 mmol) was heated to 55deg.C and purged with nitrogen. To the heated acidic solution was added phenylhydrazine (1.50 g,13.9 mmol) followed by dropwise addition of 4, 4-dimethoxy-N, N-dimethyl-butan-1-amine (2.46 g,15.3 mmol) while maintaining 55 ℃. The resulting solution was heated to reflux for 2 hours and then cooled to room temperature. To the crude reaction mixture was slowly added a solution of NaOH (10 g) in H ₂ O (50 mL) followed by extraction with EtOAc (3 times). The organic phases were combined, washed with brine, dried over Na ₂SO₄, filtered and concentrated to dryness under reduced pressure to give an orange oil (2.1 g). The crude oil was purified by silica gel column chromatography (40 g cartridge, 5-20% meoh/acetone) to give 2- (1H-indol-3-yl) -N, N-dimethyl-ethylamine (1.46 g,53% yield) as a solid ).¹H NMR(400MHz,d₆-DMSO)δ10.77(s,1H),7.51(ddt,J＝7.9,1.5,0.9Hz,1H),7.33(dt,J＝8.1,1.0Hz,1H),7.16-7.12(m,1H),7.06(ddd,J＝8.2,7.0,1.2Hz,1H),6.97(ddd,J＝7.9,7.0,1.1Hz,1H),2.86-2.77(m,2H),2.55-2.50(m,2H),2.23(s,6H).

Examples 1-2: 5-Methoxydimethyl-primary amine (5-MeO-DMT)

To a solution of magnetically stirred 4-methoxyphenylhydrazine hydrochloride (2.00 g,11.5 mmol) in water (20 mL) at room temperature under an atmosphere of N ₂ was added dropwise H ₂SO₄ (0.67 mL,12.6 mmol) while maintaining the temperature below 40 ℃. The solution was heated to 40 ℃ and stirred for 10 minutes. A mixture of 4, 4-dimethoxy-N, N-dimethyl-butan-1-amine (2.20 mL,12.0 mmol) in acetonitrile (10 mL) was added dropwise. The reaction was stirred at 40 ℃ for 1 hour. Acetonitrile was removed under reduced pressure and the resulting aqueous solution was washed with 2-MeTHF (2X 30 mL). The aqueous phase was treated with NaOH (4M,9.00mL,1.60g NaOH) to adjust the pH to about 11-12, and the product was extracted with 2-MeTHF (3X 30 mL). The organic phases were combined and concentrated under reduced pressure to give a brown oil which was then purified by silica gel column chromatography (20 g cartridge, 1-10% meoh/acetone) to give 2- (5-methoxy-1H-indol-3-yl) -N, N-dimethyl-ethylamine (1.70 g,68% yield) as an oil. UPLC-MS (4 min, alkaline): rt=1.12 min; m/z=219.2 [ m+h ] ⁺;rt＝1.12min;m/z＝219.2[M+H]⁺; two peaks identical product ;¹HNMR(400MHz,CDCl₃)δ7.97(s,1H),7.29(dd,J＝4.8,1.4Hz,1H),7.09(d,J＝2.4Hz,1H),7.04(d,J＝2.3Hz,1H),6.89(dt,J＝8.8,1.9Hz,1H),3.90(s,3H),2.99-2.90(m,2H),2.72-2.61(m,2H),2.38(s,6H).

Examples 1-3:3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid ethyl ester (Compound 20)

To a stirred solution of DMT (2- (1H-indol-3-yl) -N, N-dimethyl-ethylamine, 99mg,0.53 mmol) in THF (10 mL) at-78deg.C was added sodium bis (trimethylsilyl) amide (2.0M solution in THF, 0.53mL,1.05 mmol). The resulting solution was stirred at-78 ℃ for 15 minutes. Ethyl chloroformate (101 μl,1.05 mmol) was added dropwise and stirred at-78 ℃ for an additional 5 minutes. The reaction mixture was warmed to room temperature and then stirred for 18 hours. Saturated brine and EtOAc were added sequentially. The organic phase was separated and the aqueous phase was extracted with EtOAc (2 times). The organic phases were combined, washed with brine, dried over Na ₂SO₄, filtered and evaporated to give an orange oil. The crude oil was purified by silica gel column chromatography (4 g,0 to 20% methanol/dichloromethane) to give compound 20 (3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid ethyl ester, 77mg,56% yield) as an oil. UPLC-MS (4 min, alkaline) ):rt＝1.84min;m/z＝261.0[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ8.00(d,J＝8.2Hz,1H),7.39(ddd,J＝7.8,1.4,0.8Hz,1H),7.28(s,1H),7.18(ddd,J＝8.3,7.2,1.4Hz,1H),7.15-7.06(m,1H),4.32(q,J＝7.1Hz,2H),2.79-2.69(m,2H),2.59-2.46(m,2H),2.21(s,6H),1.31(t,J＝7.1Hz,3H);¹³C NMR(101MHz,CDCl₃)δ151.0,135.6,130.6,124.6,122.7,122.3,119.4,119.0,115.3,77.4,77.0,76.7,63.0,59.2,45.4,23.3,14.5.

Examples 1 to 4:3- [2- (dimethylamino) ethyl ] -5-methoxy-indole-1-carboxylic acid ethyl ester (compound 19).

To a stirred solution of 5-MeO DMT (2- (5-methoxy-1H-indol-3-yl) -N, N-dimethyl-ethylamine, 200mg,0.92 mmol) in THF (10 mL) at-78deg.C was added sodium bis (trimethylsilyl) amide (2.0M solution in THF, 0.69mL,1.37 mmol). The resulting solution was stirred at-78 ℃ for 15 minutes. Ethyl chloroformate (180 μl,1.83 mmol) was added dropwise and stirred at-78 ℃ for an additional 5 minutes. The reaction mixture was warmed to room temperature and then stirred for 18 hours. The reaction mixture was then diluted with EtOAc (10 mL), washed with H ₂ O (10 mL) and extracted a second time with EtOAc (10 mL). The combined organic phases were washed with brine (10 mL), dried over Na ₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (10 g, 50-100% etoac/heptane with 1% tea, over 10CV, then 100% ethyl acetate with 1% tea, 10 CV) to give compound 19 (3- [2- (dimethylamino) ethyl ] -5-methoxy-indole-1-carboxylic acid ethyl ester, 115mg,43% yield) as an oil. UPLC-MS (4 min, alkaline) ):rt＝1.79min;m/z＝291.2[M+H]⁺;100％.¹H NMR(400MHz,CDCl₃)δ8.03(s,1H),7.41(s,1H),6.99(d,J＝2.4Hz,1H),6.93(dd,J＝9.0,2.5Hz,1H),4.45(q,J＝7.1Hz,2H),3.87(s,3H),2.88-2.78(m,2H),2.67-2.58(m,2H),2.33(s,6H),1.45(t,J＝7.1Hz,3H).

Examples 1 to 5:2- (1-Diisopropoxyphosphoryl indol-3-yl) -N, N-dimethyl-ethylamine (Compound 263)

To a stirred solution of DMT (2- (1H-indol-3-yl) -N, N-dimethyl-ethylamine, 200mg,1.06 mmol) in THF (10 mL) at-78deg.C was added sodium bis (trimethylsilyl) amide (1.0M solution in THF, 1.6mL,1.59 mmol). The mixture was stirred at-78 ℃ for 15 minutes, and then 2- [ chloro (isopropyl) phosphoryl ] oxypropane (0.100 ml,0.6 mmol) was added. The mixture was warmed to room temperature, stirred for 20 hours and concentrated under reduced pressure. The resulting residue was first purified by silica gel column chromatography (12g Si,5CV DCM+1%TEA,10CV% isopropyl alcohol in dcm+1% tea,20cv 10% isopropyl alcohol in dcm+1% tea) and then further purified by preparative HPLC to give compound 263 (2- (1-diisopropyloxyphosphoryl indol-3-yl) -N, N-dimethyl-ethylamine, 123mg,33% yield) as an oil. UPLC-MS (4 min, alkaline) ):rt＝1.88min,m/z＝353.3[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.71(dt,J＝8.2,0.9Hz,1H),7.57(dtd,J＝7.5,1.6,0.7Hz,1H),7.28(dd,J＝7.1,1.3Hz,1H),7.25-7.19(m,2H),4.63(dp,J＝7.5,6.2Hz,2H),2.92-2.86(m,2H),2.68-2.60(m,2H),2.33(s,6H),1.41(d,J＝6.2Hz,6H),1.10(d,J＝6.2Hz,6H);³¹P NMR(162MHz,CDCl₃)δ-5.27(t,J＝7.7Hz).

Examples 1 to 6:2- (1-diisopropyloxyphosphoryl-5-methoxy-indol-3-yl) -N, N-dimethyl-ethylamine (compound 255).

To a stirred solution of 5-MeO DMT (2- (5-methoxy-1H-indol-3-yl) -N, N-dimethyl-ethylamine, 228mg,1.04 mmol) in THF (10 mL) at-78deg.C was added sodium bis (trimethylsilyl) amide (1.0M solution in THF, 1.6mL,1.57 mmol), and the mixture was stirred at-78deg.C for 15 min. 2- [ chloro (isopropyl) phosphoryl ] oxypropane (0.37 mL,2.1 mmol) was then added and the mixture was warmed to room temperature. The mixture was stirred at temperature for 20 hours, quenched with isopropanol (5 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (12g Si,5CV DCM+1%TEA,10CV% isopropanol in dcm+1% tea,20cv 10% isopropanol in dcm+1% tea) and then further purified by preparative HPLC to give compound 255 (2- (1-diisopropyloxyphosphoryl-5-methoxy-indol-3-yl) -N, N-dimethyl-ethylamine, 65mg,16% yield) as an oil. UPLC-MS (4 min, alkaline) ):rt＝1.82min,m/z＝383.3[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝8.9Hz,1H),7.24(dt,J＝2.2,1.1Hz,1H),7.00(t,J＝2.0Hz,1H),6.90(dd,J＝8.9,2.5Hz,1H),4.61(dhept,J＝7.5,6.2Hz,2H),3.86(s,3H),2.89-2.81(m,2H),2.67-2.58(m,2H),2.34(s,6H),1.40(d,J＝6.2Hz,6H),1.10(d,J＝6.2Hz,6H).

Examples 1 to 7: tert-butyl [3- [2- (dimethylamino) ethyl ] indol-1-yl ] methyl hydrogen (compound 511)

To a stirred solution of DMT (2- (1H-indol-3-yl) -N, N-dimethyl-ethylamine, 150mg,0.8 mmol) in DMSO (3 mL) was added K ₂CO₃, no. 325 sieve (440 mg,3.2 mmol) at room temperature. The mixture was stirred at room temperature for 15 min, followed by the addition of di-tert-butylchloromethyl phosphate (412 mg,1.59 mmol) and stirring of the mixture for 17 h. H ₂ O (2 mL) was then added and the mixture was stirred at room temperature for 21 hours. The resulting crude mixture was purified by reverse phase column chromatography (23 g, gradient of 10-50% mecn/water with 0.1% nh ₄ OH) to give compound 511 ([ 3- [2- (dimethylamino) ethyl ] indol-1-yl ] methylphosphonic acid tert-butyl ester, 219mg,78% yield) as a solid. UPLC-MS (2 min, alkaline) ):rt＝0.74min,m/z＝355.1[M+H]⁺;¹H NMR(400MHz,d₆-DMSO)δ7.68(dt,J＝7.9,1.1Hz,1H),7.54(dt,J＝8.3,0.9Hz,1H),7.33(s,1H),7.18(ddd,J＝8.2,7.0,1.2Hz,1H),7.13-6.98(m,1H),6.49(s,1H),4.86(dd,J＝8.9,3.4Hz,2H),3.55-3.41(m,2H),3.33(s,6H),3.18(td,J＝8.0,3.1Hz,2H),3.08(d,J＝1.8Hz,6H),1.31(d,J＝0.8Hz,9H);³¹P NMR(162MHz,d₆-DMSO)δ-6.09(q,J＝8.8Hz).

Examples 1 to 8: [3- [2- (dimethylamino) ethyl ] -5-methoxy-indol-1-yl ] methyl hydrogen phosphate tert-butyl ester (Compound 510)

To a stirred solution of 5-MeO DMT (2- (5-methoxy-1H-indol-3-yl) -N, N-dimethyl-ethylamine, 150mg,0.69 mmol) in DMSO (3 mL) was added K ₂CO₃, sieve No. 325 (380 mg,2.75 mmol) at room temperature. The mixture was stirred at room temperature for 15 minutes, and then chloromethyl bis (2-methyl-2-propanyl) phosphate (356 mg,1.37 mmol) was added. The resulting mixture was stirred at room temperature for 17 hours, then H ₂ O (2 mL) was added and the mixture was stirred at room temperature for an additional 21 hours. The mixture was purified by reverse phase column chromatography (C18, 23g,10-50% mecn/H ₂ O with 0.1% nh ₄ OH) to give compound 510 ([ 3- [2- (dimethylamino) ethyl ] -5-methoxy-indol-1-yl ] phosphate tert-butyl ester, 195mg,74% yield) as a solid. UPLC-MS (2 min, alkaline) ):rt＝0.75min,m/z＝385.2[M+H]⁺;¹H NMR(400MHz,d₆-DMSO)δ7.44-7.14(m,3H),6.83-6.70(m,1H),5.41(s,1H),4.85(d,J＝9.0Hz,2H),3.80(d,J＝5.4Hz,3H),3.50-3.41(m,2H),3.14(d,J＝8.5Hz,2H),3.07(s,6H),1.30(s,9H);³¹P NMR(162MHz,d₆-DMSO)δ-5.99(q,J＝8.8Hz).

Examples 1 to 9:3- [2- (dimethylamino) ethyl ] -6-methoxy-indole-1-carboxylic acid isobutyl ester (Compound 517)

To a stirred solution of 5-OMe-DMT (200 mg,0.92 mmol) in THF (10 mL) at-78deg.C was added NaHMDS (1M in THF, 1.4mL,1.4 mmol). The mixture was stirred at-78 ℃ for 15 minutes, then isobutyl chloroformate (0.24 ml,1.83 mmol) was added. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was diluted with EtOAc (10 mL), washed with H ₂ O (10 mL), brine (10 mL), dried over Na ₂SO₄, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (12 g cartridge) with a gradient elution of EtOAc (50% to 100%; v/v)/hexane (with 1% net ₃) to give 3- [2- (dimethylamino) ethyl ] -6-methoxy-indole-1-carboxylic acid isobutyl ester (compound 517, 56mg,19% yield) as an oil. UPLC-MS (4 min, alkaline) ):rt＝2.17min,m/z＝319.1[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.96(s,1H),7.34(s,1H),6.92(d,J＝2.5Hz,1H),6.87(dd,J＝9.0,2.5Hz,1H),4.12(d,J＝6.6Hz,2H),3.80(s,3H),2.81-2.72(m,2H),2.60-2.51(m,2H),2.27(s,6H),2.15-2.00(m,1H),0.98(d,J＝6.7Hz,6H).

The following compounds were prepared by a similar method to that described for 3- [2- (dimethylamino) ethyl ] -6-methoxy-indole-1-carboxylic acid isobutyl ester (compound 517)

^a After chromatography, further purification was performed using reverse phase chromatography (C18, 23g cartridge) with a gradient elution of MeCN (0.1% NEt ₃/formic acid) (5% to 98%; v/v)/water (0.1% NEt ₃/formic acid)

Examples 1 to 10:1- [3- [2- (dimethylamino) ethyl ] indol-1-yl ] ethanone (Compound 119)

To a stirred solution of DMT (378 mg,2.0 mmol) in THF (10 mL) at-78deg.C was added NaHMDS (1M solution in THF, 3.0mL,3.0 mmol). The mixture was stirred at-78deg.C for 15min, then AcCl (0.29 mL,4.0 mmol) was added. The mixture was warmed to room temperature and stirred overnight, then diluted with EtOAc (10 mL), washed with H ₂ O (10 mL), brine (10 mL), dried over Na ₂SO₄, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4 g cartridge) with a gradient of MeOH/DCM (0-10%) to give 1- [3- [2- (dimethylamino) ethyl ] indol-1-yl ] ethanone as an oil (compound 119, 52mg,11% yield). UPLC-MS analysis (4 min, alkaline ):rt＝1.51min,m/z＝231.1[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ8.34(d,J＝8.0Hz,1H),7.51-7.41(m,1H),7.28(ddd,J＝8.3,7.2,1.4Hz,1H),7.21(td,J＝7.5,1.1Hz,1H),7.19(s,1H),2.85-2.76(m,2H),2.58(dd,J＝8.9,6.8Hz,2H),2.54(s,3H),2.27(s,6H).

The following compound was prepared by a similar method to that described for isobutyl- [3- [2- (dimethylamino) ethyl ] indol-1-yl ] ethanone (compound 119)

Examples 1 to 11:3- [2- (dimethylamino) ethyl ] -N, N-dimethyl-indole-1-carboxamide (Compound 525)

To a stirred solution of DMT (145 mg,0.77 mmol) in THF (10 mL) at-78deg.C was added NaHMDS (1M solution in THF, 1.2mL,1.2 mmol). The mixture was stirred at-78 ℃ for 15 minutes, then dimethylcarbamoyl chloride (166 mg,1.54 mmol) was added. The mixture was warmed to room temperature and stirred overnight, then diluted with EtOAc (10 mL), washed with H ₂ O (3×10 mL), dried over Na ₂SO₄, filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4 g, cartridge) with a gradient elution of MeOH (0% to 10%; v/v)/DCM to give 3- [2- (dimethylamino) ethyl ] -N, N-dimethyl-indole-1-carboxamide as an oil (compound 525, 59mg,30% yield). UPLC-MS analysis (4 min, alkaline ):rt＝1.85min,m/z＝305.1[M+H]⁺;¹H NMR(400MHz,CDCl₃)δ7.61(t,J＝7.6Hz,2H),7.32(t,J＝7.7Hz,1H),7.28(s,1H),7.26-7.21(m,1H),3.34(dd,J＝10.3,5.8Hz,2H),3.22(dd,J＝10.2,5.9Hz,2H),3.09(s,6H),2.81(s,6H).

Repeated experiments were further purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid. The combined fractions were concentrated and lyophilized to give 3- (2- (dimethylamino) ethyl) -N, N-dimethyl-1H-indole-1-carboxamide (94 mg) as an oil. LC-MS (+ve mode) ):m/z＝260.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.43(s,1H,HCO),7.53(m,2H,2×ArH),7.20(m,3H,3×ArH),3.11(m,4H,2×CH₂),3.02(s,6H,2×NMe),2.67(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ167.7,154.9,135.8,128.5,142.1,121.9,118.7,114.2,113.8,57.6,43.0,38.5,21.0.

Examples 1 to 12: formic acid 3- (2- (dimethylamino) ethyl) -5-methoxy-N, N-dimethyl-1H-indole-1-carboxamide (compound 526)

To a solution of 5-OMe-DMT (115 mg,0.53 mmol) in THF (8 mL) at-78 ℃ under an atmosphere of N ₂ was added NaHMDS (1M in THF, 1.06mL,1.06 mmol) and the mixture was stirred at-78 ℃ for 30 min, then dimethylcarbamoyl chloride (110 mg,97 μl,1.06 mmol) was added. The mixture was stirred at-78 ℃ for 20 minutes, then warmed to room temperature and stirred overnight. H ₂ O (1 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0 to 50% meoh/EtOAc (containing 0.1% et ₃ N) and then further purified by reverse phase HPLC eluting with 0 to 100% acetonitrile/0.1% formic acid to give 3- (2- (dimethylamino) ethyl) -5-methoxy-N, N-dimethyl-1H-indole-1-carboxamide as an oil (compound 526, 118mg, 66%). LC-MS (+ve mode): m/z=290.15 [ M+H ] ⁺;¹H NMR(300MHz,CDCl₃) δ8.43 (s, 1H, formate salt) ),7.51(d,J＝9.0Hz,1H,ArH),7.12(s,1H,ArH),7.06(d,J＝2.4Hz,1H,ArH),6.87(dd,J＝9.0,2.5Hz,1H,ArH),3.82(s,3H,OMe),3.13(s,4H,2×CH₂),3.07(s,6H,2×NMe),2.66(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ167.7,155.5,155.0,130.7,129.3,124.6,114.6,114.0,113.3,101.2,57.4,56.0,43.0,38.5,21.1.

Examples 1 to 13: di-formic acid [1,4 '-bipiperidine ] -1' -yl (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanone (compound 527)

To a solution of DMT (146 mg,0.78 mmol) in THF (10 mL) at-78deg.C under N ₂ was added NaHMDS (1M in THF, 3.1mL,3.1 mmol) and the mixture was stirred at-78deg.C for 30 min. 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (414 mg,1.55 mmol) was added and the mixture was stirred at-78℃for 20min, then warmed to room temperature and stirred overnight. H ₂ O (2 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give bis-formic acid [1,4 '-bipiperidin ] -1' -yl (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanone (compound 527, 255mg, 69%) as a semi-solid. LC-MS (+ve mode): m/z=383.25 [ M+H ] ⁺;¹H NMR(300MHz,DMSO-d₆) δ8.26 (s, 2H,2 Xformate) ),7.62(m,2H,2×ArH),7.38(s,1H,ArH),7.27(m,1H,ArH),7.17(m,1H,ArH),3.94(m,2H,CH₂),3.60(m,1H,CH),3.06(t,J＝12.5Hz,2H,CH₂),2.89(m,2H,CH₂),2.76(m,2H,CH₂),2.61(m,6H,3x CH₂),2.38(s,6H,2×NMe),1.54(br,6H,3x CH₂),1.42(br,4H,2x CH₂);¹³C NMR(75.5MHz,DMSO-d₆)δ164.6,153.5,135.8,129.4,124.7,123.8,121.7,119.5,116.5,113.7,61.9,58.6,50.0,46.0,44.7,27.8,26.0,24.5,22.2.

Examples 1 to 14: di-formic acid [1,4 '-bipiperidine ] -1' -yl (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanone (compound 528)

To a mixture of 5-methoxy-N, N-dimethyltryptamine (169 mg,0.78 mmol) in THF (10 mL) at-78deg.C under N ₂ atmosphere was added NaHMDS (1M in THF, 3.1mL,3.1 mmol) and the mixture was stirred at-78deg.C for 30 min. 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride (414 mg,1.55 mmol) was added and the mixture was stirred at-78℃for 20min, then warmed to room temperature and stirred overnight. H ₂ O (2 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give bis-formic acid [1,4 '-bipiperidin ] -1' -yl (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methyl (compound 528, 311mg, 62%) as a semi-solid. LC-MS (+ve mode): m/z=413.30 [ M+H ] ⁺;¹H NMR(300MHz,DMSO-d₆) δ8.25 (s, 2H,2 Xformate) ),7.51(d,J＝8.9Hz,1H,ArH),7.33(s,1H,ArH),7.10(d,J＝2.5Hz,1H,ArH),6.88(dd,J＝8.9,2.5Hz,1H,ArH),3.92(m,2H,CH₂),3.80(s,3H,OMe),3.02(t,J＝12.5Hz,2H,CH₂),2.87(m,2H,CH₂),2.78(m,2H,CH₂),2.63(m,4H,2×CH₂),2.40(s,6H,2×NMe),1.82(d,J＝12.6Hz,2H,CH₂),1.47(m,8H,4x CH₂);¹³C NMR(75.5MHz,DMSO-d₆)δ164.6,155.2,153.7,130.6,130.1,125.2,116.3,114.6,113.0,102.0,61.9,58.3,55.9,50.0,46.0,44.5,27.8,25.9,25.0,22.1.

Examples 1 to 15: acetic acid 2- (4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-methyl-4-oxobutan-2-yl) -3, 5-dimethylphenyl ester (compound 413)

Step 1: acetic acid 2- (4-chloro-2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene ester

Oxalyl chloride (268 mg,0.18mL,2.12 mmol) was added to a mixture of 3- (2-acetoxy-4, 6-dimethylphenyl) -3-methylbutanoic acid (0.56 g,2.12 mmol) in DCM (2.1 mL) under an atmosphere of N ₂ at 0deg.C. The mixture was warmed to room temperature and stirred for 2 hours 45 minutes, then concentrated under reduced pressure to give 2- (4-chloro-2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene ester of acetic acid as an oil, which was used directly in the next step.

Step 2: acetic acid 2- (4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene ester

To a solution of DMT (100 mg,0.53 mmol) in THF (10 mL) at-78deg.C under N ₂ was added NaHMDS (1M in THF, 1.06mL,1.06 mmol) and the mixture was stirred at-78deg.C for 30 min. 2- (4-chloro-2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene ester acetate solution (1M in THF, 1.06mL,1.06 mmol) was added and the mixture stirred at-78℃for 20 min, then warmed to room temperature and stirred overnight. H ₂ O (2 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by reverse phase HPLC eluting with 0 to 100% acetonitrile/0.1% formic acid to give the product (56 mg). Another batch was prepared on the same scale, yielding 79mg of material.

The combined material from batches 1 and 2 (135 mg) was purified by silica gel column chromatography (MeOH/EtOAc (0.1% triethylamine), 0:1 to 1) to give 2- (4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene ester as an oil (compound 413, 67mg,15%, based on both batches). LC-MS (+ve mode) ):m/z＝435.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.41(d,J＝7.8Hz,1H,ArH),7.50(m,1H,ArH),7.28(m,3H,3×ArH),6.83(d,J＝2.1Hz,1H,ArH),6.55(d,J＝2.0Hz,1H,ArH),3.41(s,2H,CH₂),2.91(m,2H,CH₂),2.69(m,2H,CH₂),2.55(s,3H,COMe),2.41(s,6H,2×NMe),2.24(s,3H,ArMe),2.19(s,3H,ArMe),1.67(s,6H,2×CMe);¹³C NMR(75.5MHz,CDCl₃)δ170.0,169.3,149.2,138.0,136.3,136.0,133.9,132.7,130.3,125.1,123.3,123.1,122.0,119.6,118.6,117.0,60.4,58.9,45.1,39.2,31.6,25.6,23.0,21.8,20.3,17.7.

Examples 1 to 16:2- (4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2-methyl-4-oxobutan-2-yl) -3, 5-dimethylphenyl (compound 405)

Compound 405 was prepared using a procedure similar to that in examples 1-15 of compound 413 to give compound as a semi-solid (71 mg,14% yield). LC-MS (+ve mode) ):m/z＝465.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.21(d,J＝9.0Hz,1H,ArH),7.19(s,1H,ArH),6.96(d,J＝2.4Hz,1H,ArH),6.90(dd,J＝9.0,2.4Hz,1H,ArH),6.81(br.s,1H,ArH),6.56(br.s,1H,ArH),3.86(s,3H,OMe),3.37(s,2H,CH₂),2.86(m,2H,CH₂),2.66(m,2H,CH₂),2.53(s,3H,COMe),2.40(s,6H,2×NMe),2.22(s,3H,ArMe),2.20(s,3H,ArMe),1.67(s,6H,2×CMe);¹³C NMR(75.5MHz,CDCl₃)δ170.0,169.0,156.3,149.3,138.0,136.3,133.9,132.7,130.7,123.1,122.6,113.0,101.8,58.8,55.8,45.1,39.2,31.6,25.6,21.8,20.3.

Examples 1 to 17:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 2-methoxyethyl ester formate (Compound 25)

To a solution of DMT (100 mg,0.53 mmol) in THF (8 mL) at-78deg.C under N ₂ was added NaHMDS (1M in THF, 1.06mL,1.06 mmol) and the mixture was stirred at-78deg.C for 30 min. 2-methoxyethyl chloroformate (147 mg, 123. Mu.L, 1.06 mmol) was added, and the mixture was stirred at-78℃for 20 minutes, then warmed to room temperature and stirred for 2 hours. H ₂ O (2 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by reverse phase HPLC eluting with 0 to 100% acetonitrile/0.1% formic acid to give the product (45 mg). Another batch was prepared on the same scale, yielding 40mg of material.

The materials from runs 1 and 2 (85 mg) were combined to give 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 2-methoxyethyl formate (compound 25, 81mg, 23%) as an oil. LC-MS (+ve mode) ):m/z＝291.15[M+H]⁺;¹H NMR(300MHz CDCl₃)δ8.49(s,1H,HCO),8.18(d,J＝8.1Hz,1H,ArH),7.57(m,1H,ArH),7.49(s,1H,ArH),7.35(m,1H,ArH),7.30(m,1H,ArH),4.56(m,2H,CH₂),3.76(m,2H,CH₂),3.42(s,3H,OMe),3.09(m,4H,2×CH₂),2.68(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ167.7,129.8,125.1,123.1,122.9,118.8,117.1,115.5,70.3,65.9,59.1,57.4,43.2,21.2.

Examples 1 to 18:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 2-methoxyethyl ester formate (Compound 22)

Compound 22 was prepared using a procedure similar to that of examples 1-17 of compound 25. The materials from runs 1 and 2 (127 mg) were combined and the resulting material purified by silica gel column chromatography (MeOH/EtOAc (0.1% triethylamine), 0:1 to 1:1) to give 2-methoxyethyl 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylate (compound 22, 51mg, 15%) as a semi-solid. LC-MS (+ve mode) ):m/z＝321.10[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.04(d,J＝9.0Hz,1H,ArH),7.42(s,1H,ArH),7.00(d,J＝2.4Hz,1H,ArH),6.94(dd,J＝9.0,2.5Hz,1H,ArH),4.54(m,2H,CH₂),3.87(s,3H,ArOMe),3.75(m,2H,CH₂),3.44(s,3H,OMe),2.87(m,2H,CH₂),2.67(m,2H,CH₂),2.38(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ158.7,156.1,131.5,123.0,123.0,119.3,116.1,113.0,102.0,70.4,65.7,59.0,59.0,55.8,45.3,23.3.

Examples 1 to 19:4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -4-oxobutanoic acid formate salt (Compound 529)

To a mixture of DMT (100 mg,0.53 mmol) in THF (5 mL) at-78deg.C was added NaHMDS (1M in THF, 1.06mL,0.56 mmol) and the mixture was stirred for 30 min. Succinic anhydride (106 mg,1.06 mmol) was added and the resulting mixture was stirred at-78 ℃ for 30 minutes, then warmed to room temperature and stirred for 16 hours. H ₂ O (1 mL) was added and the mixture concentrated under reduced pressure. The residue was purified by preparative HPLC using H ₂ O (0.1% formic acid)/30% acetonitrile to give compound 529 (50 mg, 32%) as a solid. LC-MS (+ve mode) ):m/z＝289.10[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.42(s,1H,HCO),8.37(m,1H,ArH),7.62(m,1H,ArH),7.30(m,2H,2×ArH),3.45(m,2H,CH₂),3.15(m,2H,CH₂),2.93(s,6H,2×NMe),2.71(t,J＝6.8Hz,2H,CH₂);¹³C NMR(75.5MHz,CD₃OD)δ171.2,154.0,129.6,125.0,123.3,123.3,118.3,116.3,116.2,56.6,42.2,30.9,29.4,20.1.

Examples 1 to 20:4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -4-oxobutanoic acid (Compound 530)

Compound 530 was prepared using procedures analogous to those of examples 1-19 of compound 529, obtained as a solid (121 mg, 76%). LC-MS (+ve mode): m/z=319.10 [ M+H ] ⁺;¹H NMR(300MHz,DMSO-d₆) δ8.20 (m, 2H, HCO and ArH)7.73(s,1H,ArH),7.11(d,J＝2.8Hz,1H,ArH),6.92(dd,J＝8.8,2.8Hz,1H,ArH),3.82(s,3H,OMe),3.19(m,2H,CH₂)2.83(m,2H,CH₂),2.65(m,4H,2×CH₂),2.30(s,6H,2×NMe).

Examples 1 to 21:5- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -5-oxopentanoic acid (Compound 531)

Compound 531 was prepared using a procedure similar to that of examples 1-19 of compound 529, affording compound as an oil (53 mg, 29%). LC-MS (+ve mode) ):m/z＝303.10[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.43(dd,J＝6.9,1.4Hz,1H ArH),8.39(s,1H,HCO),7.77(s,1H,ArH),7.66(dd,J＝6.9,2.0,1H,ArH),7.35(m,2H,2×ArH),3.51(m,2H,CH₂),3.22(m,2H,CH₂),3.06(m,2H,CH₂),2.97(s,6H,2×NMe),2.47(m,2H,CH₂),2.10(m,2H,CH₂);¹³C NMR(75.5MHz,CD₃OD)δ176.4,171.6,166.6,136.0,129.6,125.1,123.4,123.3,118.2,116.3,106.3,56.6,42.1,34.4,33.1,20.1,20.1.

Examples 1 to 22:5- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -5-oxopentanoic acid (Compound 532)

Compound 532 was prepared using procedures similar to those of examples 1-19 of compound 529 to give as an oil (64 mg, 36%). LC-MS (+ve mode) ):m/z＝333.10[M+H]⁺;¹H NMR(300MHz,DMSO-d₆)δ8.24(s,1H,HCO),8.20(br,1H,ArH),7.69(s,1H,ArH),7.12(d,J＝2.4Hz,1H,ArH),6.92(dd,J＝9.0,2.4Hz,1H,ArH),3.80(s,3H,OMe),2.99(t,J＝7.2Hz,2H,CH₂),2.83(m,2H,CH₂),2.73(m,2H,CH₂),2.36(m,7H,2×NMe+CH₂),1.90(m,2H,CH₂).

Examples 1 to 23:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid (pivaloyloxy) methyl ester (Compound 369)

NaHMDS (1M in THF, 1.33mL,1.33 mmol) was added to a solution of 5-OMe-DMT (145 mg,0.67 mmol) in THF (5 mL) at-78deg.C and stirred for 30 min. Chlorocarbonyl-oxy-methyl 2, 2-dimethylpropionate (129 mg,0.67 mmol) was added and the resulting mixture was stirred at-78 ℃ for 30 minutes, then warmed to room temperature and stirred for 16 hours. H ₂ O (1 mL) was added and the mixture concentrated under reduced pressure. The residue was purified successively by column chromatography on silica gel eluting with MeOH (0.1% et ₃N)/EtOAc(0.1％Et₃ N) and preparative-HPLC using a gradient of H ₂ O/acetonitrile to give compound 369 (46 mg, 17%) as a solid. LC-MS (+ve mode) ):m/z＝377.20[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.87(br.s,1H,ArH),7.33(s,1H,ArH),6.98(d,J＝2.5Hz,1H,ArH),6.84(dd,J＝8.8,2.5Hz,1H,ArH),5.92(s,2H,CH₂),3.75(s,3H,OMe),2.78(m,2H,CH₂),2.78(m,2H,CH₂),2.26(s,6H,2×NMe),1.12(s,9H,^tBu);¹³C NMR(75.5MHz,CD₃OD)δ177.0,131.5,122.5,120.0,115.5,112.9,101.7,80.9,58.3,54.7,43.9,38.4,29.4,25.8,22.3.

Examples 1 to 24:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid (pivaloyloxy) methyl ester diformate (Compound 337)

NaHMDS (1M in THF, 5.5mL,5.5 mmol) was added to a solution of DMT (0.52 g,2.75 mmol) in anhydrous THF (40 mL) at-78deg.C and stirred for 30 min. Chlorocarbonyloxymethyl 2, 2-dimethylpropionate (0.54 g,2.75 mmol) was added and the mixture was stirred at-78 ℃ for 30min, then warmed to room temperature and stirred for 16 h. The mixture was concentrated to a semi-solid, purified by silica gel column chromatography eluting with a gradient of MeOH (0.1% et ₃N)/EtOAc(0.1％Et₃ N), then purified by reverse phase chromatography using a gradient of H ₂ O (0.1% formic acid)/acetonitrile to give compound 337 (211 mg, 19%) as a solid. LC-MS (+ve mode) ):m/z＝347.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.44(s,1H,HCO₂H),8.13(d,J＝7.8Hz,1H,ArH),7.65(m,2H,2×ArH),7.36(m,2H,2×ArH),6.05(s,2H,CH₂),3.43(m,2H,CH₂),3.17(m,2H,CH₂),2.92(s,6H,2×NMe),1.12(s,9H,^tBu);¹³C NMR(75MHz,CD₃OD)δ177.0,167.7,135.6,129.8,125.0,123.3,123.0,118.7,116.8,115.0,81.0,56.5,42.1,38.4,25.8,20.0.

Examples 1 to 25:4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -4-oxobutanoic acid methyl ester (Compound 533)

To a stirred solution of DMT (200 mg,1.06 mmol) in THF (5 mL) was added NaHMDS (1M in THF, 1.12mL,1.12 mmol) at-78deg.C. After 30 minutes, the resulting mixture was added dropwise to O-methylsuccinyl chloride [ CAS number: 1490-25-1] (163 mg,1.08 mmol) and the mixture was stirred at room temperature for 16 hours. EtOAc (30 mL) was added and the mixture was washed with saturated aqueous NaHCO ₃ (50 mL) and brine (50 mL). The organic layer was dried (MgSO ₄), filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (gradient elution with MeOH/CH ₂Cl₂) to give methyl 4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -4-oxobutanoate (100 mg, 34%) as a solid. LC-MS (+ve mode) ):m/z＝303.10[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.41(d,J＝7.8Hz,1H,ArH),7.54(d,J＝7.8Hz,1H,ArH),7.33(m,3H,3×ArH),3.73(s,3H,OMe),3.25(t,J＝9.3Hz,2H,CH₂),2.87(m,4H,2×CH₂),2.65(m,2H,CH₂),2.35(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ173.0,169.5,130.7,129.2,125.4,125.4,123.6,121.3,119.0,116.8,59.3,52.2,45.6,30.8,28.5,23.6.

Examples 1 to 26:4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -4-oxobutanoic acid methyl ester (Compound 534)

Compound 534 was prepared using a procedure similar to examples 1-25 of compound 533, obtained as an oil (54 mg, 31%). LC-MS (+ve mode) ):m/z＝333.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.28(d,J＝8.7Hz,1H,ArH),7.27(s,1H,ArH),6.93(m,2H,2×ArH),3.84(s,3H,OMe),3.71(s,3H,OMe),3.19(t,J＝6.9Hz,2H,CH₂),2.81(m,4H,2×CH₂),2.62(m,2H,CH₂),2.32(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ173.0,169.1,156.5,131.7,130.7,121.9,121.1,117.5,113.2,102.1,59.1,55.8,52.1,45.5,30.5,28.5,23.6.

Examples 1 to 27: (S) - (6- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -6-oxohexane-1, 5-diyl) dicarbamic acid di-tert-butyl ester (Compound 535)

To a stirred solution of DMT (300 mg,1.59 mmol) in THF (5 mL) was added NaHMDS (1M in THF, 1.67mL,1.67 mmol) at-78deg.C. After 30 minutes, boc-lysine- (Boc) -O-succinimide [ CAS number: 30189-36-7] (0.67 g,1.51 mmol) in THF (5 mL) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (elution with a gradient of MeOH/EtOAc) to give di-tert-butyl (S) - (6- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -6-oxohexane-1, 5-diyl) dicarbamate (186 mg, 23%) as a solid. LC-MS (+ve mode) ):m/z＝517.35[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.44(d,J＝8.1Hz,1H,ArH),7.54(dd,J＝7.5,1.8Hz,1H,ArH),7.35(m,3H,3×ArH),5.46(d,J＝9.0Hz,1H,NH),5.05(m,1H,CH),4.62(br.s,1H,NH),3.09(m,2H,CH₂),2.90(t,J＝7.5Hz,2H,CH₂),2.67(t,J＝7.2Hz,2H,CH₂),2.36(s,6H,2×NMe),1.93(m,2H,CH₂),1.75(m,2H,CH₂),1.55(m,2H,CH₂),1.46(s,9H,^tBu),1.42(s,9H,^tBu);¹³C NMR(75.5MHz,CDCl₃)δ170.8,156.2,155.7,136.2,131.0,125.7,124.1,122.0,121.2,119.1,117.0,80.4,77.4,59.0,52.8,45.5,40.3,33.4,28.6,28.5,23.5,22.6.

Examples 1 to 28: (S) - (6- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -6-oxohexane-1, 5-diyl) dicarbamic acid di-tert-butyl ester (Compound 536)

Compound 536 was prepared according to a procedure similar to that provided in examples 1-27 of compound 536 and obtained as a solid (234 mg, 43%). LC-MS (+ve mode) ):m/z＝547.35[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.32(d,J＝8.7Hz,1H,ArH),7.35(s,1H,ArH),6.97(m,2H,2×ArH),5.43(d,J＝8.7Hz,1H,NH),5.01(m,1H,CH),4.62(br.s,1H,NH),3.87(s,3H,OMe),3.10(br.s,2H,CH₂),2.87(t,J＝7.2Hz,2H,CH₂),2.66(t,J＝7.2Hz,2H,CH₂),2.37(s,6H,2×NMe,1.91(m,2H,CH₂),1.74(m,2H,CH₂),1.50(m,2H,CH₂),1.45(s,9H,^tBu),1.42(s,9H,^tBu).

Examples 1 to 29: (S) -2, 6-diamino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) hex-1-one tri-hydrochloride (Compound 537)

TFA (2.05 g,1.38mL,18 mmol) was added to a solution of di-tert-butyl (S) -6- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -6-oxohexane-1, 5-diyl) dicarbamate (compound 535, 186mg,0.36 mmol) in DCM (5 mL) and the mixture stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was azeotroped with CHCl ₃ (4 x 10 mL) and MeOH (10 mL). The residue was dissolved in 1M HCl (2 ml,2 mmol) and the resulting hydrochloride was purified by reverse phase silica gel chromatography eluting with a gradient of MeCN/0.02% HCl _{( Aqueous solution )} to give (S) -2, 6-diamino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) hex-1-one tri-hydrochloride as a solid (compound 537, 102mg, 67%). ESIMS: M/z= 317.20, consistent with the protonated parent ion of the free base [ M+H ] ⁺ ;¹H NMR(300MHz,CD₃OD)δ8.42(dd,J＝6.3,2.4Hz,1H,ArH),7.88(s,1H,ArH),7.70(dd,J＝6.3,2.1Hz,1H,ArH),7.38(m,2H,2×ArH),5.04(m,1H,CH),3.56(m,2H,CH₂),3.24(m,2H,CH₂),2.99(s,6H,2×NMe),2.90(t,J＝7.5Hz,2H,CH₂),2.10(m,2H,CH₂),1.70(m,2H,CH₂),1.53(m,2H,CH₂);¹³C NMR(75.5MHz,CD₃OD)δ169.0,137.4,131.3,127.2,125.9,123.9,120.3,120.2,117.8,57.7,54.0,43.6,40.1,32.1,28.1,22.6,21.4.

Examples 1 to 30: (S) -2, 6-diamino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) hex-1-one tri-hydrochloride (compound 538)

Compound 538 was prepared using a procedure similar to examples 1-29 of compound 537 to give (142 mg, 72%) as a solid. ESIMS: M/z= 347.25, consistent with the protonated parent ion of the free base [ M+H ] ⁺ ;¹H NMR(300MHz,CD₃OD)δ8.32(d,J＝9.0Hz,1H,ArH),7.85(s,1H,ArH),7.20(d,J＝2.7Hz,1H,ArH),7.00(dd,J＝9.3,2.7Hz,1H,ArH),5.01(m,1H,CH),3.88(s,3H,OMe),3.55(m,2H,CH₂),3.22(m,2H,CH₂),3.00(s,6H,2×NMe),2.91(m,2H,CH₂),2.09(m,2H,CH₂),1.70(m,2H,CH₂),1.57(m,2H,CH₂);¹³C NMR(75.5MHz,CD₃OD)δ168.4,159.0,132.5,131.7,124.4,120.3,118.6,115.2,103.3,57.7,56.2,53.8,43.6,40.1,32.2,28.2,22.6,21.4.

Examples 1 to 31: (S) - (1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (Compound 539)

To a stirred solution of DMT (200 mg,1.06 mmol) in anhydrous THF (5 mL) was added NaHMDS (1M in THF, 1.11mL,1.11 mmol) at-78deg.C. After 30 minutes, boc-alanine-O-succinimide (288 mg,1.01 mmol) was added and the mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed and the residue was purified by column chromatography on silica gel eluting first with EtOAc and then with a gradient of MeOH/EtOAc (0.1% et ₃ N) to give compound 539 (222 mg, 65%) as an oil. TLC: R _f = 0.16 (EtOAc-MeOH, 1:1 v/v); LC-MS (+ve mode) ):m/z＝360.20[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.37(d,J＝8.4Hz,1H,ArH),7.47(m,1H,ArH),7.28(m,3H,3×ArH),5.42(d,J＝6.8Hz,1H,NH),5.00(m,1H,CH),2.80(m,2H,CH₂),2.59(m,2H,CH₂),2.28(s,6H,2×NMe,)1.38(s,12H,^tBu,CH₃).

Examples 1 to 32: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) propan-1-one dihydrochloride (compound 540)

TFA (4.07 g,2.72mL,35.6 mmol) was added to a solution of tert-butyl (S) - (1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -1-oxopropan-2-yl) carbamate (compound 539, 256mg,0.71 mmol) in DCM (5 mL) at room temperature and stirring was continued for 4 hours. The mixture was concentrated and azeotroped with CHCl ₃ (4 x 10 mL) and MeOH (10 mL). The residue was dissolved in 1M HCl (2 ml,2 mmol) and purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% HCl _{( Aqueous solution )} to give compound 540 (236 mg, quantitative) as a solid. LC-MS (+ve mode) ):m/z＝260.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.43(m,1H,ArH),7.81(s,1H,ArH),7.71(m,1H,ArH),7.41(m,2H,ArH),4.98(q,J＝7.1Hz,1H,CH),3.55(m,2H,CH₂),3.24(m,2H,CH₂),3.00(s,6H,Hz,2×NMe),1.70(d,J＝7.1Hz,3H,CH₃);¹³C NMR(75.5MHz,CD₃OD)δ168.3,136.0,129.8,125.8,124.5,122.2,118.8,118.7,113.6,56.3,49.0,42.2,20.0,16.2,7.9.

Examples 1 to 33: (S) - (1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (Compound 541)

To a stirred mixture of 5-OMe-DMT (154 mg,71.0 mmol) in dry THF (5 mL) was added NaHMDS (1M in THF, 0.74mL,0.74 mmol) at-78deg.C. After 30 minutes, boc-alanine-O-succinimide (193 mg,0.67 mmol) was added and the mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed and the residue was purified by column chromatography on silica gel eluting first with EtOAc and then with a gradient of MeOH/EtOAc (0.1% et ₃ N) to give compound 541 (132 mg, 47%) as an oil. TLC: R _f = 0.18 (EtOAc-MeOH, 1:1 v/v); LC-MS (+ve mode) ):m/z＝390.20[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.25(d,J＝8.9Hz,1H,ArH),7.27(s,1H,ArH),6.90(m,2H,2×ArH),5.38(d,J＝8.8Hz,1H,NH),5.00(m,1H,CH),3.81(s,3H,OMe),2.82(m,2H,CH₂),2.62(m,2H,CH₂),2.32(s,6H,2×NMe)1.39(s,12H,^tBu,CH₃).

Examples 1 to 34: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) propan-1-one dihydrochloride (compound 542)

TFA (1.88 g,1.26mL,16.5 mmol) was added to a solution of tert-butyl (S) - (1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -1-oxopropan-2-yl) carbamate (compound 541, 132mg,0.33 mmol) in DCM (5 mL) at room temperature and stirring was continued for 4 hours. The mixture was concentrated and azeotroped with CHCl ₃ (4 x10 mL) and MeOH (10 mL). The residue was dissolved in 1M HCl (2 ml,2 mmol) and purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% HCl _{( Aqueous solution )} to give the product as a solid (40 mg, 72%). LC-MS (+ve mode) ):m/z＝290.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.22(d,J＝9.0Hz,1H,ArH),7.76(s,1H,ArH),7.13(d,J＝2.4Hz,1H,ArH),6.92(dd,J＝9.0,2.4Hz,1H,ArH),4.92(m,1H,CH),3.80(s,3H,OMe),3.47(m,2H,CH₂),3.13(m,2H,CH₂),2.91(d,J＝3.0Hz,6H,2×NMe),1.61(d,J＝7.2Hz,3H,CH₃);¹³C NMR(75.5MHz,CD₃OD)δ157.6,131.0,130.4,123.0,118.8,117.1,113.8,102.8,101.9,56.3,54.9,48.9,42.2,42.2,20.1,16.4.

Examples 1 to 35: (S) - (1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester (Compound 543)

To a stirred mixture of DMT (173 mg,0.92 mmol) in dry THF (13 mL) was added NaHMDS (1M in THF, 0.97mL,0.97 mmol) at-78deg.C. After 30 minutes, the resulting mixture was added dropwise to Boc-phenylalanine-OSu (300 mg,0.83 mmol) and stirring was continued at room temperature for 16 hours. The mixture was concentrated to dryness and then dissolved in a mixture of DCM (20 mL) and NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with H ₂ O (2 x 20 mL), brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give compound 543 as a semi-solid (111 mg, 31%). LC-MS (+ve mode) m/z=436.20 [ M+H ] ⁺.

Examples 1 to 36: (S) - (1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester (Compound 544)

To a stirred solution of DMT (173 mg,0.92 mmol) in anhydrous THF (13 mL) was added NaHMDS (1M in THF, 0.97mL,0.97 mmol) at-78deg.C. After 30 minutes, the mixture was added dropwise to Boc-valine-OSu (260 mg,0.83 mmol) and the mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated to dryness and then dissolved in a mixture of DCM (20 mL) and NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with H ₂ O (2 x 20 mL), brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give the product as a semi-solid (245 mg, 76%). LC-MS (+ve mode) ):m/z＝388.20[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.39(d,J＝9.0Hz,1H,ArH),7.53(d,J＝9.0Hz,1H,ArH),7.44(s,1H,ArH),7.30(m,2H,ArH),5.27(d,J＝12.0Hz,1H,NH),4.82(m,1H,CH),3.33(m,4H,2×CH₂),2.87(d,J＝6.0Hz,6H,2×NMe),2.12(m,1H,CH),1.38(s,9H,^tBu),0.98(d,J＝6.0Hz,3H,CH₃),0.89(d,J＝6.0Hz,3H,CH₃).

Examples 1 to 37: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -3-methylbutan-1-one dihydrochloride (compound 545)

Tert-butyl (S) - (1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -3-methyl-1-oxobutan-2-yl) carbamate (compound 544, 245mg,0.63 mmol) is dissolved in DCM (12.5 mL) and TFA (2.42 mL,31.6 mmol) is added at room temperature. The mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure and azeotroped with CHCl ₃ (4 x 10 mL). The residue was purified by column chromatography on silica gel with a gradient elution of MeOH/CH ₂Cl₂. This material was further purified by reverse phase silica gel chromatography eluting first with acetonitrile/0.02% hcl _{( Aqueous solution )} to give compound 545 (85.3 mg, 38%) as a solid. LC-MS (+ve mode) ):m/z＝288.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.31(d,J＝6.0Hz,1H,ArH),7.62(m,2H,2×ArH),7.41(m,2H,2×ArH),4.82(d,J＝6.0Hz,1H,CH),3.46(m,2H,CH₂),3.17(m,2H,CH₂),2.89(d,J＝1.7Hz,6H,2×NMe),2.43(m,1H,CH),1.07(d,J＝9.0Hz,3H,CH₃),0.94(d,J＝9.0Hz,3H,CH₃);¹³C NMR(75.5MHz,CDCl₃)δ168.2,135.6,129.8,126.4,125.1,122.8,119.2,119.0,116.4,57.9,56.3,42.8,42.7,30.2,20.0,18.0,16.0.

Examples 1 to 38: (S) - (1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid tert-butyl ester (Compound 546)

To a stirred solution of 5-OMe-DMT (210 mg,0.92 mmol) in anhydrous THF (13 mL) at-78deg.C was added NaHMDS (1M in THF, 0.97mL,0.97 mmol). After 30 minutes, the mixture was added dropwise to Boc-valine-OSu (260 mg,0.83 mmol) and the mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated to dryness and then dissolved in a mixture of DCM (20 mL) and NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with H ₂ O (2 x 20 mL), brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give an oil. The residue was purified by silica gel column chromatography with a gradient of MeOH/DCM to give compound 546 (216 mg, 56%) as a semi-solid. LC-MS (+ve mode) ):m/z＝418.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.27(d,J＝8.9Hz,1H,ArH),7.30(s,1H,ArH),6.95(d,J＝2.4Hz,1H,ArH),6.89(dd,J＝8.9,2.4Hz,1H,ArH),5.30(d,J＝9.2Hz,1H,CH),4.83(m,1H,CH),3.81(s,3H,OMe),2.82(m,2H,CH₂),2.62(m,2H,CH₂),2.33(s,6H,2×NCH₃),2.13(m,1H,CH),1.38(s,9H,3×CH₃),0.97(d,J＝6.8Hz,3H,CH₃),0.87(d,J＝6.8Hz,3H,CH₃).

Examples 1 to 39: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -3-methylbutan-1-one dihydrochloride (compound 547)

Tert-butyl (S) - (1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -3-methyl-1-oxobutan-2-yl) carbamate (compound 546, 216mg,0.52 mmol) is dissolved in DCM (11 mL) and TFA (2.95 g,1.98mL,25.9 mmol) is added at room temperature. The mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure and azeotroped with CHCl ₃ (4 x 10 mL). The crude residue was purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% hcl _{( Aqueous solution )} to give compound 547 (168 mg, 83%) as an oil. LC-MS (+ve mode) ):m/z＝318.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.20(d,J＝9.0Hz,1H,ArH),7.58(s,1H,ArH),7.11(d,J＝2.4Hz,1H,ArH),7.01(dd,J＝9.0,2.4Hz,1H,ArH),4.78(d,J＝5.1Hz,1H,CH),3.82(s,3H,OMe),3.45(m,2H,CH₂),3.12(m,2H,CH₂),2.89(d,J＝1.8Hz,6H,2×NCH₃),2.41(m,1H,CH),1.05(d,J＝6.9Hz,3H,CH₃),0.94(d,J＝6.9Hz,3H,CH₃);¹³C NMR(75.5MHz,CDCl₃)δ167.7,156.6,131.1,130.3,123.6,118.9,117.4,113.9,102.8,57.7,56.2,55.9,42.7,30.3,20.0,18.0,16.0.

Examples 1 to 40: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -3-phenylpropan-1-one bis-hydrochloride (compound 548)

Tert-butyl (S) - (1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -1-oxo-3-phenylpropan-2-yl) carbamate (compound 543, 111mg,0.25 mmol) was dissolved in DCM (5 mL) and TFA (1.43 g,0.96mL,12.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure and the residue azeotroped with CHCl ₃ (4 x 10 mL). The residue was purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% hydrochloric acid to give compound 548 (40.8 mg, 48%) as a solid. LC-MS (+ve mode ):m/z＝336.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.29(d,J＝6.0Hz,1H,ArH),7.55(d,J＝9.0Hz,1H,ArH),7.40(m,2H,ArH),7.10(m,6H,ArH),5.12(dd,J＝9.0,6.0Hz,1H,CH),3.33(dd,J＝13.8,5.7Hz,1H,0.5×CH₂),3.21(m,3H,0.5×CH₂+CH₂),2.91(m,8H,2×NCH₃ and CH₂);¹³C NMR(75.5MHz,D₂O)δ168.0,135.2,133.5,129.7,129.3,129.1,128.9,128.0,126.3,125.1,122.3,119.1,118.6,116.4,56.3,53.9,42.8,42.6,37.5,19.7.

Examples 1 to 41: (S) - (1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester (Compound 549)

To a stirred solution of 5-OMe-DMT (210 mg,0.96 mmol) in anhydrous THF (13 mL) at-78deg.C was added NaHMDS (1M in THF, 0.97mL,0.97 mmol). After 30 minutes, the resulting mixture was added dropwise to Boc-phenylalanine-OSu (300 mg,0.83 mmol) and stirring was continued at room temperature for 16 hours. The reaction mixture was concentrated to dryness and then dissolved in a mixture of DCM (20 mL) and NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with H ₂ O (2 x 20 mL), brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give a crude oil. The residue was purified by silica gel column chromatography with a gradient of MeOH/DCM to give compound 549 (261 mg, 67%) as a semi-solid. LC-MS (+ve mode) m/z=466.25 [ m+h ] ⁺.

Examples 1 to 42: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -3-phenylpropan-1-one bis-hydrochloride (compound 550)

Tert-butyl (S) - (1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -1-oxo-3-phenylpropan-2-yl) carbamate (compound 549, 261mg,0.56 mmol) was dissolved in DCM (11 mL) and TFA (3.19 g,2.14mL,28.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure and azeotroped with CHCl ₃ (4 x 10 mL). The residue was purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% hydrochloric acid to give compound 550 (244 mg, 83%) as a solid. LC-MS (+ve mode ):m/z＝366.20[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.17(d,J＝9.9Hz,1H,ArH),7.13(m,3H,3×ArH),7.01(m,5H,5×ArH),5.07(dd,J＝9.3,5.7Hz,1H,CH),3.81(s,3H,OMe),3.38(dd,J＝13.5,5.7Hz,1H,0.5×CH₂),3.18(m,3H,0.5×CH₂+CH₂),2.89(m,8H,2×NCH₃ and CH₂);¹³C NMR(75.5MHz,D₂O)δ167.5,164.9,156.6,133.1,131.1,129.9,129.3,128.9,128.0,118.5,117.4,113.7,102.7,56.2,55.8,53.7,42.8,42.6,37.6,36.9,31.3,19.6.

Examples 1 to 43:2- (dimethylamino) -1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) ethan-1-one hydrochloride (compound 551)

To a solution of N, N-dimethyltryptamine (282 mg,1.50 mmol) in anhydrous THF (20 mL) at-78deg.C under an atmosphere of N ₂ was added NaHMDS (1M in THF, 6.0mL,6.0 mmol) and the mixture was stirred at-78deg.C for 30 min. 2- (dimethylamino) acetyl chloride hydrochloride (470 mg,3.00 mmol) was added and the mixture was stirred at-78 ℃ for 5min, then warmed to room temperature and stirred for 4 hours. H ₂ O (3 mL) was added and the mixture was concentrated and the residue was purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.02% hydrochloric acid to give 2- (dimethylamino) -1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) ethan-1-one hydrochloride as a solid (compound 551, 79mg, 17%). LC-MS (+ve mode) ):m/z＝274.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.37(br,1H,ArH),7.73(br,1H,ArH),7.51(m,3H,3×ArH),4.89(s,2H,CH₂),3.56(m,2H,CH₂),3.26(m,2H,CH₂),3.14(s,6H,2×NMe),2.98(s,6H,2×NMe);¹³C NMR(75.5MHz,D₂O)δ163.6,134.9,129.6,126.3,124.9,121.9,121.9,119.3,119.1,59.0,56.4,44.2,42.8,20.0.

Examples 1 to 44:2- (dimethylamino) -1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) ethyl-1-one formate (compound 552)

To a solution of 5-methoxy-N, N-dimethyltryptamine (229 mg,1.05 mmol) in anhydrous THF (12 mL) at-78deg.C under N ₂ atmosphere was added NaHMDS (1M in THF, 5.5mL,5.5 mmol) and the mixture was stirred at-78deg.C for 30 min. 2- (dimethylamino) acetyl chloride hydrochloride (0.67 g,4.2 mmol) was added and the mixture was stirred at-78 ℃ for 10min, then warmed to room temperature and stirred for 3 hours. H ₂ O (2 mL) was added, the mixture was concentrated and the residue was purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give 2- (dimethylamino) -1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) ethan-1-one formate (compound 552, 108mg, 29%) as a solid. LC-MS (+ve mode) ):m/z＝304.15[M+H]⁺;¹H NMR(300MHz,D₂O)δ8.27(br,1H,ArH),7.50(s,1H,ArH),7.21(d,J＝2.5Hz,1H,ArH),7.12(dd,J＝9.0,2.5Hz,1H,ArH),4.87(s,2H,CH₂),3.93(s,3H,OMe),3.55(m,2H,CH₂),3.22(m,2H,CH₂),3.14(s,6H,2×NMe),2.98(s,6H,2×NMe);¹³C NMR(75.5MHz,D₂O)δ163.1,156.5,130.2,122.7,119.0,114.0,110.7,110.0,102.8,56.2,55.9,44.2,43.5,42.8,20.0.

Examples 1 to 45: (S) -2-amino-N- (2- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-oxoethyl) -N-methyl-3-phenylpropionamide (compound 553)

Step 1: (S) -2- (2- ((tert-Butoxycarbonyl) amino) -N-methyl-3-phenylpropionylamino) acetic acid 2, 5-dioxopyrrolidin-1-yl ester

Boc-phenylalanine-N-methyl-glycine [ CAS number: 108787-68-4] (500 mg,1.49 mmol) and N-hydroxysuccinimide (188.5 mg,1.63 mmol) were dissolved in EtOAc (50 mL) and cooled to 0deg.C. Dicyclohexylcarbodiimide (338 mg,1.64 mmol) was added and the mixture was stirred at 0 ℃ for 2 hours, then allowed to come to room temperature and stirred overnight. The mixture was filtered through celite and the filtrate was concentrated to give the product as a solid (766 mg, quantitative) which was used without further purification. LC-MS (+ve mode) m/z=434.15 [ m+h ] ⁺.

Step 2: (S) - (1- ((2- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-oxoethyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester

To a stirred solution of DMT (200 mg,1.06 mmol) in anhydrous THF (5 mL) was added NaHMDS (1M in THF, 1.67mL,1.67 mmol) at-78deg.C. After 30min, a solution of Boc-phenylalanine-N-methyl-glycine-OSu (367 mg,0.85 mmol) in THF (5 mL) was added and the mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give the product as a solid (33 mg, 8%). LC-MS (+ve mode) ):m/z＝507.30[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.32(d,J＝7.8Hz,1H,ArH),7.51(m,1H,ArH),7.32(m,6H,6×ArH),7.00(m,2H,2×ArH),5.56(m,1H,NH),4.90(m,1H,CH),4.61(s,2H,CH₂),3.07(m,6H,3×CH₂),2.95(s,3H,NMe),2.59(s,6H,2×NMe),1.34,(s,9H,^tBu).

Step 3: (S) -2-amino-N- (2- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-oxoethyl) -N-methyl-3-phenylpropionamide dihydrochloride

To a mixture of tert-butyl (S) - (1- ((2- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-oxoethyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (51 mg,0.10 mmol) in DCM (1.4 mL) was added TFA (0.57 g,0.38mL,5.03 mmol) at room temperature and stirring was continued for 3 hours. The mixture was concentrated and azeotroped with CHCl ₃ (4 x 10 mL) and the residue was purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% hcl _{( Aqueous solution )} to give the product as the dihydrochloride salt as an oil (40 mg, 83%). LC-MS (+ve mode) ):m/z＝407.25[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.42(m,1H,ArH),7.80(m,1H,ArH),7.73(m,1H,ArH),7.41(m,7H,7×ArH),4.97(obs,2H,CH₂),4.83(m,1H,CH),3.57(m,2H,CH₂),3.07(m,4H,2×CH₂),3.08(s,3H,NMe),3.02(s,6H,2×NMe).

Examples 1 to 46: (S) -2-amino-N- (2- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2-oxoethyl) -N-methyl-3-phenylpropionamide (compound 554)

Step 1: (S) - (1- ((2- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2-oxoethyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester

To a stirred solution of 5-OMe-DMT (200 mg,0.91 mmol) in anhydrous THF (5 mL) at-78deg.C was added NaHMDS (1M in THF, 0.96mL,0.96 mmol). After 30 min, a solution of Boc-phenylalanine-N-methyl-glycine-OSu (317 mg,0.73 mmol) in THF (5 mL) was added and the mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed and the residual material was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give the product as a solid (55 mg, 11%). LC-MS (+ve mode) ):m/z＝537.25[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.20(d,J＝9.0Hz,1H,ArH),7.35(s,1H,ArH),7.17(m,5H,5×ArH),7.24(d,J＝2.7Hz,1H,ArH),7.90(dd,J＝9.0,2.7Hz,2H,ArH),5.27(m,1H,NH),4.88(m,1H,CH),4.60(s,2H,CH₂),3.83(s,3H,OMe),3.07(m,6H,3×CH₂),2.94(s,3H,NMe),2.66(s,6H,2×NMe),1.34,(s,9H,^tBu).

Step 2: (S) -2-amino-N- (2- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2-oxoethyl) -N-methyl-3-phenylpropionamide

TFA (0.58 g,0.39mL,5.13 mmol) was added to a solution of tert-butyl (S) - (1- ((2- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2-oxoethyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (55 mg,0.10 mmol) in DCM (1.5 mL) at room temperature and stirring was continued for 2 hours. The mixture was concentrated and azeotroped with CHCl ₃ (4 x 10 mL) and the residue was purified by reverse phase silica gel chromatography eluting with a gradient of acetonitrile/0.02% hcl _{( Aqueous solution )} to give the product as an oil (19 mg, 37%). LC-MS (+ve mode) m/z=437.30 [ m+h ] ⁺.

Examples 1 to 47:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 2, 2-dimethyl-3- (pivaloyloxy) propyl ester formate salt (Compound 555)

Step 1: pivalic acid 3- ((chlorocarbonyl) oxy) -2, 2-dimethylpropyl ester

To a solution of 3-hydroxy-2, 2-dimethylpropyl pivalate (346 mg,1.84 mmol) in DCM (5 mL) was added DMAP (0.72 g,5.81 mmol) and triphosgene (202 mg,0.68 mmol) and the mixture was stirred at room temperature for 1 hour. This solution was used directly in the next step.

Step 2:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 2, 2-dimethyl-3- (pivaloyloxy) propyl ester formate salt

To a stirred solution of 5-OMe-DMT (200 mg,0.91 mmol) in DCM (10 mL) was added NaHMDS (1M in THF, 0.96mL,0.96 mmol) at-78deg.C. After 30 min, a solution of pivalic acid 3- ((chlorocarbonyl) oxy) -2, 2-dimethylpropyl ester (0.92 mmol) in DCM (5 mL) was added and the mixture was stirred at-78 ℃ for 10 min, then the mixture was warmed to room temperature and stirred for 16 h. The mixture was concentrated and purified by silica gel column chromatography eluting with a gradient of MeOH/DCM followed by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give compound 555 (52 mg, 13%) as an oil. LC-MS (+ve mode) ):m/z＝433.25[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.42(s,1H,HCO₂H),8.02(d,J＝9.0Hz,1H,ArH),7.60(s,1H,ArH),7.13(d,J＝2.5Hz,1H,ArH),6.97(dd,J＝9.0,2.5Hz,1H ArH),4.27(s,2H,CH₂),4.00(s,2H,CH₂),3.86(s,3H,OMe),3.44(m,2H,CH₂),3.15(m,2H,CH₂),2.93(s,6H,2×CH₃),1.19(s,9H,^tBu),1.11(s,6H,2×CH₃);¹³C NMR(75.5MHz,CDCl₃)δ178.3,167.4,156.5,150.4,130.5,123.7,115.8,115.5,113.2,101.5,71.2,68.6,56.6,54.8,48.4,48.2,47.9,47.6,47.3,47.0,46.7,42.2,38.6,35.0,26.2,20.7,20.1.

Examples 1 to 48:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 2, 2-dimethyl-3- (pivaloyloxy) propyl ester formate salt (Compound 556)

To a stirred solution of DMT (173 mg,0.92 mmol) in DCM (10 mL) was added NaHMDS (1M in THF, 0.92mL,0.92 mmol) at-78deg.C. After 30min, a solution of pivalic acid 3- ((chlorocarbonyl) oxy) -2, 2-dimethylpropyl ester (0.92 mmol) in DCM (5 mL) was added and the reaction mixture was stirred at-78 ℃ for 10min, then warmed to room temperature and stirred for 16 h. The solvent was removed and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM followed by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give compound 556 (97 mg, 23%) as an oil. LC-MS (+ve mode) ):m/z＝403.25[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.15(d,J＝7.9Hz,1H,ArH),7.62(m,1H,ArH),7.54(s,1H,ArH),7.33(m,2H,2×ArH),4.31(s,2H,CH₂),4.04(s,2H,CH₂),3.00(m,2H,CH₂),2.82(m,2H,CH₂),2.46(s,6H,2×NMe).1.12(s,9H,^tBu),1.14(s,6H,2×CH₃);¹³C NMR(75MHz,CD₃OD)δ203.4,201.2,178.4,124.4,122.6,122.2,122.1,118.9,118.6,114.7,69.0,68.9,58.4,43.7,38.6,34.7,26.2,20.6.

Examples 1 to 49:2- (1-bis (dimethylamino) phosphoryl l-indol-3-yl) -N, N-dimethyl-ethylamine (Compound 557)

To a stirred solution of DMT (200 mg,1.06 mmol) in anhydrous THF (5 mL) was added NaHMDS (1M in THF, 1.12mL,1.12 mmol) at-78deg.C. After 30 minutes, N-tetramethyl phosphorodiamidate chloride (181 mg,0.16ml,1.06 mmol) was added and the mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed in vacuo and the crude residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give compound 557 (251 mg, 74%) as an oil. TLC: R _f = 0.55 (DCM-MeOH, 8:2 v/v); LC-MS (+ve mode) ):m/z＝323.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.82(m,1H,ArH),7.53(m,1H,ArH),7.18(m,3H,3×ArH),3.10(m,2H,CH₂),2.95(m,2H,CH₂),2.68(d,12.0Hz,³J(_H-P)＝10.2Hz,2×PNMe),2.63(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ138.1(d,³J_(C-P)＝4.3Hz),130.3(d,²J_(C-P)＝8.2Hz),125.9(d,²J_(C-P)＝5.7Hz),123.6,121.5,118.6,115.8(d,³J_(C-P)＝7.2Hz),114.6,58.6,44.2,36.7(d,²J_(C-P)＝4.2Hz),22.2;³¹P NMR(121.5MHz,CDCl₃)δ14.56.

Examples 1 to 50:2- (1-bis (dimethylamino) phosphoryl l-5-methoxy-indol-3-yl) -N, N-dimethyl-ethylamine (Compound 558)

To a stirred mixture of 5-OMe-DMT (200 mg,0.92 mmol) in dry THF (5 mL) was added NaHMDS (1M in THF, 0.96mL,0.96 mmol) at-78deg.C. After 30 minutes, N-tetramethyl phosphorodiamidate chloride (157 mg,0.14ml,0.92 mmol) was added and the mixture was warmed to room temperature and stirred for 16 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give compound 558 (157 mg, 48%) as an oil. TLC: R _f = 0.34 (DCM-MeOH, 8:2 v/v); LC-MS (+ve mode) ):m/z＝353.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ7.70(d,J＝9.0,1H,ArH),7.02(m,2H,2×ArH),6.85(dd,J＝9.0,2.4Hz,1H,ArH),3.83(s,3H,OMe),2.96(m,2H,CH₂),2.77(m,2H,CH₂),2.67(s,6H,2×PNMe),2.63(s,6H,2×PNMe),2.45(s,6H,2×NMe);¹³C NMR(75.5MHz,CDCl₃)δ155.2,132.9(d,³J_(C-P)＝4.3Hz),131.3(d,²J_(C-P)＝8.3Hz),126.3(d,²J_(C-P)＝5.7Hz),116.7(d,³J_(C-P)＝7.3Hz),115.3,112.8,101.1,59.1,55.9,44.8,36.7(d,²J_(C-P)＝4.2Hz),23.0;³¹P NMR(121.5MHz,CDCl₃)δ14.64.

Examples 1 to 51: bis (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanone di-formate (Compound 170)

To a mixture of N, N-dimethyltryptamine (162 mg,0.86 mmol) in DMSO (1.5 mL) was added carbonyldiimidazole (68 mg,0.42 mmol) and the mixture was heated to 120℃under microwave irradiation and stirred for 2 hours. The mixture was quenched with saturated aqueous NaHCO ₃ (10 mL) and extracted with EtOAc (3X 25 mL). The combined organic layers were washed with H ₂ O (20 mL), saturated brine (20 mL), dried (MgSO ₄) and concentrated under reduced pressure. This material was purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give compound 170 (48 mg, 35%) as an oil. LC-MS (+ve mode) ):m/z＝403.25[M+H]⁺;¹H NMR(300MHz,MeCN-d₃)δ8.43(s,2H,2×HCO),7.99(m,2H,2×ArH),7.74(m,2H,2×ArH),7.53(s,2H,2×ArH),7.38(m,4H,4×ArH),3.06(m,4H,2×CH₂),2.96(m,4H,2×CH₂),2.50(s,12H,4×NMe).

Examples 1 to 52: bis (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanone di-formate (compound 169)

To a solution of 5-methoxy-N, N-dimethyltryptamine (175 mg,0.80 mmol) in DMSO (1.5 mL) was added CDI (63 mg,0.39 mmol) and the mixture was heated to 120℃under microwave irradiation and stirred for 2 hours. The mixture was quenched with saturated aqueous NaHCO ₃ (20 mL) and extracted with EtOAc (60 mL). The combined organic layers were washed with H ₂ O (20 mL), saturated brine (20 mL), dried (MgSO ₄), filtered and concentrated to give an oil (186 mg). This material was purified by reverse phase chromatography eluting with 0 to 100% acetonitrile/0.1% formic acid to give compound 169 (75.9 mg, 35%) as a solid. LC-MS (+ve mode) ):m/z＝463.25[M+H]⁺;¹H NMR(300MHz,MeCN-d₃)δ8.28(s,2H,2×HCO),7.89(d,J＝9.0Hz,2H,2×ArH),7.58(s,2H,2×ArH),7.24(d,J＝2.4Hz,2H,2×ArH),7.00(dd,J＝9.0,2.4Hz,2H,2×ArH),3.91(s,6H,2×OMe),3.30(m,4H,2×CH₂),3.15(m,4H,2×CH₂),2.73(s,12H,4×NMe).

Examples 1 to 53: (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanol (Compound 559)

To a mixture of DMT (188 mg,1.0 mmol) in 1, 4-dioxane (2 mL) was added K ₂CO₃ (414 mg,3.0 mmol) and paraformaldehyde (90 mg,3.0 mmol). The mixture was heated to 60 ℃ and stirred for 16 hours, then diluted with DCM (15 mL) and filtered through celite, washing with DCM (2×10 mL). The filtrate was concentrated to give compound 559 (218 mg, 100%). LC-MS (+ve mode) ):m/z＝219.10[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.53(m,1H,ArH),7.46(m,1H,ArH),7.09(m,3H,3×ArH),5.51(s,2H,CH₂),2.92(m 2H,CH₂),2.64(m,2H,CH₂)2.33(s,6H,2×N Me);¹³C NMR(75MHz,CD₃OD)δ136.3,128.6,124.9,121.4,119.0,118.2,113.0,109.4,68.3,66.7,59.8,44.0,22.7.

Examples 1 to 54: (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanol (compound 560)

To a solution of 5-OMe-DMT (218 mg,1.0 mmol) in 1, 4-dioxane (2 mL) was added K ₂CO₃ (414 mg,3.0 mmol) and paraformaldehyde (90 mg,3.0 mmol). The mixture was heated to 60 ℃ and stirred for 16 hours, then diluted with DCM (15 mL) and filtered through celite, washing with DCM (2×10 mL). The filtrate was concentrated to give compound 560 (190 mg, 76%) as an oil. LC-MS (+ve mode) ):m/z＝249.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.35(d,J＝8.9Hz,1H,Ar-H),7.07(s,1H,ArH),7.02(d,J＝2.4Hz,1H ArH),6.83(dd,ArH,J＝8.9,2.7Hz,1H),5.47(s,2H,CH₂),3.82(s,3H,OMe),2.89(m,2H,CH₂),2.64(m,2H,CH₂),2.35(s,6H,2×NMe);¹³C NMR(75.5MHz,CD₃OD)δ154.2,131.6,125.6,112.6,111.3,110.2,100.3,68.5,59.6,54.9,44.0,22.7.

Examples 1 to 55: methyl pivalate (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) (compound 187)

To DCM (5 mL) containing (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanol (compound 559, 109mg,0.5 mmol) is added pivaloyl chloride (180 mg, 183. Mu.L, 1.5 mmol), et ₃ N (228 mg, 247. Mu.L, 2.25 mmol) and DMAP (10 mg,0.13 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours, then concentrated in vacuo and the crude residue was purified by silica gel column chromatography eluting with a gradient of MeOH/EtOAc to give compound 187 (91 mg, 60%) as an oil. LC-MS (+ve mode) ):m/z＝303.10[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.57(m,1H,ArH),7.51(m,1H,ArH),7.17(m,3H,3×ArH),6.15(s,2H,CH₂),2.98(m 2H,CH₂),2.76(m,2H,CH₂),2.43(s,6H,2×NMe),1.13(s,9H,^tBu);¹³C NMR(75MHz,CD₃OD)δ179.5,138.1,130.0,127.3,123.5,121.3,119.7,115.0,110.9,69.9,60.6,45.1,39.9,28.6,27.3,23.6.

Examples 1 to 56: pivalic acid (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methyl ester (compound 188)

To DCM (5 mL) containing (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanol (compound 560, 95mg,0.38 mmol) is added pivaloyl chloride (44.6 mg, 46. Mu.L, 0.38 mmol), et ₃ N (115 mg, 106. Mu.L, 1.14 mmol) and DMAP (10 mg,0.13 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours, then concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/EtOAc to give compound 188 (30 mg, 23%) as an oil. LC-MS (+ve mode) ):m/z＝333.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.40(d,J＝8.8Hz,1H,ArH),7.15(s,1H,ArH),7.06(d,J＝2.4Hz,1H,ArH),6.88(dd,J＝8.8,2.4Hz,1H),6.10(s,2H,CH₂),3.85(s,3H,OMe),2.92(m2H,CH₂),2.71(m,2H,CH₂)2.40(s,6H,2×NMe)1.12(s,9H,^tBu);¹³C NMR(75MHz,CD₃OD)δ154.8,126.7,126.5,111.9,111.7,110.5,110.3,100.6,100.4,68.6,59.0,58.8,54.9,43.4,27.0,25.9,22.0.

Examples 1 to 57: methyl ethyl (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) carbonate (compound 561)

Ethyl chloroformate (119 mg, 105. Mu.L, 1.1 mmol) was added dropwise to anhydrous pyridine (5 mL) containing (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanol (compound 559, 218mg,1.0 mmol) under an atmosphere of N ₂ at 0 ℃. The mixture was slowly warmed to room temperature and stirred for 1 hour, then concentrated in vacuo and EtOAc (50 mL) and NaHCO ₃ (25 mL) were added. The phases were separated and the organic phase was washed with H ₂ O (25 mL), brine (25 mL), dried (MgSO ₄), filtered and the filtrate concentrated to give compound 561 (169 mg) as an oil. LC-MS (+ve mode) m/z=291.15 [ m+h ] ⁺.

Examples 1 to 58: methyl ethyl carbonate (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) (compound 562)

To anhydrous THF (5 mL) containing (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanol (compound 560, 125mg,0.5 mmol), DMAP (2 mg, 15. Mu. Mol) and trimethylamine (101 mg, 139. Mu. Mol) under N ₂ atmosphere was added dropwise a solution of ethyl chloroformate (70 mg, 60. Mu.L, 0.65 mmol) in anhydrous THF (0.4 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 1 hour, then slowly warmed to room temperature and stirred for 18 hours. Additional DMAP (24 mg, 180. Mu. Mol) and triethylamine (101 mg, 139. Mu. Mol) were added followed by a solution of ethyl chloroformate (109 mg, 96. Mu. Mol,1.0 mmol) in anhydrous THF (1 mL). The reaction mixture was stirred at room temperature for 24 hours, and then concentrated under reduced pressure to give compound 562 (189 mg) as an oil. LC-MS (+ve mode) m/z=343.10 [ M+Na ] ⁺.

Examples 1 to 59: ((3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methyl) phosphoric acid di-tert-butyl ester (Compound 264)

To a stirred solution of DMT (250 mg,1.33 mmol) in anhydrous THF (18 mL) was added NaHMDS (1M in THF, 1.4mL,1.4 mmol) at-78deg.C. After 30 min, the mixture was added dropwise to di-tert-butyl chloromethyl phosphate (310 mg,1.20 mmol), the mixture was warmed to room temperature and stirred for 16 h, then concentrated to dryness and dissolved in a mixture of DCM (20 mL) and NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with H ₂ O (2×20 mL), brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated in vacuo. The crude residue was purified by sequential column chromatography on silica gel eluting with MeOH/DCM and reverse phase chromatography eluting with MeCN/H ₂ O, and then eluted with a mixture of PE in EtOAc to MeOH-containing EtOAc usingKP-Amino D was purified to give compound 264 (123 mg). cLC-MS (+ve mode) m/z=411.20 [ M+H ] ⁺.

Examples 1 to 60: ((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methyl) phosphoric acid di-tert-butyl ester (Compound 256)

To a stirred solution of 5-OMe-DMT (150 mg,0.69 mmol) in anhydrous THF (9 mL) was added NaHMDS (1M in THF, 1.4mL,1.4 mmol) at-78deg.C. After 30 minutes, the resulting mixture was added dropwise to di-tert-butyl phosphate (160 mg,0.62 mmol), the mixture was warmed to room temperature and stirring was continued at room temperature for 16 hours. The mixture was concentrated to dryness and then dissolved in a mixture of DCM (20 mL) and NaHCO ₃ (20 mL). The phases were separated and the organic phase was washed with H ₂ O (2×20 mL), brine (20 mL), dried (MgSO ₄), filtered and the filtrate concentrated in vacuo. The residue was purified by sequential column chromatography on silica gel eluting with MeOH/DCM and reverse phase chromatography eluting with MeCN/H ₂ O, and then eluted with a mixture of PE in EtOAc to MeOH-containing EtOAc usingKP-Amino D was purified to give compound 256 (74 mg). LC-MS (+ve mode) m/z=441.20 [ m+h ] ⁺. /(I)

Examples 1 to 61:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 1- (((S) -2-amino-3-methylbutanoyl) oxy) -2-methylpropanoate di-trifluoroacetate salt (Compound 563)

Step 1:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 1-chloro-2-methylpropyl ester

To a stirred solution of 5-OMe-DMT (355 mg,1.63 mmol) in anhydrous THF (16 mL) was added NaHMDS (1M in THF, 3.25mL,3.25 mmol) at-78deg.C. After 30 minutes, 1-chloro-2-methylpropyl chloroformate (554 mg,474 μl,3.25 mmol) was added dropwise and stirring was continued at-78 ℃ for 30 minutes, then warmed to room temperature and stirred for 2 hours. The mixture was quenched with H ₂ O (10 mL) and concentrated to dryness, and the residual material was dissolved in a mixture of DCM (15 mL) and H ₂ O (15 mL). The phases were separated and the organic phase was washed with H ₂ O (2 x 15 mL), saturated brine (20 mL), dried (Na ₂SO₄), filtered and the filtrate concentrated to give a semi-solid. The material was purified by column chromatography on silica gel eluting with a gradient of MeOH/EtOAc containing 0.1% Et ₃ N to give the product as an oil (154 mg, 27%). LC-MS (+ve mode) ):m/z＝343.10&345.10[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.00(br,1H,ArH),7.29(s,1H,ArH),6.95(d,J＝2.5Hz,1H,ArH),6.89(dd,J＝8.9,2.5Hz,1H,ArH),6.47(d,J＝4.6Hz,1H,CH),3.81(s,3H,OCH₃),2.80(m,2H,CH₂),2.61(m,2H,CH₂),2.31(s,6H,2×NCH₃),1.11(dd,J＝6.8,4.5Hz,6H,2×CH₃).

Step 2: n- (tert-butoxycarbonyl) -L-valine cesium salt

N- (tert-Butoxycarbonyl) -L-valine (1.24 g,5.70 mmol) was dissolved in MeOH (24 mL) and H ₂ O (2.4 mL). A20% w/w aqueous solution of Cs ₂CO₃ was added dropwise until a pH of 7 was reached. The solution was concentrated in vacuo to give a clear residue, which was lyophilized to give N- (tert-butoxycarbonyl) -L-valine cesium salt (1.99 g, quantitative) as a solid.

Step 3:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 1- (((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanoyl) oxy) -2-methylpropyl ester

1-Chloro-2-methylpropyl 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylate (154 mg,0.44 mmol) was dissolved in MeCN (8 mL) and then N- (tert-butoxycarbonyl) -L-valine cesium salt (236 mg,0.68 mmol) and NaI (66 mg,0.44 mmol) were added. The mixture was heated to 70 ℃ and stirred overnight. DMF (4 mL) was added and the mixture was stirred at 70℃for an additional 72 h. The mixture was concentrated under reduced pressure and the residue was purified twice by silica gel column chromatography eluting with a gradient of MeOH/EtOAc to give the product as a solid (77 mg). LC-MS (+ve mode): m/z=534.30 [ M+H ] ⁺

Step 4:3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 1- (((S) -2-amino-3-methylbutanoyl) oxy) -2-methylpropyl ester

1- (((S) -2- ((tert-Butoxycarbonyl) amino) -3-methylbutanoyl) oxy) -2-methylpropyl 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylate (77 mg,0.14 mmol) was dissolved in DCM (1.5 mL) at room temperature and TFA (0.82 g,0.56mL,7.2 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue was purified by reverse phase chromatography eluting with a gradient of acetonitrile/H ₂ O to give compound 563 (34.8 mg, 38%) as a semi-solid. LC-MS (+ve mode ):m/z＝434.20[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ7.93(d,J＝8.6Hz,1H,ArH),7.54(s,1H,ArH),7.10(d,J＝2.3Hz,1H,ArH),6.93(m,2H,ArH and CH),4.02(d,J＝4.1Hz,1H,CH),3.80(s,3H,OCH₃),3.41(m,2H,CH₂),3.10(m,2H,CH₂),2.91(s,6H,2×NCH₃),2.23(m,1H,CH),1.08(dd,J＝6.8,4.9Hz,6H,2×CH₃),0.98(dd,J＝7.0,4.3Hz,6H,2×CH₃).

Examples 1 to 62:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 1- (((S) -2-amino-3-methylbutanoyl) oxy) -2-methylpropanoate di-trifluoroacetate salt (Compound 564)

Step 1:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 1-chloro-2-methylpropyl ester

To a stirred solution of DMT (288 mg,1.53 mmol) in anhydrous THF (15 mL) was added NaHMDS (1M in THF, 3.06mL,3.06 mmol) at-78deg.C. After 30 minutes, 1-chloro-2-methylpropyl chloroformate (523 mg,446 μl,3.06 mmol) was added dropwise and stirring was continued at-78 ℃ for 30 minutes, then warmed to room temperature and stirred for 2.5 hours. The mixture was quenched with H ₂ O (10 mL), then concentrated to dryness and dissolved in a mixture of DCM (15 mL) and H ₂ O (15 mL). The phases were separated and the organic phase was washed with H ₂ O (2×15 mL), saturated brine (20 mL), dried (Na ₂SO₄) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a gradient of MeOH/EtOAC to give the product as a semi-solid (98 mg, 20%). LC-MS (+ve mode) ):m/z＝323.10[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.13(br,1H,ArH),7.60(d,J＝7.6Hz,1H,ArH),7.41(s,1H,ArH),7.31(m,2H,2×ArH),6.48(d,J＝4.6Hz,1H,CH),3.32(m,2H,CH₂),3.22(m,2H,CH₂),2.82(s,6H,2×NCH₃),2.31(m,1H,CH),1.13(dd,J＝6.8,5.1Hz,6H,2×CH₃).

Step 2:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 1- (((S) -2- ((tert-butoxycarbonyl) amino) -3-methylbutanoyl) oxy) -2-methylpropyl ester

1-Chloro-2-methylpropyl 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylate (98 mg,0.30 mmol) was dissolved in DMF (6 mL) and then N- (tert-butoxycarbonyl) -L-valine (132 mg,0.61 mmol), N-diisopropylethylamine (196 mg, 265. Mu.L, 1.52 mmol) and NaI (46 mg,0.30 mmol) were added. The mixture was heated to 60 ℃ and stirred for 4 hours, then heated to 70 ℃ and stirred for an additional 96 hours. The sample was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/EtOAc to give the product as a semi-solid (78 mg). LC-MS (+ve mode) m/z=504.30 [ m+h ] ⁺.

Step 3:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 1- (((S) -2-amino-3-methylbutanoyl) oxy) -2-methylpropanoate di-trifluoroacetate salt

1- (((S) -2- ((tert-Butoxycarbonyl) amino) -3-methylbutanoyl) oxy) -2-methylpropyl 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylate (78 mg,0.16 mmol) was dissolved in DCM (1.6 mL) at room temperature and TFA (0.88 g,0.6mL,7.7 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hours, then concentrated in vacuo and the residue was purified by reverse phase chromatography with a gradient of acetonitrile/H ₂ O to give compound 564 (15.2 mg) as a semi-solid. LC-MS (+ve mode) ):m/z＝404.25[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.04(m,1H,ArH),7.59(m,2H,ArH),7.28(m,2H,ArH),6.92(d,J＝4.8Hz,1H,CH),4.01(d,J＝4.1Hz,1H,CH),3.41(m,2H,CH₂),3.11(dd,J＝9.8,6.3Hz,2H,CH₂),2.89(s,6H,2×NCH₃),2.24(m,2H,2×CH),1.38(m,6H,2×CH₃),0.96(dd,J＝7.0,4.0Hz,6H,2×CH₃).

Examples 1 to 63: ((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carbonyl) oxy) methyl) butanedioic acid tert-butyl ester (Compound 565)

Cesium 4- (tert-butoxy) -4-oxobutyrate

4- (Tert-butoxy) -4-oxobutanoic acid (0.50 g,2.88 mmol) was dissolved in MeOH (12 mL) and H ₂ O (1.2 mL). A20% w/w aqueous solution of Cs ₂CO₃ was added dropwise until a pH of 7 was reached. The mixture was concentrated in vacuo to give a clear residue which was lyophilized overnight to give the product as a solid (0.88 g, quantitative).

3- (2- (Dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid chloromethyl ester

To a stirred solution of 5-OMe-DMT (200 mg,0.92 mmol) in anhydrous THF (13 mL) at-78deg.C was added NaHMDS (1M in THF, 1.8mL,1.8 mmol). After 30 minutes, chloromethyl chloroformate (236 mg,163 μl,1.83 mmol) was added dropwise, the mixture was warmed to room temperature and stirring was continued for 20 hours. The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/EtOAc to give the product as a semi-solid (261 mg, 91%) containing about 15%5-OMe-DMT. LC-MS (+ve mode) m/z= 311.05 and 313.05[ m+h ] ⁺.

Chloromethyl 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylate ((205 mg,0.66 mmol) was dissolved in DMF (4 mL), then cesium 4- (tert-butoxy) -4-oxobutyrate (202 mg,0.66 mmol) and NaI (99 mg,0.66 mmol) were added the mixture was heated to 60 ℃ and stirred overnight, then concentrated in vacuo, the residue was purified by silica gel column chromatography eluting with a gradient of PE and MeOH/EtOAc to give compound 565 (86 mg) as an oil which was used without further purification LC-MS (+ve mode): m/z=449.20 [ m+h ] ⁺.

Examples 1 to 63:4- (((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carbonyl) oxy) methoxy) -4-oxobutanoic acid (compound 566)

Tert-butyl (((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carbonyl) oxy) methyl) succinate (compound 564, 19mg,0.04 mmol) was stirred in formic acid (0.5 mL) for 2 hours and then concentrated in vacuo to give compound 566 (17 mg) as a solid. LC-MS (+ve mode) m/z=393.15 [ m+h ] ⁺.

Examples 1 to 64:5- (((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carbonyl) oxy) methoxy) -5-oxopentanoic acid (compound 567)

Cesium 5- (tert-butoxy) -5-oxopentanoate

To a solution of mono-tert-butyl glutarate (300 mg,1.59 mmol) in MeOH (4.40 mL) and H ₂ O (0.44 mL) was added 20% w/w aqueous Cs ₂CO₃ until pH 7 was reached. The mixture was concentrated and azeotroped with MeCN (2 x 10 mL) to give the product as a semi-solid.

Chloromethyl 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylate formate (50 mg,0.16 mmol) was dissolved in DMF (1 mL), followed by cesium 5- (tert-butoxy) -5-oxopentanoate (52 mg,0.16 mmol) and NaI (24 mg,0.16 mmol). The mixture was heated to 60 ℃ and stirred overnight, then concentrated in vacuo to give a solid. The solid was stirred in formic acid (1 mL) for 2 hours, then concentrated in vacuo to give compound 567 (150 mg) as a solid. LC-MS (+ve mode) m/z=407.15 [ m+h ] ⁺.

Examples 1 to 65:6- (((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carbonyl) oxy) methoxy) -6-oxohexanoic acid (Compound 568)

Cesium 6- (tert-butoxy) -6-oxohexanoate

To a solution of 6- (tert-butoxy) -6-oxohexanoic acid (375 mg,1.85 mmol) in MeOH (7.70 mL) and H ₂ O (0.77 mL) was added 20% w/w aqueous solution (added dropwise) until pH 7 was reached. The reaction mixture was concentrated and azeotroped with MeCN (2 x 10 mL) to give the product as a semi-solid.

Chloromethyl 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylate formate (50 mg,0.16 mmol) was dissolved in DMF (1 mL), followed by cesium 6- (tert-butoxy) -6-oxohexanoate (52 mg,0.16 mmol) and NaI (24 mg,0.16 mmol). The mixture was heated to 60 ℃ and stirred overnight, then concentrated in vacuo to give a solid. The solid was stirred in formic acid (1 mL) for 2 hours, then concentrated in vacuo to give compound 568 (74 mg) as a solid. LC-MS (+ve mode) m/z=421.15 [ m+h ] ⁺.

Examples 1 to 66:3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid chloromethyl ester (Compound 569)

To a solution of DMT (1.00 g,5.3 mmol) in anhydrous tetrahydrofuran (60 mL) at-78deg.C under N ₂ was added NaHMDS (1M in THF, 10.6mL,10.6 mmol) and the mixture was stirred at-78deg.C for 30 min. Chloromethyl chloroformate (1.37 g,0.94ml,10.6 mmol) was added dropwise, the mixture was stirred at-78 ℃ for 15 minutes, and then warmed to room temperature and stirred for 2 hours. H ₂ O (5 mL) was added, the mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 0 to 50% MeOH/EtOAc to give compound 569 (996 mg) as an oil. LC-MS (+ve mode) m/z=281.10 [ m+h ] ⁺.

Examples 1-67: ((3- (2- (dimethylamino) ethyl) -1H-indole-1-carbonyl) oxy) methyl) glutarate tert-butyl ester (Compound 570)

To a solution of chloromethyl 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylate (80 mg,0.29 mmol) in anhydrous DMF (0.5 mL) under an atmosphere of N ₂ was added a solution of NaI (43 mg,0.29 mmol) and cesium 5- (tert-butoxy) -5-oxopentanoate (91 mg,0.29 mmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature overnight, then heated to 80 ℃ and stirred for 2.5 hours. The mixture was cooled to room temperature and concentrated to give compound 570 as an oil. LC-MS (+ve mode) m/z=433.20 [ m+h ] ⁺.

Examples 1 to 68:5- (((3- (2- (dimethylamino) ethyl) -1H-indole-1-carbonyl) oxy) methoxy) -5-oxopentanoic acid (compound 571)

To tert-butyl (((3- (2- (dimethylamino) ethyl) -1H-indole-1-carbonyl) oxy) methyl) glutarate (compound 570) was added formic acid (2 mL) and the mixture stirred at room temperature for 1 hour, then concentrated in vacuo to give compound 571.LC-MS (+ve mode) m/z=377.15 [ m+h ] ⁺.

Examples 1 to 69: ((3- (2- (dimethylamino) ethyl) -1H-indole-1-carbonyl) oxy) methyl) hexanedioic acid tert-butyl ester (Compound 572)

To a solution of chloromethyl 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylate (80 mg,0.29 mmol) in anhydrous DMF (0.5 mL) under an atmosphere of N ₂ was added a solution of NaI (43 mg,0.29 mmol) and cesium 6- (tert-butoxy) -6-oxohexanoate (91 mg,0.29 mmol) in anhydrous DMF (1 mL). The mixture was stirred at room temperature overnight, then heated to 80 ℃ and stirred for 2.5 hours. The mixture was cooled to room temperature and concentrated in vacuo to give compound 572 as an oil. LC-MS (+ve mode) m/z=447.20 [ m+h ] ⁺.

Examples 1 to 70:6- (((3- (2- (dimethylamino) ethyl) -1H-indole-1-carbonyl) oxy) methoxy) -6-oxohexanoic acid (Compound 573)

To tert-butyl (((3- (2- (dimethylamino) ethyl) -1H-indole-1-carbonyl) oxy) methyl) adipate (compound 572) was added formic acid (2 mL) and the reaction mixture was stirred at room temperature for 0.5H. The mixture was concentrated in vacuo to give compound 573.LC-MS (+ve mode) m/z=391.20 [ m+h ] ⁺.

Examples 1 to 71:3- (((3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) sulfonyl) oxy) -2, 2-dimethylpropionic acid ethyl ester (compound 457)

To a solution of ethyl 3-hydroxy-2, 2-dimethylpropionate (254 mg,1.74 mmol) and pyridine (84 mg,86 μl,1.06 mmol) in Et2O (5 mL) at-78 ℃ was added dropwise the sulfuryl chloride (143 mg,86 μl,1.06 mmol) in Et ₂ O (20 mL) and stirring was continued at-78 ℃ for 30min, then filtered through celite and the filtrate concentrated in vacuo to give a colourless oil which was used directly in the next step.

NaHMDS (1M in THF, 1.12mL,1.12 mmol) was added to a solution of DMT (200 mg,1.06 mmol) in anhydrous THF (5 mL) at-78 ℃ and stirring was continued for 30min, then a THF solution of ethyl 3- ((chlorosulfonyl) oxy) -2, 2-dimethylpropionate (3 mL) was added and the mixture was warmed to room temperature and stirred for 72 hours, then concentrated in vacuo to give compound 457 (512 mg) as a semi-solid. LC-MS (+ve mode) m/z=397.15 [ m+h ] ⁺.

Examples 1 to 72:3- (((3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) sulfonyl) oxy) -2, 2-dimethylpropionic acid ethyl ester (compound 433)

To a solution of ethyl 3-hydroxy-2, 2-dimethylpropionate (254 mg,1.74 mmol) and pyridine (84 mg,86 μl,1.06 mmol) in Et2O (5 mL) at-78 ℃ was added dropwise the sulfuryl chloride (143 mg,86 μl,1.06 mmol) in Et ₂ O (20 mL) and stirring was continued at-78 ℃ for 30min, then filtered through celite and the filtrate concentrated in vacuo to give an oil which was used directly in the next step.

NaHMDS (1M in THF, 1.12mL,1.12 mmol) was added to a solution of 5-OMe-DMT (231 mg,1.06 mmol) in anhydrous THF (5 mL) at-78deg.C and stirring was continued for 30 min at-78deg.C, then a solution of ethyl 3- ((chlorosulfonyl) oxy) -2, 2-dimethylpropionate (3 mL) in THF was added. The mixture was warmed to room temperature and stirred for 72 hours, then concentrated in vacuo to give compound 433 (574 mg) as a semi-solid. LC-MS (+ve mode) m/z=427.15 [ m+h ] ⁺.

Examples 1-73:4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2, 2-dimethyl-4-oxobutanoic acid hydrochloride (Compound 576)

To a stirred solution of DMT (400 mg,2.12 mmol) in anhydrous THF (10 mL) was added NaHMDS (1M in THF, 2.23mL,2.23 mmol) at-78deg.C. In a separate vessel, 4- (tert-butoxy) -3, 3-dimethyl-4-oxobutanoic acid (0.53 g,2.12 mmol) and 2-chloro-1-methylpyridine iodide(0.60 G,2.34 mmol) was dissolved in anhydrous THF (10 mL). Et ₃ N (470 mg,0.66mL,4.66 mmol) was added and the mixture was stirred at room temperature. After 30 min, DMT solution was added and the mixture was stirred at room temperature for 16 hours, then concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give an oil (1.2 g, quantitative). TLC: R _f = 0.63 (DCM-MeOH, 8:2 v/v); LC-MS (+ve mode) m/z=373.20 [ M+H ] ⁺.

The above material was dissolved in DCM (15 mL) and TFA (12.1 g,8.2mL,106 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and azeotroped with CHCl ₃ (3×20 mL) to give a black residue which was dissolved in 1M HCl (3 mL) and purified by reverse phase silica gel chromatography with a gradient of acetonitrile/0.02% hydrochloric acid to give compound 576 (170 mg,23% via 2 steps) as a solid. TLC: R _f = 0.33 (DCM-MeOH, 8:2 v/v); LC-MS (+ve mode) ):m/z＝317.15[M+H]⁺;¹H NMR(300MHz,CDCl₃)δ8.39(dd,J＝8.7,1.8Hz,1H,ArH),7.77(s,1H,ArH),7.67(m,1H,ArH),7.33(m,2H,2×ArH),3.54(m,2H,CH₂),3.32(s,2H,CH₂),3.22(m,2H,CH₂),3.00(s,6H,2×CH₃),1.41(s,6H,2×CH₃);¹³C NMR(75.5MHz,CDCl₃)δ181.1,171.1,137.4,130.9,126.5,124.7,124.7,119.7,117.7,117.5,58.0,46.2,43.6,41.4,26.2,21.5.

Examples 1 to 74:4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2, 2-dimethyl-4-oxobutanoic acid hydrochloride (Compound 577)

To a stirred solution of 5-OMe-DMT (200 mg,0.92 mmol) in anhydrous THF (5 mL) at-78deg.C was added NaHMDS (1M in THF, 0.96mL,0.96 mmol). In a separate vessel, 4- (tert-butoxy) -3, 3-dimethyl-4-oxobutanoic acid (187 mg,0.92 mmol) and 2-chloro-1-methylpyridine iodide(220 Mg,1.01 mmol) was dissolved in anhydrous THF (5 mL). Et ₃ N (204 mg,0.28mL,2.02 mmol) was added and the mixture was stirred at room temperature for 30 min, then 5-OMe-DMT solution was added and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of MeOH/DCM to give an oil. TLC: R _f = 0.68 (DCM-MeOH, 8:2 v/v); LC-MS (+ve mode) m/z=403.20 [ m+h ] ⁺.

The above material was dissolved in DCM (15 mL) and TFA (2.91 g,1.96mL,25.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo and azeotroped with CHCl ₃ (3×20 mL) to give an oil which was dissolved in 0.5MHCl (2 mL) and purified by reverse phase silica gel chromatography with a gradient elution of acetonitrile/0.02% hydrochloric acid to give compound 577 (86 mg,24% via 2 steps) as a solid. TLC: R _f = 0.26 (DCM-MeOH, 8:2 v/v); LC-MS (+ve mode) ):m/z＝347.15[M+H]⁺;¹H NMR(300MHz,CD₃OD)δ8.27(d,J＝9.0Hz,1H,ArH),7.66(s,1H,ArH),7.12(d,J＝2.4Hz,1H,ArH),6.95(dd,J＝9.0,2.7Hz,1H,ArH),3.90(s,3H,OCH₃),3.51(m,2H,CH₂),3.30(s,2H,CH₂)3.21(m,2H,CH₂),3.02(s,6H,2×CH₃),1.44(s,6H,2×CH₃);¹³C NMR(75.5MHz,CD₃OD)δ180.7,170.2,157.5,131.4,131.4,124.6,118.1,117.0,114.3,102.4,57.5,56.1,45.7,43.4,41.0,26.1,21.2.

Example 2: pharmacokinetics of selected compounds in rats after a single intravenous or oral administration.

In three male Shi Boge-doli (Sprague-Dawley; SD) rats, pharmacokinetic (PK) studies were performed after Intravenous (IV) or oral (PO) administration of 1mg/kg (IV) or 10mg/kg (PO) of Dimethylformamide (DMT), 5-methoxydimethylformamide (5-MeO-DMT), compound 19 or Compound 20.

An in vivo method.

Rat strain.

Shi Boge-Duoli rats are supplied by CHARLES RIVER (Margate UK) and are free of specific pathogens. At the time of reception, the male rats had a body weight between 175-225g and were allowed to acclimatize for 5-7 days.

The animals are kept in pens.

Rats were housed in groups in sterilized individual ventilated cages that expose the animals to HEPA filtered sterile air throughout. Animals were free to access food and water (sterile) and sterile aspen wood chip litter (at least once a week). The room temperature was maintained at 22 ℃ +/-1 ℃ with a relative humidity of 60% and a maximum background noise of 56dB. Rats were exposed to a 12 hour light/dark cycle.

And (5) processing.

Each test compound and control (DMT or 5-OMe-DMT) was diluted with 10% v/v DMSO, 40% v/v PEG-400, 50% v/v water. The test compound or control (DMT or 5-OMe-DMT) was administered at a dose volume of 2mL/kg for intravenous administration (IV) and 5mL/kg for oral administration (PO).

Single IV/PO dose pharmacokinetic study in rats.

For each route of administration, each test compound was administered in a single IV bolus (via the lateral tail vein) or in a single oral gavage in a group of 3 rats. After the dose was administered, 100 μl of whole blood sample (EDTA) was collected via the tail vein at the time points described in table 8. The blood sample is centrifuged to separate the plasma. About 40 μl of isolated plasma per time point was dispensed into 96-well plates for each rat and frozen until analysis. The separated plasma samples were subjected to biological analysis.

Table 8: sample collection points for single IV and oral dose pharmacokinetic studies.

Biological analysis method.

DMT-raw material preparation.

2.4ML of DMSO was pipetted into an amber vial containing 2.4mg of salt-free DMT. The contents were mixed by vortexing to give a standard solution of about 1000 μg/mL in DMSO.

Preparation of 5-OMe-DMT-raw material.

2.5ML of DMSO was pipetted into an amber vial containing 2.5mg of salt-free 5-OMe-DMT. The contents were mixed by vortexing to give a standard solution of about 1000 μg/mL in DMSO.

Calibration and quality control standards were prepared.

Separate calibration curves and QC standards were prepared from individual standards to minimize the probability of MRM crosstalk during analysis. Dilution was performed as described in detail in tables 9 and 10. The incorporation volume was 3 μl per 30 μl of plasma.

Table 9: calibration and QC working solutions were prepared at 1 to 5000 ng/mL.

Table 10: calibration and QC working solutions were prepared at 1 to 5000 ng/mL.

All samples were diluted to volume with 50:50 methanol/water (v/v) in individual 1.5mL Eppendorf tubes (Eppendorf tubes) and mixed by vortexing.

The control matrix was rat plasma (male Shi Boge doli, EDTA). Calibration and Quality Control (QC) standards were prepared by incorporating a working solution containing DMT or 5OMe-DMT into the control matrix.

Dosage formulation samples.

Dosage formulation samples were diluted to appropriate concentrations in two steps with 50:50 (v/v) methanol/water and then diluted with control matrix at 10:90 (v/v) to match the calibration standard in plasma.

Sample extraction procedure.

Calibration and QC standards, obtained samples, blank matrices and dosage formulation samples were extracted by protein precipitation via addition of custom-made acetonitrile (CH ₃ CN) -based Internal Standard (IS) solutions containing compounds including metoprolol (Metoprolol) and Rosuvastatin (Rosuvastatin), which were monitored during analysis. After centrifugation, a 40. Mu.L aliquot of the supernatant was diluted by adding 80. Mu.L of water. The prepared sample extracts were analyzed by LC-MS/MS.

Exemplary bioanalytical methods and analytical procedures.

1 Aliquots were added to each well of a 0.8ml 96 well plate (Abgene) according to the plate arrangement. 30 μl was used for calibration, QC standard, blank and dose formulation assays.

2 Based on analytical information, calibration and QC standards were prepared. The dosage formulation is diluted according to analytical information. The obtained samples were aliquoted according to plate arrangement and analytical information.

3 90. Mu.L of CH3CN internal standard was added and vortex mixed for 5 minutes at 850 rpm.

4 Centrifuged at nominal 4000rpm for 10 minutes.

6 Transfer 40. Mu.L of supernatant to a new 0.8mL Abgene plate.

6 To all transferred supernatants 80 μl of water was added.

Vortex mixing at 1400rpm for 30 seconds.

8 Were immediately analyzed by LC-MS/MS or stored at +4℃until analysis.

Analysis was performed using the solvent system and gradient described in table 11 below.

TABLE 11

The mass spectrometer parameters for detecting DMT and 5OMe-DMT in plasma are provided in Table 12.

Table 12

Example 2-1: in vivo pharmacokinetic analysis of DMT.

In the rat model, pharmacokinetic properties of DMT after IV (1 mg/kg) and oral administration (10 mg/kg) were evaluated. The PK parameters for DMT are summarized in Table 2-1. The average concentration-time profile of DMT after oral administration of DMT (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats is shown in FIG. 1.

TABLE 2 PK parameters for 1.DMT

Example 2-2: in vivo pharmacokinetic analysis of 5-MeO-DMT.

In the rat model, the pharmacokinetic profile of 5-MeO-DMT after IV (1 mg/kg) and oral administration (10 mg/kg) was evaluated. The PK parameters for 5-MeO-DMT are summarized in tables 2-2. The average concentration-time profile of DMT after oral administration of 5-MeO-DMT (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats is shown in FIG. 2.

TABLE 2 PK parameters for 2.5-MeO-DMT

Examples 2-3: pharmacokinetic analysis of compound 20.

Figure 3 panel a is a graph depicting (1) the time course of plasma concentrations of N, N-Dimethyltryptamine (DMT) (triangle dots) and compound 20 (square dots) in Shi Boge-doli rats administered compound 20 at 1mg/kg Intravenous (IV), and (2) the time course of plasma concentrations of N, N-Dimethyltryptamine (DMT) (circle dots) in Shi Boge-doli rats administered DMT at 1mg/kg Intravenous (IV) as controls.

Figure 3 is a graph depicting (1) the time course of plasma concentrations of N, N-Dimethyltryptamine (DMT) (triangle dots) and compound 20 (square dots) in Shi Boge-doli rats administered compound 20 orally (PO) at 10mg/kg, and (2) the time course of plasma concentrations of N, N-Dimethyltryptamine (DMT) (circle dots) in Shi Boge-doli rats administered DMT orally (PO) at 10mg/kg as a control. Tables 2-3 provide corresponding quantitative values for the data sequences represented by the triangle points in the plot B of fig. 3.

Tables 2 to 3

The pharmacokinetic profile of compound 20 after IV or oral administration was evaluated in a rat model. Compound 20: chemical name: 3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid ethyl ester; structural category: a carbamate; mechanism category: hypothetical carboxylesterases.

PK parameters for compound 20 are summarized in tables 2-3A. The average concentration-time profile of DMT after IV or oral administration of compound 20 (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats is shown in FIG. 4. The average concentration-time profile of compound 20 after IV or oral administration of compound 20 (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats is shown in fig. 5.

Tables 2-3A PK parameters of Compound 20 after IV or oral administration of Compound 20

Examples 2 to 4: in vivo pharmacokinetic analysis of compound 19.

FIG. 6 panel A is a graph depicting (1) the time course of plasma concentrations of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) (triangle dots) and compound 19 (square dots) in Shi Boge-doli rats administered compound 19 at 1mg/kg Intravenous (IV), and (2) the time course of plasma concentrations of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) (circle dots) in Shi Boge-doli rats administered 5-MeO-DMT at 1mg/kg Intravenous (IV) as a control.

FIG. 6 is a graph depicting (1) the time course of plasma concentrations of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) (triangle points) and compound 19 (square points) in Shi Boge-doli rats administered compound 19 orally (PO) at 10mg/kg, and (2) the time course of plasma concentrations of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) (circle points) in Shi Boge-doli rats administered 5-MeO-DMT orally (PO) at 10mg/kg as a control. Tables 2-4 provide corresponding quantitative values for the data sequences represented by the triangle points in figure 6, panel B.

Tables 2 to 4

The pharmacokinetic profile of compound 19 after IV or oral administration was evaluated in a rat model. Compound 19: chemical name: 3- [2- (dimethylamino) ethyl ] -5-methoxy-indole-1-carboxylic acid ethyl ester; structural category: a carbamate; mechanism category: hypothetical carboxylesterases.

PK parameters for compound 19 are summarized in tables 2-4A. The average concentration-time profile of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) following IV or oral administration of compound 19 (1 mg/kg for IV administration and 10mg/kg for oral administration) to male SD rats is shown in FIG. 7.

Tables 2-4A PK parameters of Compound 19 after IV or oral administration of Compound 19

EXAMPLES 2-5 Diisopropoxyphosphonate DMT prodrugs

Chemical name: 2- (1-diisopropyloxyphosphoryl indol-3-yl) -N, N-dimethyl-ethylamine

Structural category: phosphonic acid esters

Mechanism category: hypothetical carboxylesterase+hypothetical phosphatase

Figure 8 shows the average total concentration of DMT after administration of DMT prodrug at 10mg/kg PO to male Shi Boge doli rats.

TABLE 25 PK parameters for DMT prodrugs

Examples 2-6 Diisopropoxyphosphonate 5-MeO-DMT prodrugs

Chemical name: 2- (1-diisopropyloxyphosphoryl-5-methoxy-indol-3-yl) -N, N-dimethyl-ethylamine

Structural category: phosphonic acid esters

Mechanism category: hypothetical carboxylesterase+hypothetical phosphatase

FIG. 10 average total concentration of 5-MeO-DMT after administration of 5-MeO-DMT prodrug at 10mg/kg to male Shi Boge Du rats PO.

FIG. 11 average total concentration of 5-MeO-DMT prodrug after administration to male Shi Boge Du rats IV, PO at 1, 10 mg/kg.

TABLE 2 6.5-MeO-DMT prodrug PK parameters

Examples 2-7 isopropyl carbamate DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid isopropyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 12 shows the mean concentration versus time curve of DMT CP-2 and metabolite DMT after oral administration of DMT CP-2 (10 mg/Kg) to male SD rats.

TABLE 2-7 DMT prodrugs and DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-8. Tert-butyl carbamate DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid tert-butyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 13 mean concentration-time curve of DMT CP-3 and metabolite DMT after oral administration of DMT CP-3 (10 mg/Kg) to male SD rats

TABLE 2-8 DMT prodrugs and DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-9 propyl carbamate DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid propyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 14 mean concentration-time curve of DMT CP-4 and metabolite DMT after oral administration of DMT CP-4 (10 mg/Kg) to male SD rats

Tables 2-9.DMT prodrugs and DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-10 isobutyl carbamate DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] indole-1-carboxylic acid isobutyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 15 mean concentration-time curve of DMT CP-5 and metabolite DMT after oral administration of DMT CP-5 (10 mg/Kg) to male SD rats

TABLE 2-10 DMT prodrugs and DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-11 Methylamide DMT prodrugs

Chemical name: 1- [3- [2- (dimethylamino) ethyl ] indol-1-yl ] ethanone

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 16 mean concentration-time curve of DMT AP-1 and metabolite DMT after oral administration of DMT AP-1 (10 mg/Kg) to male SD rats

TABLE 2-11 DMT prodrugs and DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-12 isopropyl carbamate 5-MeO-DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] -5-methoxy-indole-1-carboxylic acid isopropyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 17 average concentration-time curve of 5-MeO-DMT CP-2 and metabolite 5-MeO DMT after oral administration of 5-MeO-DMT CP-2 (10 mg/Kg) to male SD rats

TABLE 2-12.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-13. Tert-butyl carbamate 5-MeO-DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] -5-methoxy-indole-1-carboxylic acid tert-butyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 18 average concentration-time curves of 5-MeO-DMT CP-3 and metabolite 5-MeO DMT after oral administration of 5-MeO-DMT CP-3 (10 mg/Kg) to male SD rats.

TABLE 2-13.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-14 propyl carbamate 5-MeO-DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] -5-methoxy-indole-1-carboxylic acid propyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 19 average concentration-time curve of 5-MeO-DMT CP-4 and metabolite 5-MeO DMT after oral administration of 5-MeO-DMT CP-4 (10 mg/Kg) to male SD rats

TABLE 2-14.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-15 isobutyl carbamate 5-MeO-DMT prodrugs

Chemical name: 3- [2- (dimethylamino) ethyl ] -6-methoxy-indole-1-carboxylic acid isobutyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 20 average concentration-time curve of 5-MeO-DMT CP-5 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT CP-5 (10 mg/Kg) to male SD rats

TABLE 2 15.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-16 Methylamide 5-MeO-DMT prodrugs

Chemical name: 1- [3- [2- (dimethylamino) ethyl ] -5-methoxy-indol-1-yl ] ethanone

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 21 average concentration-time curve of 5-MeO-DMT AP-1 and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT AP-1 (10 mg/Kg) to male SD rats

TABLE 2 16.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 17.DMT benzamide

Chemical name: [3- [2- (dimethylamino) ethyl ] indol-1-yl ] -phenyl-methanone

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 22 average concentration-time curve of DMT benzamide and metabolite DMT after oral administration of DMT benzamide (10 mg/Kg) to male SD rats

TABLE 2-17 DMT prodrugs and DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-18.5-MeO-DMT succinate

Chemical name: 4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -4-oxobutanoic acid

Structural category: amides and their use

Mechanism category: hypothesized pH-dependent cyclization

FIG. 23 average concentration-time curve of 5-MeO-DMT prodrug and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT prodrug (10 mg/Kg) to male SD rats

TABLE 2-18.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 19.5-MeO-DMT glutarate

Chemical name: 5- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -5-oxopentanoic acid

Structural category: amides and their use

Mechanism category: hypothesized pH-dependent cyclization

FIG. 24 mean concentration-time curve of 5-MeO-DMT prodrug and metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT prodrug (10 mg/Kg) to male SD rats

TABLE 2-19.5-MeO-DMT prodrugs and 5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 20.5-MeO-DMT carbamic acid methyl pivaloyl ester

Chemical name: 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid (pivaloyloxy) methyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterase+chemical decomposition

FIG. 25 average concentration-time curve of metabolite 5-MeO-DMT after oral administration of methyl pivaloyl 5-MeO-DMT carbamate (10 mg/Kg) to male SD rats

TABLE 2-20.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 21.DMT methoxyethyl carbamate

Chemical name: 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 2-methoxyethyl ester formate

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 26 average concentration-time curve of metabolite DMT after oral administration of DMT methoxyethyl carbamate (10 mg/Kg) to male SD rats

TABLE 2-21 DMT PK parameters

Examples 2-22.5-MeO-DMT carbamate

Chemical name: 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 2-methoxyethyl ester

Structural category: carbamates (Carbamates)

Mechanism category: hypothetical carboxylesterases

FIG. 27 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of methoxyethyl 5-MeO-DMT carbamate (10 mg/Kg) to male SD rats

TABLE 2-22.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 23 DMT trimethyl lock amide

Chemical name: acetic acid 2- (4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-methyl-4-oxobutan-2-yl) -3, 5-dimethylbenzene ester

Structural category: amides and their use

Mechanism category: hypothetical carboxylesterase + intramolecular cyclization

FIG. 28 mean concentration-time curve of metabolite DMT after oral administration of DMT trimethyllocker (10 mg/Kg) to male SD rats

TABLE 2-23 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 24.5-MeO-DMT trimethyl lock amide

Chemical name: 2- (4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2-methyl-4-oxobutan-2-yl) -3, 5-dimethylphenyl

Structural category: amides and their use

Mechanism category: hypothetical carboxylesterase + intramolecular cyclization

FIG. 29 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT trimethyllocked amide (10 mg/Kg) to male SD rats

TABLE 2-24.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 25.DMT 4-piperidinopiperidine urea formate

Chemical name: [1,4 '-bipiperidin ] -1' -yl (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanone

Structural category: urea

Mechanism category: hypothesized amidase

TABLE 27 average concentration-time profile of metabolite DMT after oral administration of DMT 4-piperidinourea formate (10 mg/Kg) to male SD rats

BLQ: below the lower limit of quantification (0.5 ng/mL)

Examples 2-26.5-MeO-DMT 4-piperidinopiperidine Urea formate

Chemical name: [1,4 '-bipiperidin ] -1' -yl (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanone

Structural category: urea

Mechanism category: hypothesized amidase

FIG. 30 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT 4-piperidinopiperidine urea formate (10 mg/Kg) to male SD rats

TABLE 2-26.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2-27.5-MeO-DMT N, N-dimethylurea formate

Chemical name: 3- (2- (dimethylamino) ethyl) -5-methoxy-N, N-dimethyl-1H-indole-1-carboxamide

Structural category: urea

Mechanism category: hypothesized amidase

FIG. 31 mean concentration-time profile of metabolite 5-MeO-DMT after oral administration of 5-MeO-DMT N, N-dimethylurea formate prodrug (10 mg/Kg) to male SD rats

TABLE 2-27.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 28.DMT lysine tri-hydrochloride

Chemical name: (S) - (6- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -6-oxohexane-1, 5-diyl) dicarbamic acid di-tert-butyl ester

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 32 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT lysine tri-hydrochloride (10 mg/Kg) to male SD rats

TABLE 2 28 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-29.5-MeO-DMT lysine tri-hydrochloride

Chemical name: (S) -2, 6-diamino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) hex-1-one

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 33 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT lysine tri-hydrochloride (10 mg/Kg) to male SD rats

TABLE 2-29.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-30 Di-DMT urea (symmetrical urea) Di-formate

Chemical name: bis (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanone

Structural category: symmetrical dimer (Urea)

Mechanism category: hypothesized amidase

FIG. 34 mean concentration-time curve of metabolite DMT after oral administration of the prodrug di-DMT urea (symmetrical urea) di-formate (10 mg/Kg) to male SD rats

TABLE 2 30 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-31 bis-5-MeO-DMT urea (symmetrical Urea) bis-formate salt

Chemical name: bis (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanone

Structural category: symmetrical dimer (Urea)

Mechanism category: hypothesized amidase

FIG. 35 mean concentration-time profile of metabolite 5-MeO-DMT after oral administration of the prodrug di-5-MeO-DMT urea (symmetrical urea) di-formate (10 mg/Kg) to male SD rats

TABLE 2-31.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

EXAMPLE 32 DMT valine di-hydrochloride

Chemical name: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -3-methylbutan-1-one

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 36 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT valine di-hydrochloride (10 mg/Kg) to male SD rats

TABLE 232 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-33.5-MeO-DMT valine di-hydrochloride

Chemical name: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -3-methylbutan-1-one

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 37 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT valine di-hydrochloride (10 mg/Kg) to male SD rats

TABLE 2-33.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-34.5-MeO-DMT N, N-dimethylglycine formate salt

Chemical name: 2- (dimethylamino) -1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) ethan-1-one

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 38 mean concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT N, N-dimethylglycinate (10 mg/Kg) to male SD rats

TABLE 2-34.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-35 Phe-N-Me-Gly DMT di-hydrochloride (DMT dipeptide)

Chemical name: (S) -2-amino-N- (2- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2-oxoethyl) -N-methyl-3-phenylpropionamide

Structural category: amides and their use

Mechanism category: pH-dependent cyclization

FIG. 39 mean concentration-time curve of metabolite DMT after oral administration of the prodrug Phe-N-Me-Gly DMT di-hydrochloride (DMT dipeptide) (10 mg/Kg) to male SD rats

TABLE 2-35 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 36 DMT alanine di-hydrochloride

Chemical name: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) propan-1-one

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 40 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT alanine di-hydrochloride (10 mg/Kg) to male SD rats

TABLE 236 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-37.5-MeO-DMT alanine di-hydrochloride

Chemical name: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) propan-1-one

Structural category: amides and their use

Mechanism category: hypothesized amidase

FIG. 41 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT alanine di-hydrochloride (10 mg/Kg) to male SD rats

TABLE 2-37.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 38 DMT tetramethyl phosphorodiamidite

Chemical name: 2- (1-bis (dimethylamino) phosphoryl l-indol-3-yl) -N, N-dimethyl-ethylamine

Structural category: phosphorodiamidite prodrugs

Mechanism category: hypothetical phosphatases

FIG. 42 average concentration-time profile of metabolite DMT after oral administration of prodrug DMT tetramethyl phosphorodiamidate (10 mg/Kg) to male SD rats

TABLE 2-38 DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2-39.5-MeO-DMT tetramethyl phosphorodiamidate

Chemical name: 2- (1-bis (dimethylamino) phosphoryl l-5-methoxy-indol-3-yl) -N, N-dimethyl-ethylamine

Structural category: phosphorodiamidite prodrugs

Mechanism category: hypothetical phosphatases

FIG. 43 average concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT tetramethyl phosphorodiamidate (10 mg/Kg) to male SD rats

TABLE 2-39.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 40.DMT phenylalanine di-hydrochloride

Chemical name: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -3-phenylpropan-1-one bis-hydrochloride

Structural category: amino acid prodrugs

Mechanism category: hypothesized amidase

FIG. 44 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT phenylalanine di-hydrochloride (10 mg/Kg) to male SD rats

TABLE 2 40 DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2-41.5-MeO-DMT phenylalanine di-hydrochloride

Chemical name: (S) -2-amino-1- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -3-phenylpropan-1-one bis-hydrochloride

Structural category: amino acid prodrugs

Mechanism category: hypothesized amidase

FIG. 45 mean concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT phenylalanine di-hydrochloride (10 mg/Kg) to male SD rats

TABLE 41.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-42.5-MeO-DMT carbamic acid pivalic acid 2, 2-dimethylpropyl ester formate salt

Chemical name: 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 2, 2-dimethyl-3- (pivaloyloxy) propyl ester formate salt

Structural category: carbamate prodrugs

Mechanism category: hypothetical carboxylesterase + intramolecular cyclization

FIG. 46 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of prodrug 2, 2-dimethylpropyl carbamate formate (10 mg/Kg) to male SD rats

TABLE 2-42.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 43 DMT N, N-dimethylglycine hydrochloride

Chemical name: 2- (dimethylamino) -1- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) ethan-1-one hydrochloride

Structural category: amino acid prodrugs

Mechanism category: hypothesized amidase

FIG. 47 mean concentration-time profile of metabolite DMT after oral administration of prodrug DMT N, N-dimethylglycine hydrochloride (10 mg/Kg) to male SD rats

TABLE 2 43 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 44 DMT N, N-dimethylurea formate

Chemical name: 3- [2- (dimethylamino) ethyl ] -N, N-dimethyl-indole-1-carboxamide structural class: urea prodrugs

Mechanism category: hypothesized amidase

Tables 2-44 mean concentration-time profile of metabolite DMT after oral administration of prodrug DMT N, N-dimethylurea formate (10 mg/Kg) to male SD rats

BLQ: below the lower limit of quantification (0.5 ng/mL)

Examples 2 to 45 DMT methyl pivalate

Chemical name: pivalic acid (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methyl ester

Structural category: acyloxymethyl prodrugs

Mechanism category: hypothetical carboxylesterase+chemical decomposition

FIG. 48 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT pivalate (10 mg/Kg) to male SD rats

TABLE 2 45 DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 46.5-MeO-DMT pivalate methyl ester

Chemical name: pivalic acid (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methyl ester

Structural category: acyloxymethyl prodrugs

Mechanism category: hypothetical carboxylesterase+chemical decomposition

FIG. 49 average concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT pivalate (10 mg/Kg) to male SD rats

TABLE 2-46.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 47 DMT-3, 3-Dimethylsuccinate hydrochloride

Chemical name: 4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -2, 2-dimethyl-4-oxobutanoic acid hydrochloride

Structural category: amide prodrugs

Mechanism category: hypothesized pH-dependent cyclization

Tables 2-47 mean concentration-time profile of metabolite DMT after oral administration of prodrug DMT-3, 3-dimethylbuccinate hydrochloride (10 mg/Kg) to male SD rats

BLQ: below the lower limit of quantification (0.5 ng/mL)

Examples 2-48.5-MeO-DMT-3, 3-Dimethylsuccinate hydrochloride

Chemical name: 4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -2, 2-dimethyl-4-oxobutanoic acid hydrochloride

Structural category: amide prodrugs

Mechanism category: hypothesized pH-dependent cyclization

FIG. 50 mean concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT-3, 3-dimethylbuccinate hydrochloride (10 mg/Kg) to male SD rats

TABLE 2-48.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 49.DMT carbamic acid pivalate 2, 2-dimethylpropyl ester formate salt

Chemical name: 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid 2, 2-dimethyl-3- (pivaloyloxy) propyl ester formate salt

Structural category: carbamate prodrugs

Mechanism category: hypothetical carboxylesterase + intramolecular cyclization

FIG. 51 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT valproate 2, 2-dimethylpropyl carbamate (10 mg/Kg) to male SD rats

Tables 2-49.DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 50.DMT methanol

Chemical name: (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) methanol

Structural category: methyleneoxy prodrugs

Mechanism category: hypothetical chemical decomposition

FIG. 52 average concentration-time curve of metabolite DMT after oral administration of prodrug DMT methanol (10 mg/Kg) to male SD rats

TABLE 2 50 DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 51.5-MeO-DMT methanol

Chemical name: (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) methanol

Structural category: methyleneoxy prodrugs

Mechanism category: hypothetical chemical decomposition

FIG. 53 mean concentration-time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT methanol (10 mg/Kg) to male SD rats

TABLE 2-51.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2-52.5-MeO-DMT valine carboxy-isopropyl ester di-trifluoroacetate salt

Chemical name: 3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indole-1-carboxylic acid 1- (((S) -2-amino-3-methylbutanoyl) oxy) -2-methylpropanoate di-trifluoroacetate salt

Structural category: carbamic acid acyloxymethyl ester prodrugs

Mechanism category: hypothetical carboxylesterase+chemical decomposition

FIG. 54 average concentration-time curve of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT valine carboxy-isopropyl ester di-trifluoroacetate salt (10 mg/Kg) to male SD rats

TABLE 2-52.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

NC: not calculated

Examples 2 to 53 DMT methyl succinate

Chemical name: 4- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -4-oxobutanoic acid methyl ester

Structural category: amide prodrugs

Mechanism category: hypothetical carboxylesterase+pH dependent cyclization

FIG. 55 mean concentration-time curve of metabolite DMT after oral administration of prodrug DMT succinate (10 mg/Kg) to male SD rats

TABLE 2 53 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 54.5-MeO-DMT succinic acid methyl ester

Chemical name: 4- (3- (2- (dimethylamino) ethyl) -5-methoxy-1H-indol-1-yl) -4-oxobutanoic acid methyl ester

Structural category: amide prodrugs

Mechanism category: hypothetical carboxylesterase+pH dependent cyclization

FIG. 56 average concentration-time profile of metabolite 5-MeO-DMT after oral administration of prodrug 5-MeO-DMT methyl succinate (10 mg/Kg) to male SD rats

TABLE 2 54.5-MeO-DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2 to 55. Methyl pivaloyl carbamate formate salt

Chemical name: 3- (2- (dimethylamino) ethyl) -1H-indole-1-carboxylic acid (pivaloyloxy) methyl ester diformate

Structural category: carbamate prodrugs

Mechanism category: hypothetical carboxylesterase+chemical decomposition

FIG. 57 shows the mean concentration-time profile of metabolite DMT after oral administration of prodrug DMT carbamate formate (10 mg/Kg) to male SD rats

TABLE 2 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Examples 2-56. Glutarate prodrugs of DMT

Chemical name: 5- (3- (2- (dimethylamino) ethyl) -1H-indol-1-yl) -5-oxopentanoic acid

Structural category: amide prodrugs

Mechanism category: hypothesized pH-dependent cyclization

FIG. 58 mean concentration-time curve of metabolite DMT after oral administration of glutarate prodrug of DMT (10 mg/Kg) to male SD rats

TABLE 256 DMT PK parameters

* The median of the calculated Tmax and Tlast.

Comparison of the results of examples 2-3 to examples 2-37 shows that the various derivative forms of DMT or 5-OMe-DMT described herein have significantly different pharmacokinetic properties. When comparing different DMT or 5-OMe-DMT derived compounds, oral administration of the compounds tested in examples 2-3 to examples 2-37 resulted in measured total body plasma exposure to DMT or 5-OMe-DMT spanning several orders of magnitude. These results are unexpected and cannot be predicted based solely on structural knowledge of the compound.

While preferred embodiments of the present invention have been shown and described herein, it should be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, 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 methods and structures within the scope of these claims and their equivalents are thereby contemplated.

Claims

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

Wherein:

r ¹ is methoxy or hydrogen;

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 each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, amino acid side chain, aryl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-N R(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR-OC (O) N (R ¹⁸)R¹⁹;

With the proviso that when R ¹ is hydrogen then R ³ is not tert-butyl.

2. The compound of claim 1, having the structure of formula (Ia), or a pharmaceutically acceptable salt thereof:

3. A compound according to claim 1 or claim 2 wherein R ³ is alkyl or heteroalkyl.

4. A compound according to any one of claims 1 to 3 wherein R ³ is alkyl.

5. The compound of any one of claims 1 to 4, wherein R ³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or 3-methyl-1-butyl.

6. A compound according to claim 1 or claim 2 wherein R ³ is ethyl.

7. A compound according to claim 1 or claim 2 wherein R ³ is heterocyclylalkyl.

8. The compound of claim 1 or claim 2, wherein R ³ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

9. The compound of any one of claims 1 to 4, wherein R ³ is alkyl substituted with heteroaryl.

10. The compound of any one of claims 1 to 4 or claim 9, wherein R ³ is

11. The compound of claim 1 or claim 2, having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1、R^A2、R^A3 and R ^A4 are each independently hydrogen OR alkyl which is independently unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR

-OC (O) N (R ¹⁸)R¹⁹ substitution, and

R ^A5 is heteroalkyl, heterocyclylalkyl, heteroaryl or -C(O)OR¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴、-C(O)R¹⁴、-OC(O)R¹⁵ or

-OC (O) OR ¹⁶, wherein each heteroalkyl, heterocyclylalkyl and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹).

12. The compound of claim 11, wherein one of R ^A1、R^A2、R^A3 and R ^A4 is alkyl and each of R ^A1、R^A2、R^A3 and R ^A4 that is not alkyl is hydrogen.

13. The compound of claim 11, wherein both of R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 and R ^A4 that is not alkyl is hydrogen.

14. A compound according to claim 12 or claim 13 wherein each alkyl is independently methyl, ethyl, tert-butyl or isopropyl.

15. The compound of claim 11, having the structure of formula (Ib 1), or a pharmaceutically acceptable salt thereof:

16. The compound of claim 11 or claim 15, wherein R ^A5 is heteroalkyl.

17. The compound of claim 11 or claim 15, wherein R ^A5 is methoxy, ethoxy, cyclopropyloxy, methylamino or dimethylamino.

18. The compound of claim 11 or claim 15, wherein R ^A5 is heterocyclylalkyl.

19. The compound of any one of claims 11, 15 and 18, wherein R ^A5 is

20. The compound of claim 11 or claim 15, wherein R ^A5 is-OC (O) R ¹⁵.

21. The compound of any one of claims 1, 11, 15, and 20, wherein R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl.

22. The compound of any one of claims 1, 11, 15, 20, and 21, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl.

23. The compound of any one of claims 1, 11, 15, 20, and 21, wherein R ¹⁵ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

24. The compound of claim 11 or claim 15, wherein R ^A5 is-N (R ¹³)C(O)OR¹⁴.

25. The compound of claim 11 or claim 15, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴.

26. The compound of any one of claims 1, 11, 15, 24, and 25, wherein R ¹⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl.

27. The compound of any one of claims 1, 11, 15, 24, and 25, wherein R ¹³ is hydrogen.

28. The compound of any one of claims 1, 11, 15, 24, and 25, wherein R ¹⁴ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

29. The compound of claim 1 or claim 2, having the structure of formula (Ic), or a pharmaceutically acceptable salt thereof:

30. The compound of any one of claims 1,2, or 29, wherein R ¹⁸ and R ¹⁹ are each independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, -CH ₂CH₂ OMe, or-CH ₂CH₂SO₂ Me.

31. The compound of any one of claims 1,2, or 29, wherein R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form a heterocyclylalkyl ring.

32. The compound of any one of claims 1,2, or 29, wherein R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form an azetidine ring, a pyrrolidine ring, or a piperidine ring.

33. The compound of claim 1, having the structure of formula (Id), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy; r ⁵ is alkyl or cycloalkyl each independently unsubstituted or substituted with one or more R ^A, or hydrogen; and R ^A6 is hydrogen OR alkyl, which is unsubstituted OR substituted by one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ OR-OC (O) N (R ¹⁸)R¹⁹).

34. The compound of claim 33, wherein R ⁵ is alkyl.

35. The compound of claim 33, wherein R ⁵ is hydrogen, methyl, ethyl, or isopropyl.

36. The compound of any one of claims 33 to 35, wherein R ^A6 is alkyl.

37. The compound of any one of claims 33 to 35, wherein R ^A6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, or benzyl.

38. The compound of claim 1, having the structure of formula (Ie), or a pharmaceutically acceptable salt thereof:

39. The compound of claim 38, wherein R ⁵ is hydrogen.

40. The compound of claim 38, wherein R ⁵ is alkyl.

41. A compound according to claim 38 or claim 40, wherein R ⁵ is methyl, ethyl or isopropyl.

42. The compound of claim 1, having the structure of formula (If), or a pharmaceutically acceptable salt thereof:

43. A compound of claim 42, wherein R ⁹ and R ¹⁰ are each independently alkyl or cycloalkyl.

44. A compound of claim 42, wherein R ⁹ and R ¹⁰ are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, t-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl or 3-methyl-1-butyl.

45. A compound according to claim 42, wherein R ⁹ and R ¹⁰ are each independently CH ₂CHF₂、CH₂CF₃ or CH ₂ cPr.

46. The compound of claim 42, wherein R ⁹ is hydrogen and R ¹⁰ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.

47. The compound of claim 42, wherein R ⁹ is hydrogen and R ¹⁰ is methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, t-butyl, n-pentyl, n-heptyl, n-octyl, n-nonyl or 3-methyl-1-butyl.

48. A compound of claim 42, wherein R ⁹ is hydrogen and R ¹⁰ is-CH ₂CHF₂、-CH₂CF₃ or-CH ₂ cPr.

49. The compound of claim 42, wherein R ⁹ is hydrogen and R ¹⁰ is

50. The compound of claim 1 or claim 42, having the structure of formula (If 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

51. The compound of claim 50, wherein X ¹ is-CH ₂ -and X ² is-N (Y ¹) -.

52. A compound according to claim 50 or claim 51, wherein Y ¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl or-CH ₂CH₂ OMe.

53. The compound of claim 50, wherein X ¹ and X ² are each-O-or-NH-.

54. The compound of any one of claims 50 to 53, wherein R ¹⁰ is hydrogen.

55. The compound of claim 1 or claim 42, having the structure of formula (Ig), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

-OC (O) OR ¹⁶ wherein the heteroalkyl, heterocyclylalkyl, heteroaryl are each unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴,

-OC (O) R ¹⁵、-OC(O)OR¹⁶ or-OC (O) N (R ¹⁸)R¹⁹).

56. The compound of claim 55, wherein one R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 and R ^A4, which is not alkyl, is hydrogen.

57. The compound of claim 55, wherein both of R ^A1、R^A2、R^A3 and R ^A4 are alkyl and each of R ^A1、R^A2、R^A3 and R ^A4, which is not alkyl, is hydrogen.

58. A compound of claim 56 or claim 57, wherein each alkyl is independently methyl, ethyl, t-butyl, or isopropyl.

59. The compound of any one of claims 55 to 58, wherein R ^A5 is heteroalkyl.

60. The compound of any one of claims 55 to 58, wherein R ^A5 is methoxy, ethoxy, cyclopropyloxy, methylamino or dimethylamino.

61. The compound of any one of claims 55 to 58, wherein R ^A5 is heterocyclylalkyl.

62. The compound of any one of claims 55 to 58, wherein R ^A5 is

63. The compound of any one of claims 55 to 62, wherein R ¹⁰ is hydrogen, methyl, ethyl, n-propyl or isopropyl.

64. The compound of any one of claims 55 to 62, wherein R ¹⁰ is-CH ₂CH₂ OMe or-CH ₂CH₂SO₂ Me.

65. The compound of any one of claims 55 to 58, wherein R ^A5 is-OC (O) R ¹⁵.

66. The compound of any one of claims 55 to 58 or claim 65, wherein R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl.

67. The compound of any one of claims 55 to 58 or claim 65, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or 3-methyl-1-butyl.

68. The compound of any one of claims 55 to 58 or claim 65, wherein R ¹⁵ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

69. The compound of any one of claims 55 to 58, wherein R ^A5 is N (R ¹³)C(O)OR¹⁴.

70. The compound of any one of claims 55 to 58, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴.

71. The compound of claim 69 or claim 70 wherein R ¹³ is hydrogen or alkyl.

72. The compound of claim 69 or claim 70 wherein R ¹⁴ is alkyl.

73. The compound of claim 69 or claim 70 wherein R ¹⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or 3-methyl-1-butyl.

74. The compound of claim 69 or claim 70 wherein R ¹⁴ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl or 6-pyrimidinyl.

75. The compound of claim 1 or claim 42 having the structure of formula (Ih), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy;

R ¹⁸ and R ¹⁹ are each independently hydrogen, alkyl, cycloalkyl or heteroalkyl, where

Each alkyl, cycloalkyl or heterocyclylalkyl is independently 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 that is unsubstituted or substituted with one or more R ^B.

76. The compound of claim 75 wherein R ¹⁰ is hydrogen, methyl, ethyl, n-propyl or isopropyl.

77. The compound of claim 75, wherein R ¹⁰ is CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

78. The compound of any one of claims 75 to 77, wherein R ¹⁸ and R ¹⁹ are each independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

79. The compound of any one of claims 75 to 77, wherein R ¹⁸ is hydrogen and R ¹⁹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, tert-butyl, CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

80. The compound of any one of claims 75 to 77, wherein R ¹⁸ and R ¹⁹ together with the atoms to which they are attached form a heterocyclylalkyl ring.

81. The compound of any one of claims 75 to 77, wherein R ¹⁸ and R ¹⁹, together with the atoms to which they are attached, form an azetidine ring, a morpholine ring, a pyrrolidine ring, or a piperidine ring, each of which is substituted or unsubstituted.

82. The compound of claim 1 or claim 42, having the structure of formula (Ii), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy; and

R ^A6 is independently hydrogen, alkyl, heteroalkyl, OR cycloalkyl, each of which is unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR

-OC (O) N (R ¹⁸)R¹⁹ substitution).

83. The compound of claim 82, wherein each of R ⁵、R¹⁰ and R ^A6 is independently hydrogen, alkyl, or cycloalkyl.

84. The compound of claim 82, wherein each of R ⁵、R¹⁰ and R ^A6 is independently hydrogen, methyl, ethyl, n-propyl, or isopropyl.

85. The compound of claim 82, wherein each of R ⁵、R¹⁰ and R ^A6 is hydrogen.

86. The compound of claim 1 or claim 42, having the structure of formula (Ij), or a pharmaceutically acceptable salt thereof:

Wherein R ¹ is hydrogen or methoxy, and R ⁵ and R ¹⁰ are each hydrogen, alkyl or heteroalkyl, wherein each alkyl and heteroalkyl is independently unsubstituted or substituted with one or more R ^A.

87. The compound of claim 86, wherein R ⁵ is methyl, ethyl, or isopropyl.

88. The compound of claim 86, wherein R ⁵ is hydrogen.

89. The compound of any one of claims 86 to 88, wherein R ¹⁰ is CH ₂CH₂ OMe or CH ₂CH₂SO₂ Me.

90. The compound of any one of claims 86 to 88, wherein R ¹⁰ is hydrogen.

91. The compound of claim 1, having the structure of formula (Ik), or a pharmaceutically acceptable salt thereof:

92. The compound of claim 1 or claim 91, wherein R ⁴ is alkyl.

93. The compound of claim 1 or claim 91, wherein R ⁴ is CH ₂CF₃.

94. The compound of claim 1 or claim 91, wherein R ⁴ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, 3-methyl-1-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, or n-nonyl.

95. The compound of claim 1 or claim 91, wherein R ⁴ is cycloalkyl.

96. The compound of claim 1 or claim 91, wherein R ⁴ is cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, or cyclooctyl.

97. The compound of claim 1 or claim 91, wherein R ⁴ is aryl.

98. The compound of claim 1 or claim 91, wherein R ⁴ is phenyl.

99. The compound of claim 1 or claim 91, wherein R ⁴ is heteroaryl.

100. The compound of claim 1 or claim 91, wherein R ⁴ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 3-pyrimidinyl, or 6-pyrimidinyl.

101. The compound of claim 1 or claim 91, wherein R ⁴ is heterocyclylalkyl.

102. The compound of claim 1 or claim 91, wherein R ⁴ is

103. The compound of claim 1 or claim 91, wherein R ⁴ is

104. The compound of claim 103, wherein R ¹⁴ is alkyl, cycloalkyl, or aryl.

105. The compound of claim 103, wherein R ¹⁴ is methyl, ethyl, n-propyl, isopropyl, or CH ₂CH₂ OMe.

106. The compound of claim 103, wherein R ¹⁴ is phenyl.

107. The compound of claim 1 or claim 91, wherein R ⁴ isWherein R ^A7 is hydrogen or alkyl.

108. The compound of claim 107, wherein R ^A7 is hydrogen.

109. The compound of claim 107, wherein R ^A7 is alkyl.

110. The compound of claim 107, wherein R ^A7 is methyl, ethyl, n-propyl, isopropyl, or n-butyl.

111. The compound of claim 107, wherein R ^A7 is benzyl.

112. The compound of claim 1 or claim 91 having the structure of formula (Ik 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

113. The compound of claim 112, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is heteroalkyl.

114. The compound of claim 112, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is alkylsulfonyl.

115. The compound of claim 112, wherein R ^A1、R^A2、R^A3 and R ^A4 are each hydrogen and R ^A5 is methylsulfonyl.

116. The compound of claim 112, wherein R ^A5 is-OC (O) R ¹⁵.

117. The compound of claim 116, wherein R ¹⁵ is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocyclylalkyl.

118. The compound of claim 116, wherein R ¹⁵ is alkyl.

119. The compound of claim 116, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl or 3-methyl-1-butyl.

120. The compound of claim 1 or claim 91 having the structure of formula (Ik 2), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

P is 0,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

121. The compound of claim 120, wherein R ¹³ is alkyl.

122. The compound of claim 120, wherein R ¹³ is unsubstituted alkyl.

123. The compound of claim 120, wherein R ¹³ is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, or 3-methyl-1-butyl.

124. The compound of claim 120, wherein R ¹³ is aryl.

125. The compound of claim 120, wherein R ¹³ is phenyl.

126. The compound of claim 120, wherein R ¹³ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

127. The compound of claim 1 or claim 91 having the structure of formula (Ik 3), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A5 is-N (R ¹⁸)R¹⁹ or-N (R ¹³)C(O)R¹⁴).

128. The compound of claim 127, wherein R ^A5 is-N (R ¹³)C(O)R¹⁴.

129. The compound of claim 127, wherein R ^A5 is-N (R ¹⁸)R¹⁹.

130. The compound of claim 127 or claim 129, wherein R ¹⁹ is alkyl, cycloalkyl, or aryl.

131. The compound of claim 127 or claim 129, wherein R ¹⁸ is hydrogen and R ¹⁹ is alkyl, cycloalkyl, or aryl.

132. The compound of claim 127 or claim 129, wherein R ¹⁸ is hydrogen and R ¹⁹ is methyl, ethyl, isopropyl, tert-butyl, or phenyl.

133. The compound of claim 1, having the structure of formula (Il), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

134. The compound of claim 1 or claim 133, wherein R ⁶ is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl or cyclopropyl.

135. The compound of any one of claims 1, 133 and 134, wherein R ⁵ is hydrogen and R ⁶ is methyl, ethyl, isopropyl, tert-butyl, 2-dimethylaminoethyl or cyclopropyl.

136. The compound of claim 1, having the structure of formula (Im), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

137. The compound of claim 1 or claim 136, wherein R ⁵ is hydrogen.

138. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each alkyl.

139. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ is hydrogen and R ¹² is cycloalkyl, aryl, heteroaryl, or alkyl.

140. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each

141. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl.

142. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each tert-butyl.

143. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

144. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each phenyl.

145. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

146. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each 4-nitrophenyl.

147. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ and R ¹² are each benzyl.

148. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ is hydrogen and R ¹² is cycloalkyl, aryl, heteroaryl, or alkyl.

149. The compound of any one of claims 1, 136 and 137, wherein R ¹¹ is hydrogen and R ¹² is alkyl.

150. The compound of claim 1 or claim 136 having the structure of formula (Im 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

Wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently unsubstituted OR substituted with one OR more alkyl, aryl, halogen, -OR ¹³,

-NR (R ¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶ or

-OC (O) N (R ¹⁸)R¹⁹ substitution).

151. The compound of claim 150, wherein R ^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

152. The compound of claim 150 or claim 151, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵.

153. The compound of claim 152, wherein each R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl.

154. The compound of claim 150 OR claim 151, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶.

155. The compound of claim 154, wherein each R ¹⁶ is alkyl, cycloalkyl, aryl, or heteroaryl.

156. The compound of any one of claims 1, 136 and 150 having the structure of formula (Im 1 a), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

157. The compound of claim 156, wherein R ^B1 and R ^B2 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pent-3-yl, or benzyl.

158. The compound of claim 156 or claim 157, wherein R ^A1、R^A3 and R ⁵ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

159. The compound of claim 156 or claim 157, wherein R ^A1、R^A3 and R ⁵ are each hydrogen.

160. The compound of claim 1, having the structure of formula (In), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl;

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl,

161. The compound of claim 1 or claim 160, wherein R ⁵ is hydrogen, methyl, ethyl, or tert-butyl.

162. The compound of any one of claims 1, 160, and 161, wherein R ⁸ is alkyl or cycloalkyl.

163. The compound of any one of claims 1 and 160 to 162, wherein R ⁹ is hydrogen.

164. The compound of any one of claims 1 and 160 to 163, wherein R ¹⁰ is alkyl.

165. The compound of claim 1 or claim 160 having the structure of formula (In 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

166. The compound of claim 165, wherein R ⁵ and R ^A1 are each hydrogen or alkyl.

167. The compound of claim 165, wherein R ⁵ and R ^A1 are each hydrogen, methyl, ethyl, or t-butyl.

168. The compound of any one of claims 165 to 167, wherein R ⁸ is alkyl or cycloalkyl.

169. The compound of any one of claims 165 to 168, wherein R ¹³ is alkyl.

170. The compound of claim 1, having the structure of formula (Io), or a pharmaceutically acceptable salt thereof:

Wherein:

R ¹ is methoxy or hydrogen; and

171. The compound of claim 1 or claim 170, wherein R ¹¹ is hydrogen and R ¹² is cycloalkyl, aryl, heteroaryl, or alkyl.

172. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each alkyl.

173. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each

174. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, or 3-methyl-1-butyl.

175. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each tert-butyl.

176. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

177. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each phenyl.

178. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl.

179. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each 4-nitrophenyl.

180. The compound of claim 1 or claim 170, wherein R ¹¹ and R ¹² are each benzyl.

181. The compound of claim 1 or claim 170, wherein R ¹¹ is hydrogen and R ¹² is cycloalkyl, aryl, heteroaryl, or alkyl.

182. The compound of claim 1 or claim 170, wherein R ¹¹ is hydrogen and R ¹² is alkyl.

183. The compound of claim 1 or claim 170, having the structure of formula (Io 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ^A1 and R ^A3 are each independently hydrogen, alkyl or cycloalkyl; and

184. The compound of claim 183, wherein R ^A1、R^A3 and R ⁴ are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

185. The compound of claim 183 or claim 184, wherein R ^A2 and R ^A4 are each-OC (O) R ¹⁵.

186. The compound of any one of claims 183 to 184, wherein each R ¹⁵ is alkyl, cycloalkyl, aryl, or heteroaryl.

187. The compound of claim 183 OR claim 184, wherein R ^A2 and R ^A4 are each-OC (O) OR ¹⁶.

188. The compound of any one of claims 183, 184 and 187, wherein each R ¹⁶ is alkyl, cycloalkyl, aryl or heteroaryl.

189. The compound of claim 1 or claim 170, having the structure of formula (Io 2), or a pharmaceutically acceptable salt thereof:

190. The compound of claim 189, wherein R ^A1 is aryl.

191. The compound of claim 189, wherein R ^A1 is aryl substituted with halo.

192. The compound of claim 189, wherein R ^A1 isWherein Z ¹、Z² and Z ³ are each independently hydrogen or halogen.

193. The compound of claim 192, wherein Z ¹、Z² and Z ³ are each independently hydrogen, fluoro, chloro, bromo, or iodo.

194. The compound of claim 189, wherein R ^A1 is

195. The compound of any one of claims 1, 170, and 183, having the structure of formula (Io 1 a), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

196. The compound of claim 195, wherein R ^B1 and R ^B2 are each independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pent-3-yl, or benzyl.

197. The compound of claim 195 or claim 196, wherein R ^A1 and R ^A3 are each independently hydrogen, methyl, ethyl, isopropyl, or tert-butyl.

198. The compound of claim 195 or claim 196, wherein R ^A1 and R ^A3 are each independently hydrogen.

199. The compound of claim 1, having the structure of formula (Ip), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ⁸ is hydrogen, alkyl, cycloalkyl, aryl, heterocyclylalkyl, or heteroaryl; and is combined with

And is also provided with

R ⁹ and R ¹⁰ are each independently hydrogen or alkyl,

200. The compound of claim 1 or claim 199, wherein R ⁸ is alkyl or cycloalkyl.

201. The compound of claim 1 or claim 199, wherein R ⁸ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

202. The compound of any one of claims 1, 200, and 201, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁹ is hydrogen.

203. The compound of any one of claims 1, 200, and 201, wherein R ⁹ is hydrogen and R ¹⁰ is alkyl.

204. The compound of claim 1 or claim 199, having the structure of formula (Ip 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

205. The compound of claim 204, wherein R ^A1 is hydrogen, methyl, ethyl, or t-butyl.

206. The compound of claim 204, wherein R ^A1 is hydrogen.

207. The compound of any one of claims 204 to 206 wherein R ⁸ is hydrogen.

208. The compound of any one of claims 204 to 206 wherein R ⁸ is alkyl or cycloalkyl.

209. The compound of any one of claims 204 to 206 wherein R ⁸ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

210. The compound of claim 1, having the structure of formula (Iq):

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl; and

R ⁶ is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl or heteroaryl,

211. The compound of claim 1 or claim 210, wherein R ⁵ is hydrogen.

212. The compound of claim 1 or claim 210, wherein R ⁵ is alkyl.

213. The compound of claim 1 or claim 210, wherein R ⁵ is methyl, isopropyl, tert-butyl, or-CH (Et) ₂.

214. The compound of any one of claims 1 and 210 to 213, wherein R ⁶ is alkyl.

215. The compound of any one of claims 1 and 210 to 213, wherein R ⁶ is methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl.

216. The compound of any one of claims 1 and 210 to 213, wherein R ⁶ is heteroalkyl.

217. The compound of any one of claims 1 and 210 to 213, wherein R ⁶ is CH (R ^A1)NH₂, wherein R ^A1 is hydrogen, alkyl, heteroalkyl, or an amino acid side chain.

218. The compound of claim 217, wherein R ^A1 is an amino acid side chain.

219. The compound of claim 217, wherein R ^A1 is methyl, ethyl, n-propyl, isopropyl, t-butyl, CH (Me) Et, CH ₂CH(Me)₂, or CH ₂CH₂ SMe.

220. The compound of claim 217, wherein R ^A1 is benzyl.

221. The compound of claim 1 or claim 210, having the structure of formula (Iq 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

Q ¹ isWherein the method comprises the steps of

222. The compound of claim 221, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independentlyWherein R ^Z1 is hydrogen or alkyl.

223. The compound of claim 222, wherein R ^Z1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or CH (Et) ₂.

224. The compound of claim 222, wherein R ^Z1 is benzyl.

225. The compound of claim 222, wherein R ^Z1 is hydrogen.

226. The compound of claim 1, having the structure of formula (Ir), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

r ⁵ is hydrogen, alkyl or cycloalkyl; and

R ⁶ is alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, aryl or heteroaryl,

227. The compound of claim 1 or claim 226, having the structure of formula (Ir 1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

Q ¹ isWherein the method comprises the steps of

228. The compound of claim 227, wherein Y ¹、Y² or Y ³ are each-N (R ^Y1) -or-NC (O) R ^Y2, wherein R ^Y1 and R ^Y2 are each independentlyWherein R ^Z1 is hydrogen or alkyl.

229. The compound of claim 228, wherein R ^Z1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, or CH (Et) ₂.

230. The compound of claim 228, wherein R ^Y1 and R ^Y2 are each independently

231. The compound of claim 1 or claim 91 having the structure of formula (Is), or a pharmaceutically acceptable salt thereof:

232. The compound of claim 231, wherein R ¹⁵ is alkyl.

233. The compound of claim 231, wherein R ¹⁵ is methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl.

234. The compound of claim 231, wherein R ¹⁵ is-CH [ CH (Me) ₂]NH₂.

235. The compound of claim 231, wherein R ¹⁵ is- (CH ₂)_qCO₂ H, wherein q is 1,2, 3, 4, 5, or 6.

236. The compound of claim 1, having the structure of formula (It), or a pharmaceutically acceptable salt thereof:

237. The compound of claim 236, wherein R ¹³ isWherein R ^B1 is hydrogen or alkyl, and Z ¹ is-O-, -S (O) -, S (O) ₂ -or-N (R ^C1) -, wherein R ^C1 is hydrogen, alkyl, acetyl or benzoyl.

238. The compound of claim 236, wherein R ¹³ isWherein R ^C1 is alkyl.

239. The compound of claim 238, R ^C1 is methyl, acetyl, or benzoyl.

240. The compound of claim 236, wherein R ¹³ is

241. The compound of claim 236, wherein R ¹³ is Wherein Y ¹、Y² or Y ³ are each independently-O-, -S-, -S (O) -, -S (O) ₂ -, or-N (R ^B2) -, wherein each R ^B2 is independently hydrogen, alkyl, acetyl or benzoyl.

242. The compound of claim 236, wherein R ¹³ is Wherein R ^B2 is unsubstituted alkyl.

243. The compound of claim 242, wherein each R ^B2 is independently methyl, acetyl, or benzoyl.

244. The compound of claim 236, wherein R ¹³ is

245. The compound of claim 236, wherein R ¹³ is-CH ₂CH₂R^B3, wherein R ^B3 is heteroaryl or heterocyclylalkyl.

246. The compound of claim 236, wherein R ^B3 is heterocyclylalkyl.

247. The compound of claim 236, wherein R ^B3 is

248. The compound of claim 1, having the structure of formula (Iu), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy;

249. The compound of claim 248, wherein R ^A1 is alkyl.

250. The compound of claim 248, wherein R ^A1 is hydrogen.

251. The compound of any one of claims 1 and 248 to 250, wherein R ²⁰ and R ²¹ are each alkyl.

252. The compound of any one of claims 1 and 248 to 250, wherein R ²⁰ is hydrogen and R ²¹ is alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen, wherein alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl.

253. The compound of any one of claims 1 and 248 to 250, wherein R ²⁰ and R ²¹ are each independently alkyl or cycloalkyl.

254. The compound of any one of claims 1 and 248 to 250, wherein R ²⁰ and R ²¹ are each independently methyl, ethyl, n-propyl, isopropyl, t-butyl, 3-methyl-1-butyl, n-pentyl or n-hexyl.

255. The compound of claim 1, having the structure of formula (Ib-1), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is methoxy or hydrogen;

R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 are each independently hydrogen or alkyl,

The alkyl groups are independently unsubstituted OR substituted with one OR more alkyl groups, aryl groups, halogen, -OR ¹³、-NR(R¹⁸)R¹⁹、-C(O)R¹⁴、-OC(O)R¹⁵、-OC(O)OR¹⁶, OR

-OC (O) N (R ¹⁸)R¹⁹ substitution, and

256. The compound of claim 255, wherein one of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 is alkyl and each of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 that is not alkyl is hydrogen.

257. The compound of claim 255, wherein both of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 are alkyl and each of R ^A1、R^A2、R^A3、R^A4、R^A6 and R ^A7 that is not alkyl is hydrogen.

258. The compound of claim 255, wherein R ^A3 and R ^A4 are each independently alkyl, and R ^A1、R^A2、R^A6 and R ^A7 are each hydrogen.

259. The compound of any one of claims 255 to 258, wherein R ^A5 is heterocyclylalkyl.

260. The compound of any one of claims 255-258, wherein R ^A5 is-OC (O) R ¹⁵.

261. The compound of claim 260, wherein R ¹⁵ is alkyl.

262. The compound of claim 260, wherein R ¹⁵ is methyl, ethyl, isopropyl, n-propyl, t-butyl, isobutyl, or n-butyl.

263. The compound of claim 260, wherein R ¹⁵ is isobutyl.

264. The compound of claim 1, having the structure of formula (Iv), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy;

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

Or R ¹¹ and R ¹² together with the atoms to which they are attached form a heterocyclylalkyl ring that is unsubstituted or substituted with one or more R ^A.

265. The compound of claim 263, wherein R ⁹ and R ¹⁰ are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen.

266. The compound of claim 263 or claim 265, wherein R ¹¹ and R ¹² are each independently alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, or hydrogen.

267. The compound of claim 263, wherein R ⁹、R¹⁰、R¹¹ and R ¹² are each independently alkyl, cycloalkyl, or hydrogen.

268. The compound of claim 263, wherein R ⁹、R¹⁰、R¹¹ and R ¹² are each independently hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, tert-butyl, or n-butyl.

269. The compound of claim 263, wherein R ⁹、R¹⁰、R¹¹ and R ¹² are each methyl.

270. The compound of claim 1, having the structure of formula (Iw), or a pharmaceutically acceptable salt thereof:

Wherein:

r ¹ is hydrogen or methoxy;

R ^A3 is-OR ¹³、-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 (b)

-OP (O) OR ²⁰(OR²¹), and

P is 1, 2, 3,4, 5, 6, 7, 8, 9 or 10.

271. The compound of claim 270, wherein each R ^A1 and R ^A2 is independently hydrogen, alkyl, or cycloalkyl.

272. The compound of claim 270, wherein each R ^A1 and R ^A2 is independently hydrogen.

273. The compound of any one of claims 270 to 272, wherein R ^A3 is-C (O) OR ¹³、-N(R¹³)C(O)OR¹⁴、-N(R¹³)C(O)R¹⁴ OR-C (O) R ¹⁴.

274. The compound of any one of claims 270 to 272, wherein R ^A3 is-C (O) OR ¹³.

275. The compound of claim 273 or claim 274, wherein R ¹³ is hydrogen or alkyl.

276. The compound of claim 273 or claim 274, wherein R ¹³ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

277. The compound of claim 273 or claim 274, wherein R ¹³ is hydrogen or tert-butyl.

278. The compound of any one of claims 1 to 277, wherein R ¹ is hydrogen.

279. The compound of any one of claims 1 to 277, wherein R ¹ is methoxy.

280. A pharmaceutical composition comprising a compound of any one of claims 1-279, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

281. A method of treating or preventing a disease, disorder, or condition that would benefit from increased levels of a tryptamine hallucinogen such as DMT or 5-OMe-DMT, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 280, or a pharmaceutically acceptable salt thereof.

282. The method of claim 281, wherein the disorder 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 substance abuse.